首页 期刊 论文 学科刊群 资讯 加盟 关于
EN
image
Article(id=1222469877034635459, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469875008790921, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2019-0577, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1563552000000, receivedDateStr=2019-07-20, revisedDate=1565625600000, revisedDateStr=2019-08-13, acceptedDate=null, acceptedDateStr=null, onlineDate=1769389131076, onlineDateStr=2026-01-26, pubDate=1573488000000, pubDateStr=2019-11-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1769389131076, onlineIssueDateStr=2026-01-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1769389131076, creator=13701087609, updateTime=1769389131076, updator=13701087609, issue=Issue{id=1222469875008790921, tenantId=1146029695717560320, journalId=1189982191388893191, year='2019', volume='54', issue='11', pageStart='1881', pageEnd='2140', issueExtLink='null', onlineDate='null', pubDate='1573488000000', pubDateStr='2019-11-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1769389130593, creator='13701087609', updateTime=1769389577080, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1222471747778109959, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469875008790921, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1222471747778109960, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469875008790921, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1940, endPage=1948, ext={EN=ArticleExt(id=1222469877588283594, articleId=1222469877034635459, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Application of benzoxaboroles compounds in medicinal chemistry, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Benzoxaborole is a series of compounds with five member ring and boron atom. Since the approval of crisaborole and tavaborole by FDA, benzoxaborole gained lots of research interests and become widely used in current drug discovery. Specially, benzoxaborole derivatives were found to exhibit anti-bacterial, anti-fungal, anti-protozoal, anti-tumor and anti-inflammatory activities. Here, we will review the properties of benzoxaborole, structure activity relationships as well as the recent progress in the biological activity of benzoxaborole derivatives.

, authors=null, authorsList=Chuan WANG, Xu-ben HOU, Hao FANG, authorCompany=null, correspAuthors=Hao FANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2019 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1222469882868912722, articleId=1222469877034635459, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=苯并硼唑类化合物在药物化学中的应用, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

苯并硼唑（benzoxaborole）是一类含有硼原子的五元杂环化合物。近年来，苯并硼唑类化合物在药物研发中的应用越来越广，以其为骨架的药物他伐硼罗（tavaborole）和克立硼罗（crisaborole）相继被FDA批准上市。特别是，研究人员在对苯并硼唑类化合物设计探索的过程中，发现了新型的抗菌、抗寄生虫、抗肿瘤和抗炎药物。本文主要介绍苯并硼唑类化合物的性质、构效关系以及相关生物活性研究。

, authors=null, authorsList=王川, 侯旭奔, 方浩, authorCompany=null, correspAuthors=方浩, authorNote=null, correspAuthorsNote=
*方浩, Tel: 86-531-88382019, E-mail:
, copyrightStatement=版权所有©《药学学报》编辑部2019, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=fQHHKyfjzcvJC84GFB9n7A==, magXml=6V5lBBG13wXK2zKH2z0L8A==, pdfUrl=null, pdf=qQrndEHCjlMalOyaffoEqQ==, pdfFileSize=658342, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=Rclh6HEcL7w+YDPs2Z22GA==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=P1eQR1iR5bW5VlsHs8TrZg==, mapNumber=null, fund=null)}, authors=[Author(id=1222469883363840649, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469883464503958, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469883363840649, language=EN, stringName=Chuan WANG, firstName=Chuan, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469883565167266, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469883363840649, language=CN, stringName=王川, firstName=川, middleName=null, lastName=王, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=山东大学药学院药物化学研究所, 山东 济南 250012, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469883191874164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, xref=null, ext=[AuthorCompanyExt(id=1222469883196068469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1222469883204457078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院药物化学研究所, 山东 济南 250012)])]), Author(id=1222469885540684460, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469885683290811, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885540684460, language=EN, stringName=Xu-ben HOU, firstName=Xu-ben, middleName=null, lastName=HOU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469885825897160, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885540684460, language=CN, stringName=侯旭奔, firstName=旭奔, middleName=null, lastName=侯, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=山东大学药学院药物化学研究所, 山东 济南 250012, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469883191874164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, xref=null, ext=[AuthorCompanyExt(id=1222469883196068469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1222469883204457078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院药物化学研究所, 山东 济南 250012)])]), Author(id=1222469885968503510, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=haofangcn@sdu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1222469886115304163, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885968503510, language=EN, stringName=Hao FANG, firstName=Hao, middleName=null, lastName=FANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469886207578860, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885968503510, language=CN, stringName=方浩, firstName=浩, middleName=null, lastName=方, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=山东大学药学院药物化学研究所, 山东 济南 250012, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469883191874164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, xref=null, ext=[AuthorCompanyExt(id=1222469883196068469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1222469883204457078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院药物化学研究所, 山东 济南 250012)])])], keywords=[Keyword(id=1222469886350185209, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, orderNo=1, keyword=benzoxaboroles), Keyword(id=1222469886446654210, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, orderNo=2, keyword=tavaborole), Keyword(id=1222469886610232078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, orderNo=3, keyword=crisaborole), Keyword(id=1222469886731866906, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, orderNo=4, keyword=structure activity relationships), Keyword(id=1222469886836724515, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, orderNo=5, keyword=biological activity), Keyword(id=1222469887004496691, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, orderNo=1, keyword=苯并硼唑), Keyword(id=1222469887121937216, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, orderNo=2, keyword=他伐硼罗), Keyword(id=1222469887205823307, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, orderNo=3, keyword=克立硼罗), Keyword(id=1222469887298098002, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, orderNo=4, keyword=构效关系), Keyword(id=1222469887415538526, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, orderNo=5, keyword=生物活性)], refs=[Reference(id=1222469892075409597, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=null, pmid=null, pmcid=null, year=1957, volume=10, issue=null, pageStart=507, pageEnd=511, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=Torssell K, journalName=Ark Kemi, refType=null, unstructuredReference= Torssell K . Bromination of tolylboronic acids according to Wohl-Ziegler[J]. Ark Kemi, 1957, 10: 507-511., articleTitle=Bromination of tolylboronic acids according to Wohl-Ziegler, refAbstract=null), Reference(id=1222469892142518468, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.jorganchem.2009.07.022, pmid=null, pmcid=null, year=2009, volume=694, issue=null, pageStart=3533, pageEnd=3541, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=Adamczyk-Woźniak A, Cyrański MK, Żubrowska A, journalName=J Organomet Chem, refType=null, unstructuredReference= Adamczyk-Woźniak A , Cyrański MK , Żubrowska A et al . Benzoxaboroles-old compounds with new applications[J]. J Organomet Chem, 2009, 694: 3533-3541., articleTitle=Benzoxaboroles-old compounds with new applications, refAbstract=null), Reference(id=1222469892255764683, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1021/jm0603724, pmid=null, pmcid=null, year=2006, volume=49, issue=null, pageStart=4447, pageEnd=4450, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=Baker SJ, Zhang YK, Akama T, journalName=J Med Chem, refType=null, unstructuredReference= Baker SJ , Zhang YK , Akama T et al . Discovery of a new boron-containing antifungal agent, 5-fluoro-1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole (AN2690), for the potential treatment of onychomycosis[J]. J Med Chem, 2006, 49: 4447-4450., articleTitle=Discovery of a new boron-containing antifungal agent, 5-fluoro-1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole (AN2690), for the potential treatment of onychomycosis, refAbstract=null), Reference(id=1222469892360622291, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=null, pmid=null, pmcid=null, year=2017, volume=52, issue=null, pageStart=1012, pageEnd=1018, url=http://www.yxxb.com.cn:8081/aps/CN/abstract/abstract16731.shtml, language=null, rfNumber=[4], rfOrder=3, authorNames=Guo ZR, journalName=Acta Pharm Sin (药学学报), refType=null, unstructuredReference= Guo ZR . R & D of tavaborole and crisaborole as external medication[J]. Acta Pharm Sin (药学学报), 2017, 52: 1012-1018., articleTitle=R & D of tavaborole and crisaborole as external medication, refAbstract=null), Reference(id=1222469892465479899, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1080/13543776.2018.1473379, pmid=null, pmcid=null, year=2018, volume=28, issue=null, pageStart=493, pageEnd=504, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=Nocentini A, Supuran CT, Winum JY, journalName=Expert Opin Ther Pat, refType=null, unstructuredReference= Nocentini A , Supuran CT , Winum JY . Benzoxaborole compounds for therapeutic uses: a patent review (2010-2018)[J]. Expert Opin Ther Pat, 2018, 28: 493-504., articleTitle=Benzoxaborole compounds for therapeutic uses: a patent review (2010-2018), refAbstract=null), Reference(id=1222469892549365984, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.bmcl.2009.03.007, pmid=null, pmcid=null, year=2009, volume=19, issue=null, pageStart=2129, pageEnd=2132, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=Akama T, Baker SJ, Zhang YK, journalName=Bioorg Med Chem Lett, refType=null, unstructuredReference= Akama T , Baker SJ , Zhang YK et al . Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis[J]. Bioorg Med Chem Lett, 2009, 19: 2129-2132., articleTitle=Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis, refAbstract=null), Reference(id=1222469894558437604, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1021/ml200215j, pmid=null, pmcid=null, year=2012, volume=3, issue=null, pageStart=48, pageEnd=52, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=Tomsho JW, Arnab P, Hall DG, journalName=ACS Med Chem Lett, refType=null, unstructuredReference= Tomsho JW , Arnab P , Hall DG et al . Ring structure and aromatic substituent effects on the pKa of the benzoxaborole pharmacophore[J]. ACS Med Chem Lett, 2012, 3: 48-52., articleTitle=Ring structure and aromatic substituent effects on the pKa of the benzoxaborole pharmacophore, refAbstract=null), Reference(id=1222469894659100907, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1021/cr500642d, pmid=null, pmcid=null, year=2015, volume=115, issue=null, pageStart=5224, pageEnd=5247, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=Adamczyk-Wozniak A, Borys KM, Sporzynski A, journalName=Chem Rev, refType=null, unstructuredReference= Adamczyk-Wozniak A , Borys KM , Sporzynski A . Recent developments in the chemistry and biological applications of benzoxaboroles[J]. Chem Rev, 2015, 115: 5224-5247., articleTitle=Recent developments in the chemistry and biological applications of benzoxaboroles, refAbstract=null), Reference(id=1222469894726209778, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1039/c0cs00131g, pmid=null, pmcid=null, year=2011, volume=40, issue=null, pageStart=4279, pageEnd=4285, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=Baker SJ, Tomsho JW, Benkovic SJ, journalName=Chem Soc Rev, refType=null, unstructuredReference= Baker SJ , Tomsho JW , Benkovic SJ . Boron-containing inhibitors of synthetases[J]. Chem Soc Rev, 2011, 40: 4279-4285., articleTitle=Boron-containing inhibitors of synthetases, refAbstract=null), Reference(id=1222469894826873080, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1021/ja01537a021, pmid=null, pmcid=null, year=1958, volume=80, issue=null, pageStart=835, pageEnd=838, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=Snyder H, Reedy AJ, Lennarz WJ, journalName=J Am Chem Soc, refType=null, unstructuredReference= Snyder H , Reedy AJ , Lennarz WJ . Synthesis of aromatic boronic acids. aldehydo boronic acids and a boronic acid analog of tyrosine1[J]. J Am Chem Soc, 1958, 80: 835-838., articleTitle=Synthesis of aromatic boronic acids. aldehydo boronic acids and a boronic acid analog of tyrosine1, refAbstract=null), Reference(id=1222469894919147774, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1126/science.1142189, pmid=null, pmcid=null, year=2007, volume=316, issue=null, pageStart=1759, pageEnd=1761, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=Rock FL, Mao W, Yaremchuk A, journalName=Science, refType=null, unstructuredReference= Rock FL , Mao W , Yaremchuk A et al . An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site[J]. Science, 2007, 316: 1759-1761., articleTitle=An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site, refAbstract=null), Reference(id=1222469895024005380, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.jaad.2015.04.010, pmid=null, pmcid=null, year=2015, volume=73, issue=null, pageStart=62, pageEnd=69, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=Elewski BE, Aly R, Baldwin SL, journalName=J Am Acad Dermatol, refType=null, unstructuredReference= Elewski BE , Aly R , Baldwin SL et al . Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-Ⅲ studies[J]. J Am Acad Dermatol, 2015, 73: 62-69., articleTitle=Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-Ⅲ studies, refAbstract=null), Reference(id=1222469895120474380, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1517/14656566.2012.681779, pmid=null, pmcid=null, year=2012, volume=13, issue=null, pageStart=1131, pageEnd=1142, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=Gupta AK, Simpson FC, journalName=Expert Opin Pharmacother, refType=null, unstructuredReference= Gupta AK , Simpson FC . New therapeutic options for onychomycosis[J]. Expert Opin Pharmacother, 2012, 13: 1131-1142., articleTitle=New therapeutic options for onychomycosis, refAbstract=null), Reference(id=1222469895229526291, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1128/AAC.03774-14, pmid=null, pmcid=null, year=2015, volume=59, issue=null, pageStart=289, pageEnd=298, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=O'dwyer K, Spivak AT, Ingraham K, journalName=Antimicrob Agents Chemother, refType=null, unstructuredReference= O'dwyer K , Spivak AT , Ingraham K et al . Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections[J]. Antimicrob Agents Chemother, 2015, 59: 289-298., articleTitle=Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections, refAbstract=null), Reference(id=1222469895330189590, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1038/srep02475, pmid=null, pmcid=null, year=2013, volume=3, issue=null, pageStart=2475, pageEnd=null, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=Hu QH, Liu RJ, Fang ZP, journalName=Sci Rep, refType=null, unstructuredReference= Hu QH , Liu RJ , Fang ZP et al . Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase[J]. Sci Rep, 2013, 3: 2475, articleTitle=Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase, refAbstract=null), Reference(id=1222469895405687066, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.tet.2016.03.038, pmid=null, pmcid=null, year=2016, volume=72, issue=null, pageStart=3795, pageEnd=3801, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=Alam MA, Arora K, Gurrapu S, journalName=Tetrahedron, refType=null, unstructuredReference= Alam MA , Arora K , Gurrapu S et al . Synthesis and evaluation of functionalized benzoboroxoles as potential anti-tuberculosis agents[J]. Tetrahedron, 2016, 72: 3795-3801., articleTitle=Synthesis and evaluation of functionalized benzoboroxoles as potential anti-tuberculosis agents, refAbstract=null), Reference(id=1222469895485378845, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1021/acs.jmedchem.7b00631, pmid=null, pmcid=null, year=2017, volume=60, issue=null, pageStart=8011, pageEnd=8026, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=Li X, Hernandez V, Rock FL, journalName=J Med Chem, refType=null, unstructuredReference= Li X , Hernandez V , Rock FL et al . Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (s)-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1, 2]oxaborol-1(3H)-ol (GSK656)[J]. J Med Chem, 2017, 60: 8011-8026., articleTitle=Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (s)-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1, 2]oxaborol-1(3H)-ol (GSK656), refAbstract=null), Reference(id=1222469895581847841, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1097/QCO.0b013e32834c630e, pmid=null, pmcid=null, year=2011, volume=24, issue=null, pageStart=586, pageEnd=592, url=null, language=null, rfNumber=[18], rfOrder=17, authorNames=Jacobs RT, Plattner JJ, Keenan M, journalName=Curr Opin Infect Dis, refType=null, unstructuredReference= Jacobs RT , Plattner JJ , Keenan M . Boron-based drugs as antiprotozoals[J]. Curr Opin Infect Dis, 2011, 24: 586-592., articleTitle=Boron-based drugs as antiprotozoals, refAbstract=null), Reference(id=1222469895686705444, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1080/14756366.2017.1414808, pmid=null, pmcid=null, year=2018, volume=33, issue=null, pageStart=286, pageEnd=289, url=null, language=null, rfNumber=[19], rfOrder=18, authorNames=Nocentini A, Cadoni R, Dumy P, journalName=J Enzyme Inhib Med Chem, refType=null, unstructuredReference= Nocentini A , Cadoni R , Dumy P et al . Carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani chagasi are inhibited by benzoxaboroles[J]. J Enzyme Inhib Med Chem, 2018, 33: 286-289., articleTitle=Carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani chagasi are inhibited by benzoxaboroles, refAbstract=null), Reference(id=1222469895854477607, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.bmcl.2013.03.067, pmid=null, pmcid=null, year=2013, volume=23, issue=null, pageStart=2829, pageEnd=2843, url=null, language=null, rfNumber=[20], rfOrder=19, authorNames=Biamonte MA, Wanner J, Le Roch KG, journalName=Bioorg Med Chem Lett, refType=null, unstructuredReference= Biamonte MA , Wanner J , Le Roch KG . Recent advances in malaria drug discovery[J]. Bioorg Med Chem Lett, 2013, 23: 2829-2843., articleTitle=Recent advances in malaria drug discovery, refAbstract=null), Reference(id=1222469895971918129, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1038/nrd4573, pmid=null, pmcid=null, year=2015, volume=14, issue=null, pageStart=424, pageEnd=null, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=Wells TN, Van Huijsduijnen RH, Van Voorhis WC, journalName=Nat Rev Drug Discov, refType=null, unstructuredReference= Wells TN , Van Huijsduijnen RH , Van Voorhis WC . Malaria medicines: a glass half full[J]. Nat Rev Drug Discov, 2015, 14: 424, articleTitle=Malaria medicines: a glass half full, refAbstract=null), Reference(id=1222469896080970038, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.bmcl.2010.12.034, pmid=null, pmcid=null, year=2011, volume=21, issue=null, pageStart=644, pageEnd=651, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=Zhang YK, Plattner JJ, Freund YR, journalName=Bioorg Med Chem Lett, refType=null, unstructuredReference= Zhang YK , Plattner JJ , Freund YR et al . Synthesis and structure-activity relationships of novel benzoxaboroles as a new class of antimalarial agents[J]. Bioorg Med Chem Lett, 2011, 21: 644-651., articleTitle=Synthesis and structure-activity relationships of novel benzoxaboroles as a new class of antimalarial agents, refAbstract=null), Reference(id=1222469896190021946, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1021/acs.jmedchem.7b00621, pmid=null, pmcid=null, year=2017, volume=60, issue=null, pageStart=5889, pageEnd=5908, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=Zhang YK, Plattner JJ, Easom EE, journalName=J Med Chem, refType=null, unstructuredReference= Zhang YK , Plattner JJ , Easom EE et al . Benzoxaborole antimalarial agents. Part 5. Lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate[J]. J Med Chem, 2017, 60: 5889-5908., articleTitle=Benzoxaborole antimalarial agents. Part 5. Lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate, refAbstract=null), Reference(id=1222469896261325118, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.2174/156802611795429167, pmid=null, pmcid=null, year=2011, volume=11, issue=null, pageStart=1255, pageEnd=1274, url=null, language=null, rfNumber=[24], rfOrder=23, authorNames=Jacobs RT, Nare BA, Phillips M, journalName=Curr Top Med Chem, refType=null, unstructuredReference= Jacobs RT , Nare BA , Phillips M . State of the art in African trypanosome drug discovery[J]. Curr Top Med Chem, 2011, 11: 1255-1274., articleTitle=State of the art in African trypanosome drug discovery, refAbstract=null), Reference(id=1222469896361988421, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.4155/fmc.11.80, pmid=null, pmcid=null, year=2011, volume=3, issue=null, pageStart=1259, pageEnd=1278, url=null, language=null, rfNumber=[25], rfOrder=24, authorNames=Jacobs RT, Plattner JJ, Nare B, journalName=Future Med Chem, refType=null, unstructuredReference= Jacobs RT , Plattner JJ , Nare B et al . Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis[J]. Future Med Chem, 2011, 3: 1259-1278., articleTitle=Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis, refAbstract=null), Reference(id=1222469896487817547, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1128/AAC.00160-13, pmid=null, pmcid=null, year=2013, volume=57, issue=null, pageStart=2849, pageEnd=2857, url=null, language=null, rfNumber=[26], rfOrder=25, authorNames=Mendes RE, Alley MRK, Sader HS, journalName=Antimicrob Agents Chemother, refType=null, unstructuredReference= Mendes RE , Alley MRK , Sader HS et al . Potency and spectrum of activity of AN3365, a novel boron-containing protein synthesis inhibitor, tested against clinical isolates of Enterobacteriaceae and nonfermentative Gram-negative bacilli[J]. Antimicrob Agents Chemother, 2013, 57: 2849-2857., articleTitle=Potency and spectrum of activity of AN3365, a novel boron-containing protein synthesis inhibitor, tested against clinical isolates of Enterobacteriaceae and nonfermentative Gram-negative bacilli, refAbstract=null), Reference(id=1222469896596869456, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.bmc.2017.01.034, pmid=null, pmcid=null, year=2017, volume=25, issue=null, pageStart=1543, pageEnd=1555, url=null, language=null, rfNumber=[27], rfOrder=26, authorNames=Vermelho AB, Capaci GR, Rodrigues IA, journalName=Bioorg Med Chem, refType=null, unstructuredReference= Vermelho AB , Capaci GR , Rodrigues IA et al . Carbonic anhydrases from Trypanosoma and Leishmania as anti-protozoan drug targets[J]. Bioorg Med Chem, 2017, 25: 1543-1555., articleTitle=Carbonic anhydrases from Trypanosoma and Leishmania as anti-protozoan drug targets, refAbstract=null), Reference(id=1222469898572386646, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.2332/allergolint.13-RAI-0564, pmid=null, pmcid=null, year=2013, volume=62, issue=null, pageStart=151, pageEnd=161, url=null, language=null, rfNumber=[28], rfOrder=27, authorNames=Leung DY, journalName=Allergol Int, refType=null, unstructuredReference= Leung DY . New insights into atopic dermatitis: role of skin barrier and immune dysregulation[J]. Allergol Int, 2013, 62: 151-161., articleTitle=New insights into atopic dermatitis: role of skin barrier and immune dysregulation, refAbstract=null), Reference(id=1222469898664661337, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1007/s40265-017-0784-3, pmid=null, pmcid=null, year=2017, volume=77, issue=null, pageStart=1389, pageEnd=1397, url=null, language=null, rfNumber=[29], rfOrder=28, authorNames=Ahluwalia J, Udkoff J, Waldman A, journalName=Drugs, refType=null, unstructuredReference= Ahluwalia J , Udkoff J , Waldman A et al . Phosphodiesterase 4 inhibitor therapies for atopic dermatitis: progress and outlook[J]. Drugs, 2017, 77: 1389-1397., articleTitle=Phosphodiesterase 4 inhibitor therapies for atopic dermatitis: progress and outlook, refAbstract=null), Reference(id=1222469898748547419, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/S0091-6749(97)70297-5, pmid=null, pmcid=null, year=1997, volume=99, issue=null, pageStart=28, pageEnd=37, url=null, language=null, rfNumber=[30], rfOrder=29, authorNames=Essayan DM, Huang SK, Kagey-Sobotka A, journalName=J Allergy Clin Immunol, refType=null, unstructuredReference= Essayan DM , Huang SK , Kagey-Sobotka A et al . Differential efficacy of lymphocyte-and monocyte-selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression[J]. J Allergy Clin Immunol, 1997, 99: 28-37., articleTitle=Differential efficacy of lymphocyte-and monocyte-selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression, refAbstract=null), Reference(id=1222469898828239196, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.jaad.2016.05.046, pmid=null, pmcid=null, year=2016, volume=75, issue=null, pageStart=494, pageEnd=503, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=Paller AS, Tom WL, Lebwohl MG, journalName=J Am Acad Dermatol, refType=null, unstructuredReference= Paller AS , Tom WL , Lebwohl MG et al . Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4(PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults[J]. J Am Acad Dermatol, 2016, 75: 494-503., articleTitle=Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4(PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults, refAbstract=null), Reference(id=1222469898899542368, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=null, journalName=null, refType=null, unstructuredReference=FDA. Clinical pharmacology review of crisaborole[EB/OL]. 2016[2016-01-07]. https://www.fda.gov/media/102760., articleTitle=null, refAbstract=null), Reference(id=1222469899008594276, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1016/j.bmcl.2016.10.024, pmid=null, pmcid=null, year=2016, volume=26, issue=null, pageStart=5797, pageEnd=5801, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=Zhang J, Yang F, Qiao Z, journalName=Bioorg Med Chem Lett, refType=null, unstructuredReference= Zhang J , Yang F , Qiao Z et al . Chalcone-benzoxaborole hybrids as novel anticancer agents[J]. Bioorg Med Chem Lett, 2016, 26: 5797-5801., articleTitle=Chalcone-benzoxaborole hybrids as novel anticancer agents, refAbstract=null), Reference(id=1222469899167977835, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, doi=10.1021/acs.jmedchem.9b00736, pmid=null, pmcid=null, year=2019, volume=62, issue=null, pageStart=6765, pageEnd=6784, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=Zhang J, Zhang J, Hao G, journalName=J Med Chem, refType=null, unstructuredReference= Zhang J , Zhang J , Hao G et al . Design, synthesis, and structure-activity relationship of 7-propanamide benzoxaboroles as potent anticancer agents[J]. J Med Chem, 2019, 62: 6765-6784., articleTitle=Design, synthesis, and structure-activity relationship of 7-propanamide benzoxaboroles as potent anticancer agents, refAbstract=null)], funds=[Fund(id=1222469891936997558, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, awardId=21672127, language=CN, fundingSource=国家自然科学基金资助项目(21672127), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1222469883191874164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, xref=null, ext=[AuthorCompanyExt(id=1222469883196068469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1222469883204457078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院药物化学研究所, 山东 济南 250012)])], figs=[ArticleFig(id=1222469887587505010, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=6qqSrVcaBeU6pmURq51Bww==, figureFileBig=Rclh6HEcL7w+YDPs2Z22GA==, tableContent=null), ArticleFig(id=1222469887679779707, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 1, caption= Chemical structures of benzoxaborole-based small molecule inhibitors , figureFileSmall=6qqSrVcaBeU6pmURq51Bww==, figureFileBig=Rclh6HEcL7w+YDPs2Z22GA==, tableContent=null), ArticleFig(id=1222469887889494925, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=BbrI9rssfPD4qJ5edKm2IA==, figureFileBig=mY0nQjD7lwUg6T1nWZr6lQ==, tableContent=null), ArticleFig(id=1222469887990158230, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 2, caption= Comparison of p<i>K</i><sub>a</sub> values of benzoxaboroles (a) and phenylboronic acids (b) , figureFileSmall=BbrI9rssfPD4qJ5edKm2IA==, figureFileBig=mY0nQjD7lwUg6T1nWZr6lQ==, tableContent=null), ArticleFig(id=1222469888086627232, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=SzZlELJ+8fFW/1WRBNF+1w==, figureFileBig=Uurw1etZrVoF3H2lqmFpkQ==, tableContent=null), ArticleFig(id=1222469888183096237, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 3, caption= (a) Inhibition mechanism of AN2690 against LeuRS; (b) Adenosine-AN2690 adduct inside the editing active site of <i>T. thermophilus</i> LeuRS (PDB 2V0G) , figureFileSmall=SzZlELJ+8fFW/1WRBNF+1w==, figureFileBig=Uurw1etZrVoF3H2lqmFpkQ==, tableContent=null), ArticleFig(id=1222469888271176628, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=sKKlBY5I4oDLRXkTIi4koQ==, figureFileBig=iwwhekx6yZOYkWW7PXMDyA==, tableContent=null), ArticleFig(id=1222469888388617151, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 4, caption= Chemical structures of benzoxaborole-based antifungal inhibitors , figureFileSmall=sKKlBY5I4oDLRXkTIi4koQ==, figureFileBig=iwwhekx6yZOYkWW7PXMDyA==, tableContent=null), ArticleFig(id=1222469888535417800, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=Jl48B6LV8kEWsbwXCtYTNA==, figureFileBig=9nvCwnhOH8+b7/MJ9g125g==, tableContent=null), ArticleFig(id=1222469888631886799, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 5, caption= Chemical structures of benzoxaborole-based antibacterial inhibitors , figureFileSmall=Jl48B6LV8kEWsbwXCtYTNA==, figureFileBig=9nvCwnhOH8+b7/MJ9g125g==, tableContent=null), ArticleFig(id=1222469888732550101, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=rkTBlA6ikeg6PBKb1+G1vQ==, figureFileBig=OWIx0tFd+QUuoFpuncsqrg==, tableContent=null), ArticleFig(id=1222469888858379229, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 6, caption= Chemical structures of novel amide pyrazinyloxy benzoxaboroles , figureFileSmall=rkTBlA6ikeg6PBKb1+G1vQ==, figureFileBig=OWIx0tFd+QUuoFpuncsqrg==, tableContent=null), ArticleFig(id=1222469889000985578, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=yq3cYqBo07gpcyiMbC9lSw==, figureFileBig=Kv2qa1FH4L0ucvUafEj3Ug==, tableContent=null), ArticleFig(id=1222469889114231792, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 7, caption= Chemical structure of benzoxaborole-based HAT inhibitor , figureFileSmall=yq3cYqBo07gpcyiMbC9lSw==, figureFileBig=Kv2qa1FH4L0ucvUafEj3Ug==, tableContent=null), ArticleFig(id=1222469889219089402, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=8ooOPHBf/lBdTUAWlap3xQ==, figureFileBig=6OGITQLuU8hegLheZeMeLw==, tableContent=null), ArticleFig(id=1222469889453969410, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 8, caption= Chemical structure of benzoxaborole-based carbonic anhydrases inhibitor , figureFileSmall=8ooOPHBf/lBdTUAWlap3xQ==, figureFileBig=6OGITQLuU8hegLheZeMeLw==, tableContent=null), ArticleFig(id=1222469889596575760, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=tN6yG8tR3N0en6KJfKRttw==, figureFileBig=nOaO4bW6tcOIo4y/T7lEMA==, tableContent=null), ArticleFig(id=1222469889730793498, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 9, caption= Metabolites of crisaborole <i>in vivo</i> , figureFileSmall=tN6yG8tR3N0en6KJfKRttw==, figureFileBig=nOaO4bW6tcOIo4y/T7lEMA==, tableContent=null), ArticleFig(id=1222469889865011233, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=rQIft1Y1Zxb+kCANiH27NQ==, figureFileBig=hxTzNm50ePxIIQujE0APng==, tableContent=null), ArticleFig(id=1222469889982451753, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 10, caption= Chemical structures of benzoxaboroles-based antitumor inhibitors , figureFileSmall=rQIft1Y1Zxb+kCANiH27NQ==, figureFileBig=hxTzNm50ePxIIQujE0APng==, tableContent=null), ArticleFig(id=1222469890133446704, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=K2jfyXH+b5W2gE4GMyqO2A==, figureFileBig=OjW+nQICqrun4qmhbXjwQw==, tableContent=null), ArticleFig(id=1222469890255081528, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Figure 11, caption= Development of 7-propionamide benzoxaboroles as anti-tumor compounds , figureFileSmall=K2jfyXH+b5W2gE4GMyqO2A==, figureFileBig=OjW+nQICqrun4qmhbXjwQw==, tableContent=null), ArticleFig(id=1222469890389299267, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. R1 R2 Minimum inhibitory concentration/μg·mL-1
T. rubrum T. mentagrophytes C. albicans C. neoformans A. fumigatus
7 H 4 4 4 8 4
8 5-F 1 2 0.5 2 2
9 H 8 8 2 4 4
10 5-F ≤1 2 0.5 0.5 1
11 5-F 4 2 1 4 2
12 5-F 4 4 4 4 4
13 5-F 1 4 1 1 1
14 5-F 1 2 1 1 1
15 5-F 16 32 4 16 16
16 H OH 8 4 2 1 2
3 5-F OH 1 1 0.5 0.25 0.25
17 5-F CH3 32 16 16 32 16
18 6-F - 8 8 8 8 8
19 H - 8 8 8 16 16
20 6-F - 32 32 64 > 64 32
Ciclopirox 0.5 0.5 0.5 0.5 1
), ArticleFig(id=1222469890510934089, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Table 1, caption=

Structure-activity relationship of AN2690 and its analogs

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. R1 R2 Minimum inhibitory concentration/μg·mL-1
T. rubrum T. mentagrophytes C. albicans C. neoformans A. fumigatus
7 H 4 4 4 8 4
8 5-F 1 2 0.5 2 2
9 H 8 8 2 4 4
10 5-F ≤1 2 0.5 0.5 1
11 5-F 4 2 1 4 2
12 5-F 4 4 4 4 4
13 5-F 1 4 1 1 1
14 5-F 1 2 1 1 1
15 5-F 16 32 4 16 16
16 H OH 8 4 2 1 2
3 5-F OH 1 1 0.5 0.25 0.25
17 5-F CH3 32 16 16 32 16
18 6-F - 8 8 8 8 8
19 H - 8 8 8 16 16
20 6-F - 32 32 64 > 64 32
Ciclopirox 0.5 0.5 0.5 0.5 1
), ArticleFig(id=1222469890603208784, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Configuration R X IC50/μmol·L-1 Mtb LeuRS MIC/μmol·L-1 Mtb H37Rv
27 (S) -CH2CH3 F 0.08 0.2
28 (S) -CH2CH3 Cl 0.056 0.1
29 (S) -CH2CH3 Br 0.075 0.1
30 (S) -CH2CH2CH3 Cl 0.31 0.16
31 (S) -CH2CH2CH2CH3 Cl 0.27 0.6
32 (S) -CH2CH2CH2OH Cl 0.47 0.14
33 Racemate -CH2CH2OH Cl 0.24 0.63
34 (S) -CH2CH2OH Cl 0.2 0.08
35 (R) -CH2CH2OH Cl 10 5
36 Racemate -CH2CH2OH Br 0.15 0.16
37 (S) -CH2CH2OH Br 0.12 0.08
38 (R) -CH2CH2OH Br 14.2 10
39 Racemate -CH2CH2CH2OH Cl 0.44 > 5
40 Racemate -CH2CH2CH2OH Br 0.37 > 5
41 Racemate -CH2CH2OH Cl 1.11 > 5
42 Racemate -CH2CH2OH Br 0.89 > 5
), ArticleFig(id=1222469890783563867, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Table 2, caption=

Structure-activity relationship of 3-aminoethyl 4-halogen benzoborazole analogs as LeuRS inhibitors

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Configuration R X IC50/μmol·L-1 Mtb LeuRS MIC/μmol·L-1 Mtb H37Rv
27 (S) -CH2CH3 F 0.08 0.2
28 (S) -CH2CH3 Cl 0.056 0.1
29 (S) -CH2CH3 Br 0.075 0.1
30 (S) -CH2CH2CH3 Cl 0.31 0.16
31 (S) -CH2CH2CH2CH3 Cl 0.27 0.6
32 (S) -CH2CH2CH2OH Cl 0.47 0.14
33 Racemate -CH2CH2OH Cl 0.24 0.63
34 (S) -CH2CH2OH Cl 0.2 0.08
35 (R) -CH2CH2OH Cl 10 5
36 Racemate -CH2CH2OH Br 0.15 0.16
37 (S) -CH2CH2OH Br 0.12 0.08
38 (R) -CH2CH2OH Br 14.2 10
39 Racemate -CH2CH2CH2OH Cl 0.44 > 5
40 Racemate -CH2CH2CH2OH Br 0.37 > 5
41 Racemate -CH2CH2OH Cl 1.11 > 5
42 Racemate -CH2CH2OH Br 0.89 > 5
), ArticleFig(id=1222469890884227168, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. R n X IC50/μmol·L-1
43 -COOH 2 C 0.026
44 -COOH 3 C 0.62
45 -COOH 4 C 2.01
46 -COOH 2 O 0.46
47 -COOH 2 NH 0.95
48 -COOH 2 NMe > 5
49 -C(O)Me 2 C 2.7
50 -COOMe 2 C 0.32
51 -C(O)NH2 2 C 1.30
52 -C(O)NMe2 2 C > 5
53 -C(O)NHSO2-c-Pr 2 C 0.46
54 -CN 2 C 1.02
55 -CH2NH2 2 C 0.52
56 -CN4H 2 C 0.16
57 -6-CH2CH2COOH 2 C 0.12
58 -5-CH2CH2COOH 2 C 2.89
59 -4-CH2CH2COOH 2 C > 5
60 - - - > 5
61 - - - > 5
), ArticleFig(id=1222469890963918955, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Table 3, caption=

Structure-activity relationship of 7-carbonyl ethyl substituted benzobonazole derivatives

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. R n X IC50/μmol·L-1
43 -COOH 2 C 0.026
44 -COOH 3 C 0.62
45 -COOH 4 C 2.01
46 -COOH 2 O 0.46
47 -COOH 2 NH 0.95
48 -COOH 2 NMe > 5
49 -C(O)Me 2 C 2.7
50 -COOMe 2 C 0.32
51 -C(O)NH2 2 C 1.30
52 -C(O)NMe2 2 C > 5
53 -C(O)NHSO2-c-Pr 2 C 0.46
54 -CN 2 C 1.02
55 -CH2NH2 2 C 0.52
56 -CN4H 2 C 0.16
57 -6-CH2CH2COOH 2 C 0.12
58 -5-CH2CH2COOH 2 C 2.89
59 -4-CH2CH2COOH 2 C > 5
60 - - - > 5
61 - - - > 5
), ArticleFig(id=1222469891039416436, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. R IC50/μmol·L-1 or inhibition % at 10 μmol·L-1
PDE4 TNF-α IL-2 IFN-γ IL-5 IL-10
6 4'-CN 0.49 0.54 0.61 0.83 2.4 5.3
66 2'-CN 3.7 8.5 4.0 4.1 7.8 8.0
67 4'-SO2NEt2 3.4 > 10 > 10 > 10 > 10 > 10
68 4'-SO2N(CH2CH2)2-NMe > 30 > 10 > 10 > 10 > 10 > 10
69 4'-COOH 6.4 > 10 > 10 > 10 > 10 > 10
70 4'-CONEt2 1.5 1.3 1.4 0.43 4.3 2.0
71 4'-CON(CH2CH2)2O 0.57 0.44 0.33 0.17 1.9 0.37
72 5-PhO 6.8 > 10 > 10 > 10 > 10 > 10
73 3'-CN 4.4 8.6 3.3 3.4 4.7 8.9
74 4'-F 7.7 > 10 55% 15% 53% > 10
75 4'-Cl 1.3 > 10 62% 29% > 10 > 10
76 4'-Me 2.0 > 10 > 10 29% > 10 > 10
77 4'-OMe 2.7 > 10 > 10 39% > 10 > 10
78 4'-CF3 0.45 6.1 3.6 2.2 12% 49%
79 4-CN-PhO 6.0 > 10 3.9 > 10 8.2 > 10
80 6-CN-PhO > 30 > 10 > 10 > 10 > 10 > 10
81 7-CN-PhO > 30 > 10 > 10 > 10 > 10 > 10
82 5-MeO - > 10 > 10 > 10 > 10 > 10
Rolipram 0.86 0.16 0.23 0.23 0.5 0.88
), ArticleFig(id=1222469891156856958, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Table 4, caption=

Structure-activity relationship of crisaborole and its derivatives

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. R IC50/μmol·L-1 or inhibition % at 10 μmol·L-1
PDE4 TNF-α IL-2 IFN-γ IL-5 IL-10
6 4'-CN 0.49 0.54 0.61 0.83 2.4 5.3
66 2'-CN 3.7 8.5 4.0 4.1 7.8 8.0
67 4'-SO2NEt2 3.4 > 10 > 10 > 10 > 10 > 10
68 4'-SO2N(CH2CH2)2-NMe > 30 > 10 > 10 > 10 > 10 > 10
69 4'-COOH 6.4 > 10 > 10 > 10 > 10 > 10
70 4'-CONEt2 1.5 1.3 1.4 0.43 4.3 2.0
71 4'-CON(CH2CH2)2O 0.57 0.44 0.33 0.17 1.9 0.37
72 5-PhO 6.8 > 10 > 10 > 10 > 10 > 10
73 3'-CN 4.4 8.6 3.3 3.4 4.7 8.9
74 4'-F 7.7 > 10 55% 15% 53% > 10
75 4'-Cl 1.3 > 10 62% 29% > 10 > 10
76 4'-Me 2.0 > 10 > 10 29% > 10 > 10
77 4'-OMe 2.7 > 10 > 10 39% > 10 > 10
78 4'-CF3 0.45 6.1 3.6 2.2 12% 49%
79 4-CN-PhO 6.0 > 10 3.9 > 10 8.2 > 10
80 6-CN-PhO > 30 > 10 > 10 > 10 > 10 > 10
81 7-CN-PhO > 30 > 10 > 10 > 10 > 10 > 10
82 5-MeO - > 10 > 10 > 10 > 10 > 10
Rolipram 0.86 0.16 0.23 0.23 0.5 0.88
), ArticleFig(id=1222469891261714564, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Dose Inhibition/%
6 1 mg/ear ×2 78
78 1 mg/ear ×2 68
Dexamethasone 1 mg/ear ×2 72
Rolipram 1 mg/ear ×2 6
3 mg/ear ×2 5
), ArticleFig(id=1222469891400126609, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Table 5, caption=

Anti-inflammatory activities of compound 6 and 78 in animal models

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd. Dose Inhibition/%
6 1 mg/ear ×2 78
78 1 mg/ear ×2 68
Dexamethasone 1 mg/ear ×2 72
Rolipram 1 mg/ear ×2 6
3 mg/ear ×2 5
), ArticleFig(id=1222469891513372824, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Scale Grade Defination
0 Clear Minor residual hypopigmentation/hyperpigmentation; no erythema or induration/papulation; no oozing/crusting
1 Almost clear Trace faintpink erythema, with barely perceptible induration/papulation and no oozing/crusting
2 Mild Faint pink erythema with mild induration/papulation and no oozing/crusting
3 Moderate Pink-red erythema with moderate induration/papulation with or without oozing/crusting
4 Severe Deep or bright red erythema with severe induration/papulation and with oozing/crusting
), ArticleFig(id=1222469891618230432, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Table 6, caption=

The evaluation criteria of ISGA

, figureFileSmall=null, figureFileBig=null, tableContent=
Scale Grade Defination
0 Clear Minor residual hypopigmentation/hyperpigmentation; no erythema or induration/papulation; no oozing/crusting
1 Almost clear Trace faintpink erythema, with barely perceptible induration/papulation and no oozing/crusting
2 Mild Faint pink erythema with mild induration/papulation and no oozing/crusting
3 Moderate Pink-red erythema with moderate induration/papulation with or without oozing/crusting
4 Severe Deep or bright red erythema with severe induration/papulation and with oozing/crusting
), ArticleFig(id=1222469891706310820, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. Trial Success in ISGAa
1 Crisaborole (n = 503) 32.8%
Vehicle (n = 256) 25.4%
2 Crisaborole (n = 513) 31.4%
Vehicle (n = 250) 18.0%
), ArticleFig(id=1222469891815362732, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, language=CN, label=Table 7, caption=

Clinical study of crisaborole. aDefined as an ISGA score of 0 or 1

, figureFileSmall=null, figureFileBig=null, tableContent=
No. Trial Success in ISGAa
1 Crisaborole (n = 503) 32.8%
Vehicle (n = 256) 25.4%
2 Crisaborole (n = 513) 31.4%
Vehicle (n = 250) 18.0%
)], attaches=null, journal=Journal(id=1189982048455397383, delFlag=0, nameCn=药学学报, nameEn=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, issn=0513-4870, eissn=null, cn=11-2163/R, coden=null, periodic=0, language=CN, oaType=null, ccby=null, superviseOffice=null, ownerOffice=null, pubOffice=null, editorOffice=null, officeType=null, aims=null, clcCode=null, officeProv=null, officeCity=null, officeAddr=null, officeZip=null, officeEmail=null, officePhone=null, editDirector=null, officeDirector=null, officeDirectorPhone=null, officeStaffNum=null, officeEmpNum=null, coverPicUrl=BTxjudbJDVO4PqdBR6On6Q==, journalPrice=null, startedYear=null, abbrevIsoEn=null, journalRemark=null, publicationField=null, createdTime=1761643429151, updatedTime=1788948913902, createdBy=18614031015, updatedBy=13041195026, firstLetterCn=Y, firstLetterEn=Y, subjectCode=Medical and Pharmaceutical Sciences, subjectName=Life Sciences, subjectCodeEn=Medical and Pharmaceutical Sciences, subjectNameEn=null, picCn=BTxjudbJDVO4PqdBR6On6Q==, picEn=c4l1ckL55nWbhl1KrFdWIA==, jcr=null, cjcr=null, exts=[JournalExt(id=1304509553505227679, language=CN, name=药学学报, nameHistory1=null, nameHistory2=null, managedBy=中国科学技术协会, sponsoredBy=中国药学会、中国医学科学院药物研究所, publishedBy=《药学学报》编辑委员会编辑出版, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1788948914171, updatedTime=1788948914171, createdBy=13041195026, updatedBy=13041195026, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""}), JournalExt(id=1304509553559753632, language=EN, name=Acta Pharmaceutica Sinica, nameHistory1=null, nameHistory2=null, managedBy=, sponsoredBy=, publishedBy=, editorOffice=, officeProv=null, officeCity=null, officeAddr=, officeZip=, editDirector=, officeDirector=null, officePhone=null, coverPicUrl=null, journalRemark=, submitArticleUrl=null, websiteUrl=, createdTime=1788948914184, updatedTime=1788948914184, createdBy=13041195026, updatedBy=13041195026, submissionGuidelinesUrl=, submissionAuthorUrl=https://www.yxxb.com.cn/journalx_yxxb/authorLogOn.action, submissionEditorUrl=https://www.yxxb.com.cn/journalx_yxxb/editorLogOn.action, submissionReviewUrl=https://www.yxxb.com.cn/journalx_yxxb/expertLogOn.action, submissionCeEditorUrl=, submissionAeEditorUrl=, option={"copyright":""})], databaseList=null, tenantJournalId=1189982191388893191, websiteList=[Website(id=1189982271588340489, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/CN, language=CN, createTime=1761643482348, createBy=18614031015, updateTime=1761643498101, updateBy=18614031015, name=药学学报-中文, tplId=1146099689490845704, title=药学学报, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982873114448678, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=articleTextType, value=kx, createTime=1761643625763, updateTime=1761643625763, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873093477155, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=banner, value=null, createTime=1761643625758, updateTime=1761643625758, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873135420201, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=grayFlag, value=0, createTime=1761643625768, updateTime=1761643625768, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873085088546, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643625756, updateTime=1761643625756, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873152197419, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=minRunFlag, value=0, createTime=1761643625772, updateTime=1761643625772, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873110254373, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/CN/file/pic, createTime=1761643625762, updateTime=1761643625762, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873143808810, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=silenceFlag, value=0, createTime=1761643625770, updateTime=1761643625770, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873101865764, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_cn_619/, createTime=1761643625760, updateTime=1761643625760, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873122837287, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeColor, value=null, createTime=1761643625765, updateTime=1761643625765, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982873127031592, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271588340489, code=themeStyle, value=null, createTime=1761643625766, updateTime=1761643625766, creator=18614031015, updator=18614031015)]), Website(id=1189982271655449355, webName=null, webTitle=null, webDomain=null, webCopyrigh=null, webIpcNo=null, seoTitle=null, seoKeywords=null, seoDescription=null, tenantJournalId=null, journalId=1189982191388893191, journalNameCn=null, journalNameEn=null, grayFlag=null, tenantId=1146029695717560320, platformId=null, journalGroupId=null, journalGroupNameCn=null, journalGroupNameEn=null, type=1, domain=https://castjournals.cast.org.cn/joweb/yxxb/EN, language=EN, createTime=1761643482364, createBy=18614031015, updateTime=1761643514085, updateBy=18614031015, name=药学学报-英文, tplId=1146101810881728533, title=Acta Pharmaceutica Sinica, delFlag=0, indexPage=/home, props=[WebsiteProps(id=1189982903015633534, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=articleTextType, value=kx, createTime=1761643632892, updateTime=1761643632892, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902990467707, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=banner, value=null, createTime=1761643632886, updateTime=1761643632886, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903036605057, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=grayFlag, value=0, createTime=1761643632897, updateTime=1761643632897, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902982079098, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=logo, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic?fileId=w+t2v8bJnX5lh3+hRRJcDA==, createTime=1761643632884, updateTime=1761643632884, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903053382275, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=minRunFlag, value=0, createTime=1761643632901, updateTime=1761643632901, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903007244925, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=picServerUrl, value=https://castjournals.cast.org.cn/joweb/yxxb/EN/file/pic, createTime=1761643632890, updateTime=1761643632890, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903044993666, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=silenceFlag, value=0, createTime=1761643632899, updateTime=1761643632899, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982902998856316, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=staticResourcePath, value=https://castjournals.cast.org.cn/joweb/cast_kjdb_en_623/, createTime=1761643632888, updateTime=1761643632888, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903019827839, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeColor, value=null, createTime=1761643632893, updateTime=1761643632893, creator=18614031015, updator=18614031015), WebsiteProps(id=1189982903028216448, tenantId=1146029695717560320, journalId=null, journalGroupId=null, siteId=1189982271655449355, code=themeStyle, value=null, createTime=1761643632895, updateTime=1761643632895, creator=18614031015, updator=18614031015)])], journalTitle=药学学报, weixinUrl=null, journalUrl=https://www.yxxb.com.cn/aps, iacademicId=null, status=1, seqNo=null, journalTitleEn=Acta Pharmaceutica Sinica, journalPhotoCn=BTxjudbJDVO4PqdBR6On6Q==, journalPhotoEn=c4l1ckL55nWbhl1KrFdWIA==, journalFirstLetter=Y, journalRecommend=null, journalNew=null, journalCollection=null, jcrJf=null, cjcrJf=null, jcrJfStr=null, cjcrJfStr=null, submissionFirstDecision=null, sciSubjectClassification=null, casSubjectClassification=null, citeScore=null, totalCitationFrequency=null, icpCode=null, psCode=null, advertisingLicenseCode=null, copyrightInformation=null, country=null, option=, provinceCode=null, provinceName=null, collectFlag=false, interPubPlatform=, interPubPlatformUrl=null), detailUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2019-0577, detailUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/10.16438/j.0513-4870.2019-0577, pdfUrlCn=https://castjournals.cast.org.cn/joweb/yxxb/CN/PDF/10.16438/j.0513-4870.2019-0577, pdfUrlEn=https://castjournals.cast.org.cn/joweb/yxxb/EN/PDF/10.16438/j.0513-4870.2019-0577, aliStartDate=null, aliEndDate=null, collectionFlag=false, citedCount=null, citedUrl=null, previewStatus=0, delFlag=0, hasFullText=1, orderTime=1573488000000, fullTextJson=null, articleText=null, reference=null)
收藏切换
苯并硼唑类化合物在药物化学中的应用
收藏切换
PDF下载
王川 , 侯旭奔 , 方浩 *
药学学报 | 综述 2019,54(11): 1940-1948
收起
收藏切换
药学学报 |综述 2019 , 54 (11) : 1940 -1948
苯并硼唑类化合物在药物化学中的应用
全屏
[Author(id=1222469883363840649, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, orderNo=0, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469883464503958, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469883363840649, language=EN, stringName=Chuan WANG, firstName=Chuan, middleName=null, lastName=WANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469883565167266, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469883363840649, language=CN, stringName=王川, firstName=川, middleName=null, lastName=王, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=山东大学药学院药物化学研究所, 山东 济南 250012, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469883191874164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, xref=null, ext=[AuthorCompanyExt(id=1222469883196068469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1222469883204457078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院药物化学研究所, 山东 济南 250012)])]), Author(id=1222469885540684460, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, orderNo=1, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=null, emailSecond=null, emailThird=null, correspondingAuthor=0, authorType=1, ext={EN=AuthorExt(id=1222469885683290811, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885540684460, language=EN, stringName=Xu-ben HOU, firstName=Xu-ben, middleName=null, lastName=HOU, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469885825897160, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885540684460, language=CN, stringName=侯旭奔, firstName=旭奔, middleName=null, lastName=侯, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=null, address=山东大学药学院药物化学研究所, 山东 济南 250012, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469883191874164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, xref=null, ext=[AuthorCompanyExt(id=1222469883196068469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1222469883204457078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院药物化学研究所, 山东 济南 250012)])]), Author(id=1222469885968503510, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, orderNo=2, firstName=null, middleName=null, lastName=null, nameCn=null, orcid=null, stid=null, country=null, authorPic=null, dead=0, email=haofangcn@sdu.edu.cn, emailSecond=null, emailThird=null, correspondingAuthor=1, authorType=1, ext={EN=AuthorExt(id=1222469886115304163, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885968503510, language=EN, stringName=Hao FANG, firstName=Hao, middleName=null, lastName=FANG, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1222469886207578860, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, authorId=1222469885968503510, language=CN, stringName=方浩, firstName=浩, middleName=null, lastName=方, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=*, address=山东大学药学院药物化学研究所, 山东 济南 250012, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null)}, companyList=[AuthorCompany(id=1222469883191874164, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, xref=null, ext=[AuthorCompanyExt(id=1222469883196068469, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China), AuthorCompanyExt(id=1222469883204457078, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469877034635459, companyId=1222469883191874164, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=山东大学药学院药物化学研究所, 山东 济南 250012)])])]
王川, 侯旭奔, 方浩*
作者信息
  • 山东大学药学院药物化学研究所, 山东 济南 250012
通讯作者:
*方浩, Tel: 86-531-88382019, E-mail:
Application of benzoxaboroles compounds in medicinal chemistry
Chuan WANG, Xu-ben HOU, Hao FANG*
Affiliations
  • Department of Medicinal Chemistry, School of Pharmaceutical Science, Shandong University, Jinan 250012, China
出版时间: 2019-11-12 doi: 10.16438/j.0513-4870.2019-0577
文章导航
收藏切换
摘要
收起

苯并硼唑（benzoxaborole）是一类含有硼原子的五元杂环化合物。近年来，苯并硼唑类化合物在药物研发中的应用越来越广，以其为骨架的药物他伐硼罗（tavaborole）和克立硼罗（crisaborole）相继被FDA批准上市。特别是，研究人员在对苯并硼唑类化合物设计探索的过程中，发现了新型的抗菌、抗寄生虫、抗肿瘤和抗炎药物。本文主要介绍苯并硼唑类化合物的性质、构效关系以及相关生物活性研究。

苯并硼唑  /  他伐硼罗  /  克立硼罗  /  构效关系  /  生物活性

Benzoxaborole is a series of compounds with five member ring and boron atom. Since the approval of crisaborole and tavaborole by FDA, benzoxaborole gained lots of research interests and become widely used in current drug discovery. Specially, benzoxaborole derivatives were found to exhibit anti-bacterial, anti-fungal, anti-protozoal, anti-tumor and anti-inflammatory activities. Here, we will review the properties of benzoxaborole, structure activity relationships as well as the recent progress in the biological activity of benzoxaborole derivatives.

benzoxaboroles  /  tavaborole  /  crisaborole  /  structure activity relationships  /  biological activity
王川, 侯旭奔, 方浩. 苯并硼唑类化合物在药物化学中的应用. 药学学报, 2019 , 54 (11) : 1940 -1948 . DOI: 10.16438/j.0513-4870.2019-0577
Chuan WANG, Xu-ben HOU, Hao FANG. Application of benzoxaboroles compounds in medicinal chemistry[J]. Acta Pharmaceutica Sinica, 2019 , 54 (11) : 1940 -1948 . DOI: 10.16438/j.0513-4870.2019-0577
正文
收起
苯并硼唑是一类含有硼原子的五元杂环骨架的化合物(图 1)。该类化合物由一个苯环和一个硼唑环2连接而成, 于1957年首次被Torssell[1]合成。通常, 未取代的苯并硼唑1被命名为1, 3-二氢-1-羟基-2, 1-苯并硼唑。最初, 该结构并未引起药物化学家的重视[2], 直到2006年他伐硼罗3 (tavaborole, 图 1)被发现具有显著的抗真菌活性后, 越来越多的药物化学科研工作者开始针对其进行深入的结构改造[3]。
近年来, 苯并硼唑类化合物在药物发现领域的应用取得了许多突破性的进展。2014年用于治疗甲癣(灰指甲/趾甲)的他伐硼罗被FDA批准上市[4]; 2015年用于治疗人类非洲锥虫病(昏睡病)的化合物4 (图 1)成功完成Ⅰ期临床试验, 目前正处于临床试验ⅡB/Ⅲ期[5]; 2016年用于治疗过敏性皮炎的特效药克立硼罗5 (crisaborole, 图 1)被美国FDA批准上市[6]; 2016年用于治疗银屑病的化合物6 (图 1)进入了Ⅱ期临床试验[5]。
1 苯并硼唑类化合物的基本性质
收起
Lewis酸性是有机硼酸及其类似物的重要性质之一。与芳基硼酸相比, 苯并硼唑类化合物酸性更强。例如, 苯并硼唑的pKa值约为7~8, 比相应的苯硼酸低1~2个单位[7] (图 2), 一般认为这主要是由于苯并硼唑的五元环张力引起的。环张力的存在使苯并硼唑容易被亲核试剂(如OH-)进攻, 更易由sp2杂化形式(trigonal planar)转换成阴离子型的sp3杂化(tetrahedral)形式。例如, 在生理pH的水溶液中, 50%的苯并硼唑类化合物以阴离子型的sp3杂化形式存在[8]。这使得苯硼唑类化合物比苯硼酸具有更高的水溶性。众所周知, 良好的溶解性是临床候选药物的关键性质之一[9]。因此, 苯并硼唑类化合物具有较好的成药性。
此外, 相比芳基硼酸而言, 苯并硼唑的硼氧键不易被水解, 且硼碳键(B-C)的强度也更高。实验表明, 在10% HCl或15% NaOH回流条件下, 苯并硼唑的稳定性要高于芳基硼酸[10]。
综上所述, 与芳基硼酸类化合物相比, 苯并硼唑类化合物稳定性强、水溶性高, 更适于作为类药化合物, 因此近年来也受到药物化学领域的更多重视。本文将就苯硼类化合物近来在创新药物研究领域的应用进行综述。
2 苯并硼唑类化合物的生物活性研究
收起
对于苯并硼唑类化合物而言, 其特殊的路易斯酸特性是其分子作用机制的基础。当苯并硼唑与酶的活性位点特异性结合时, 酶的生物学活性受到抑制从而发挥疗效。迄今为止, 苯并硼唑类化合物主要的作用靶点是亮氨酸-tRNA合成酶(LeuRS)。其中, 针对于真菌、细菌和LeuRS的苯并硼唑类化合物相继被报道, 其作用机制都是一致的。下文将以抗真菌药物他伐硼罗(AN2690)为例进行介绍。此外, 苯并硼唑类化合物还可以选择抑制包括磷酸二酯酶PDE 4 (phosphodiesterases 4)在内的其他作用靶标。但是一些苯并硼唑类化合物的作用机制并未被研究清楚, 例如抗寄生虫和抗肿瘤类苯并硼唑。由于该类化合物在药物发现的独特生物学活性, 药学科研工作者针对苯并硼唑骨架进行了大量结构改造。本文将按照其临床治疗用途进行分类。
2.1 抗真菌
他伐硼罗(AN2690)是第一个被批准上市的苯并硼唑类药物。该药由Anacor公司研发, 可用于治疗甲癣(俗称灰指甲)。其作用机制如图 3所示, 该药通过抑制真菌亮氨酸-tRNA合成酶(LeuRS)而发挥作用。由于五元苯硼唑环存在环张力, 他伐硼罗在生理pH下主要以阴离子形式Ⅱ存在。该药在tRNA合成酶的活性结合口袋中与腺苷酸核糖环(Ⅲ)两个羟基(2'-羟基和3'-羟基)形成中间体Ⅳ来阻断LeuRS的酶催化活性[11]。
他伐硼罗的研发过程已有详细的介绍[4], 本文主要就研究人员对于他伐硼罗的构效关系(SAR, structure activity relationships)研究进行简单的介绍。他伐硼罗系列的构效关系显示(表 1): ①当R2为苯环时, 化合物展现出中等程度的抗真菌活性, 活性明显高于杂环取代; ②当母核5位为F原子时, 对所有真菌的抑制活性明显提高; ③ 3位引入甲基, 化合物活性显著降低; ④当R2为OH时, 没有F原子的化合物活性一般, 但当5位引入F原子后, 化合物活性最好。之后研究人员对化合物3进行了临床试验研究。
在Ⅲ期临床试验中, 通过两项双盲、随机的临床对照试验进一步证实了他伐硼罗的有效性和安全性。两项临床试验中共纳入1194名患者, 其中试验组795人, 对照组399人, 连续用药48周, 并在给药结束的第52周进行疗效评价。结果表明他伐硼罗对于甲癣的治愈率均在50%以上, 明显优于对照组[12]。2014年, 他伐硼罗被FDA批准上市, 商品名为Kerydin。
Anacor公司还进一步开发了许多具有抗真菌作用的苯并硼唑类化合物, 结构通式为21。这类化合物可渗透到皮肤、指甲和头发等部位, 从而实现对真菌的抑制作用。其中AN2718 (化合物22, 图 4)属于这类结构的氯代衍生物, 对真菌T. mentagrophytes和T. rubrum具有良好的抑制作用, 穿透指甲能力与他伐硼罗相似[13]。目前AN2718已经完成Ⅰ期临床试验, 结果表明其对皮肤的刺激很低。
2.2 抗细菌感染
苯并硼唑类化合物对于亮氨酸-tRNA合成酶(LeuRS)的抑制作用不仅局限于真菌, 对于细菌也有同样的作用, 其作用机制与真菌相似。AN3365 (23, GSK 2251052, 图 5)被设计用来抑制革兰氏阴性菌(包括大肠杆菌和铜绿假单胞菌)的亮氨酸-tRNA合成酶(LeuRS)。X-射线单晶衍射结果表明AN3365与细菌LeuRS的结合方式与苯并硼唑在真菌LeuRS的结合方式基本一致。然而, 在治疗复杂泌尿道感染的Ⅱ期临床试验中, 细菌对AN3365产生了耐药性, 因此该药的临床试验也被停止[14]。
肺炎链球菌引起的细菌性肺炎是发病率和死亡率极高的疾病。2013年Hu等[15]报道了一种LeuRS抑制剂24, 体外实验表明该化合物对于肺炎链球菌的LeuRS具有显著的抑制作用, 其IC50为1.72 μmol·L-1, 并且该化合物对人类正常细胞中LeuRS的抑制作用极低, 其IC50大于250 μmol·L-1。
结核病是由结核分枝杆菌引起的一种高传染性的慢性细菌感染, 世界上将近三分之一的人口受到潜伏性肺结核的影响, 结核分岐杆菌(M.tuberculosis, Mtb)是造成肺结核的元凶[16]。2017年, GlaxoSmithKline公司和Anacor公司报道了一种针对Mtb亮氨酸-tRNA合成酶(LeuRS)的3-氨基乙基4-卤素苯并硼唑类抑制剂(表 2)[17], 并测试了该系列化合物对Mtb LeuRS酶活活性和体外抗Mtb H37Rv活性。通过SAR研究发现(表 2):苯并硼唑3-位手性碳的构型对活性有重要影响, 通常S构型化合物的生物活性好于R构型和消旋体; 增加R取代基的碳链长度对化合物活性影响小; 当R从-CH2CH3变为亲水侧链-CH2CH2OH时, 化合物活性得到很大提高; 7位取代的化合物活性普遍不如6位取代高。体外酶活性测试发现, 化合物34对其LeuRS有明显的抑制作用, 其IC50为56.1 nmol·L-1, 且该化合物具有良好的抗Mtb H37Rv活性, 其MIC = 0.08 μmol·L-1。目前该化合物正在进行治疗肺结核的Ⅰ期临床试验[17]。
2.3 抗寄生虫
寄生虫病是由于原生动物侵入人体而引起的疾病, 此类疾病较为常见, 尤以贫穷落后、卫生条件差的国家和地区最为严重[18]。尽管这些疾病严重影响了贫困地区和国家人民的健康和生活, 但是由于利润低, 制药公司很少针对此类疾病开发新药。随着苯并硼唑类药物抗真菌、抗细菌和抗炎活性研究的逐步深入[9], 研究人员将其应用到了寄生虫病药物的治疗和开发。除抗恰克斯病和利什曼病作用靶点-碳酸酐酶已被报道[19], 其他类抗寄生虫苯并硼唑的作用靶点有待进一步研究。
疟疾是经按蚊(疟疾传播的主要媒介)叮咬或输入携带疟原虫患者血液而感染所引起的虫媒传染病[20]。据估计, 全球每年有2.5亿人感染疟疾, 并且每年会导致100万人死亡[5]。然而, 抗疟药物的研发存在众多挑战, 新型抗疟药物应当具有药效强、口服生物利用度高、针对多种疟原虫有效、对儿童和孕妇的安全性高、生产成本低等优点[21]。Anacor公司设计了一系列针对7-羰基乙基取代的苯并硼唑类化合物, 并测试了该系列化合物对恶性疟原虫的活性, SAR显示(表 3):增加链长会使化合物活性降低, 当n=2时, 化合物活性最好; 当R取代基从羧基换成其他基团时, 化合物活性降低; 母核上取代基的位置对化合物活性有很大的影响, 活性以7位取代化合物最佳; 改变硼氧环的大小, 或在硼氧环中引入基团后化合物无活性。其中含有丙酸的衍生物43 (表 3)展现出良好的活性。该药抑制疟原虫的IC50 = 26 nmol·L-1, 并且对人类细胞的毒性很低, 并且由于其分子量低, 亲水性强, 水溶性好, 为以后设计新型抗疟药物提供了思路[22], 但是其作用机制有待进一步研究。
2017年Zhang等[23]报道了一系列新型酰胺吡嗪氧基苯并硼唑类抗疟抑制剂62 (图 6), 并通过一系列活性测试、药动学和体内安全性实验发现化合物63 (图 6)对培养的恶性疟原虫有较好的抑制作用(IC50 = 33 nmol·L-1), 并且其对小鼠体内感染的恶性疟原虫和毕氏疟原虫均具有较好的抑制作用。
人类非洲锥虫病(human African trypanosomiasis, HAT)又称非洲昏睡病, 通常由原生动物布氏锥虫(Trypanosoma Brucei)引起, 主要通过舌蝇传播[24]。研究人员对大量苯并硼唑类化合物进行了筛选, 发现化合物64 (图 7)对于HAT的活性最好[25]。研究表明, 苯并硼唑结构中所含的硼原子是该类化合物发挥活性所必需的, 相应的碳类似物和非环硼酸结构对HAT是没有活性的。
恰克斯病和利什曼病是世界卫生组织报告中提到应当关注的热带疾病。这两种疾病都是由动浆虫科寄生虫引起, 属于媒介传播疾病, 每年影响2 000万人, 造成5万多人死亡[19, 26]。碳酸酐酶是一种金属酶, 通过催化可逆的CO2水合反应, 通过释放质子生成碳酸氢盐, 且该酶被认为是致病微生物生长和毒性的重要因素[27]。2018年Nocentini等[19]报道了一种可用于该类疾病治疗的新型苯并硼唑类碳酸酐酶抑制剂。该类化合物通过对碳酸酐酶发挥抑制作用而产生活性。其中含有硫脲结构的苯并硼唑类抑制剂(65, 图 8)不仅对克氏锥虫的碳酸酐酶具有良好的抑制活性(IC50=0.91 μmol·L-1), 而且抑制人类碳酸酐酶的活性很低(IC50 > 100 μmol·L-1), 故具有良好的选择性。上述研究也为碳酸酐酶用于恰克斯病和利什曼病的治疗提供了新的思路。
2.4 抗炎
特异性皮炎(atopic dermatitis)是一种常见的以瘙痒性湿疹为特征的炎症性皮肤病, 经常反复发作。该病多见于儿童, 可引起皮肤屏障破坏、水分流失和皮肤干燥[28], 导致皮肤过敏、感染、以及皮肤的易感性增加。
研究发现炎症与磷酸二酯酶PDE (phosphodiesterases)活性升高有关, 其中PDE4在炎症细胞(如:巨噬细胞、T细胞、单核细胞和中性粒细胞)中的含量显著增加。PDE4通过控制环磷酸腺苷(cAMP)的降解, 参与炎症细胞中IL-4、IL-5、IL-10、IL-13和前列腺素PGE2等炎性细胞因子的产生[29]。由于该酶参与了特异性皮炎的病理过程, 因此PDE4可作为该病治疗的潜在治疗靶点。
克立硼罗5 (图 1)是一种含有苯并硼唑结构的选择性PDE4抑制剂, 它可调节多种免疫和炎症通路[30]。克立硼罗由于其特殊的理化性质和低分子量, 能够穿透表皮和真皮, 到达炎症部位, 适合于局部制剂。该药进入循环系统后, 将被迅速转化为无活性的代谢物Ⅴ或者Ⅵ (图 9), 之后二者会被人体迅速代谢, 对人体的毒害较小[31]。
Ancor研究人员发现化合物94具有一定的抑制PDE 4活性, 之后以该化合物为先导化合物设计了一系列的苯氧基类化合物, 并进行了SAR研究, 结果显示(表 4):当4'位为氰基(-CN)、吗啉甲酰基(-CON(CH2CH2)2O)和三氟甲基(-CF3)时, 化合物活性较好; 氰基取代的位置是发挥活性的关键, 以4'位最佳, 当氰基取代在2'位或3'位时, 活性减弱; 4'-氰苯氧基连接到母核5位是发挥活性的关键, 当其移至4、6或7位时活性降低。5-甲氧基取代的化合物无任何活性。
之后, Ancor公司对具有优良活性的化合物6和78进行了动物抗炎实验(表 5), 结果显示, 6和78对于动物耳部炎症具有明显的抑制作用, 在同等剂量下6的活性略高于阳性药dexamethasone, 强于3倍剂量的rolipram。随后Ancor公司对化合物6进行了临床试验。
在克立硼罗的临床试验[32]中, 研究人员设计了两项双盲、随机的临床对照试验以评价克立硼罗的疗效和安全性。该研究招募了2~79岁之间的1 522名志愿者, 志愿者患有5%~95%不同程度的炎症。根据最新的炎症评价标准-ISGA[31] (表 6), 38.5%参与者得分为2 (mild), 61.5%参与者得分为3 (moderate)。
在两项试验中, 受试者均以2:1的随机比例接受克立硼罗或安慰剂治疗, 每天两次, 持续28天。并且在第29天以ISGA得分为标准评价疗效, 将得分为0或1定义为治愈。临床试验结果(表 7)表明:克立硼罗对患者的治愈率在32%以上, 明显高于安慰剂。克立硼罗于2016年12月被FDA批准上市, 被用于轻至中度特异性皮炎患者的治疗。它是目前第一种也是唯一种抑制PDE-4酶的非甾体单药, 并在美国以Eucrisa商品名销售。
2.5 抗肿瘤
2016年, 周虎臣课题组设计并合成了一系列苯并硼唑-查尔酮化合物83 (图 10), 并用MTT法对SKOV3、MDA-MB-231、HCT116、MCF-10A和WI-38五种肿瘤细胞进行了抗增殖活性筛选。结果发现, 化合物84 (IC50=1.4 μmol·L-1)和85(IC50=1.7 μmol·L-1)对于SKOV3细胞具有良好的抑制活性。其中, 84细胞毒性较大, 对正常细胞MCF-10A也具有很强的抑制作用; 而85对于正常细胞的毒性较小[33]。但是其作用机制并未研究清楚。
2019年Zhang等[34]报道了一种7-丙酰胺类苯并硼唑衍生物, 并检测了其对于肿瘤细胞SKOV3和正常细胞WI-38的抗增殖活性, 研究人员以抗疟类苯并硼唑43为先导化合物, 设计合成了86系列化合物, SAR研究发现当R1为苯环时, 化合物(87)活性最高; 之后, 研究人员考察了87上苯环的不同取代基团对活性的影响。最终筛选出活性最好的化合物89和90 (图 11), 其中89对于SKOV3肿瘤细胞的IC50为21 nmol·L-1, 好于阳性对照药阿霉素(SKOV3肿瘤细胞IC50=32 nmol·L-1)。此外, 该化合物对正常细胞WI-38的IC50为3.7 μmol·L-1。虽然苯并硼唑类化合物的作用机制还未研究清楚, 但是上述活性结构为以后苯并硼唑类抗癌药物的发现提供了新的方向。
3 小结
收起
随着苯并硼唑类药物他伐硼罗和克立硼罗的相继上市, 苯并硼唑类化合物在药物化学领域的应用越来越广。与早期硼酸类蛋白酶体抑制剂(例如:硼替佐米等)相比, 苯并硼唑五元环类化合物的酸性强、水溶性好, 更易制成制剂, 易于作为设计新型酶抑制剂的关键结构片段。
本文介绍了两种已上市的苯并硼唑类药物(克立硼罗和他伐硼罗)以及多个处于临床阶段的苯并硼唑类化合物, 其适应症包括抗真菌、抗细菌、抗寄生虫、抗炎和抗肿瘤等, 并对代表性化合物的构效关系进行了综述。考虑到目前的研究现状和应用价值, 未来在抗细菌、抗寄生虫和抗肿瘤领域苯并硼唑类以其独特的理化性质将成为研究的热点。我们相信, 通过研究人员不懈的努力未来会出现更多的具有更好疗效和更低毒性的苯并硼唑类药物造福于人类。
基金
收起
  • 国家自然科学基金资助项目(21672127)
文献
收起
参考文献 引证文献
排序方式：
[1]
Torssell K . Bromination of tolylboronic acids according to Wohl-Ziegler[J]. Ark Kemi, 1957, 10: 507-511.
[2]
Adamczyk-Woźniak A , Cyrański MK , Żubrowska A et al . Benzoxaboroles-old compounds with new applications[J]. J Organomet Chem, 2009, 694: 3533-3541.
[3]
Baker SJ , Zhang YK , Akama T et al . Discovery of a new boron-containing antifungal agent, 5-fluoro-1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole (AN2690), for the potential treatment of onychomycosis[J]. J Med Chem, 2006, 49: 4447-4450.
[4]
Guo ZR . R & D of tavaborole and crisaborole as external medication[J]. Acta Pharm Sin (药学学报), 2017, 52: 1012-1018. http://www.yxxb.com.cn:8081/aps/CN/abstract/abstract16731.shtml
[5]
Nocentini A , Supuran CT , Winum JY . Benzoxaborole compounds for therapeutic uses: a patent review (2010-2018)[J]. Expert Opin Ther Pat, 2018, 28: 493-504.
[6]
Akama T , Baker SJ , Zhang YK et al . Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis[J]. Bioorg Med Chem Lett, 2009, 19: 2129-2132.
[7]
Tomsho JW , Arnab P , Hall DG et al . Ring structure and aromatic substituent effects on the pKa of the benzoxaborole pharmacophore[J]. ACS Med Chem Lett, 2012, 3: 48-52.
[8]
Adamczyk-Wozniak A , Borys KM , Sporzynski A . Recent developments in the chemistry and biological applications of benzoxaboroles[J]. Chem Rev, 2015, 115: 5224-5247.
[9]
Baker SJ , Tomsho JW , Benkovic SJ . Boron-containing inhibitors of synthetases[J]. Chem Soc Rev, 2011, 40: 4279-4285.
[10]
Snyder H , Reedy AJ , Lennarz WJ . Synthesis of aromatic boronic acids. aldehydo boronic acids and a boronic acid analog of tyrosine1[J]. J Am Chem Soc, 1958, 80: 835-838.
[11]
Rock FL , Mao W , Yaremchuk A et al . An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site[J]. Science, 2007, 316: 1759-1761.
[12]
Elewski BE , Aly R , Baldwin SL et al . Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-Ⅲ studies[J]. J Am Acad Dermatol, 2015, 73: 62-69.
[13]
Gupta AK , Simpson FC . New therapeutic options for onychomycosis[J]. Expert Opin Pharmacother, 2012, 13: 1131-1142.
[14]
O'dwyer K , Spivak AT , Ingraham K et al . Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections[J]. Antimicrob Agents Chemother, 2015, 59: 289-298.
[15]
Hu QH , Liu RJ , Fang ZP et al . Discovery of a potent benzoxaborole-based anti-pneumococcal agent targeting leucyl-tRNA synthetase[J]. Sci Rep, 2013, 3: 2475
[16]
Alam MA , Arora K , Gurrapu S et al . Synthesis and evaluation of functionalized benzoboroxoles as potential anti-tuberculosis agents[J]. Tetrahedron, 2016, 72: 3795-3801.
[17]
Li X , Hernandez V , Rock FL et al . Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (s)-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1, 2]oxaborol-1(3H)-ol (GSK656)[J]. J Med Chem, 2017, 60: 8011-8026.
[18]
Jacobs RT , Plattner JJ , Keenan M . Boron-based drugs as antiprotozoals[J]. Curr Opin Infect Dis, 2011, 24: 586-592.
[19]
Nocentini A , Cadoni R , Dumy P et al . Carbonic anhydrases from Trypanosoma cruzi and Leishmania donovani chagasi are inhibited by benzoxaboroles[J]. J Enzyme Inhib Med Chem, 2018, 33: 286-289.
[20]
Biamonte MA , Wanner J , Le Roch KG . Recent advances in malaria drug discovery[J]. Bioorg Med Chem Lett, 2013, 23: 2829-2843.
[21]
Wells TN , Van Huijsduijnen RH , Van Voorhis WC . Malaria medicines: a glass half full[J]. Nat Rev Drug Discov, 2015, 14: 424
[22]
Zhang YK , Plattner JJ , Freund YR et al . Synthesis and structure-activity relationships of novel benzoxaboroles as a new class of antimalarial agents[J]. Bioorg Med Chem Lett, 2011, 21: 644-651.
[23]
Zhang YK , Plattner JJ , Easom EE et al . Benzoxaborole antimalarial agents. Part 5. Lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate[J]. J Med Chem, 2017, 60: 5889-5908.
[24]
Jacobs RT , Nare BA , Phillips M . State of the art in African trypanosome drug discovery[J]. Curr Top Med Chem, 2011, 11: 1255-1274.
[25]
Jacobs RT , Plattner JJ , Nare B et al . Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis[J]. Future Med Chem, 2011, 3: 1259-1278.
[26]
Mendes RE , Alley MRK , Sader HS et al . Potency and spectrum of activity of AN3365, a novel boron-containing protein synthesis inhibitor, tested against clinical isolates of Enterobacteriaceae and nonfermentative Gram-negative bacilli[J]. Antimicrob Agents Chemother, 2013, 57: 2849-2857.
[27]
Vermelho AB , Capaci GR , Rodrigues IA et al . Carbonic anhydrases from Trypanosoma and Leishmania as anti-protozoan drug targets[J]. Bioorg Med Chem, 2017, 25: 1543-1555.
[28]
Leung DY . New insights into atopic dermatitis: role of skin barrier and immune dysregulation[J]. Allergol Int, 2013, 62: 151-161.
[29]
Ahluwalia J , Udkoff J , Waldman A et al . Phosphodiesterase 4 inhibitor therapies for atopic dermatitis: progress and outlook[J]. Drugs, 2017, 77: 1389-1397.
[30]
Essayan DM , Huang SK , Kagey-Sobotka A et al . Differential efficacy of lymphocyte-and monocyte-selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression[J]. J Allergy Clin Immunol, 1997, 99: 28-37.
[31]
Paller AS , Tom WL , Lebwohl MG et al . Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4(PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults[J]. J Am Acad Dermatol, 2016, 75: 494-503.
[32]
FDA. Clinical pharmacology review of crisaborole[EB/OL]. 2016[2016-01-07]. https://www.fda.gov/media/102760.
[33]
Zhang J , Yang F , Qiao Z et al . Chalcone-benzoxaborole hybrids as novel anticancer agents[J]. Bioorg Med Chem Lett, 2016, 26: 5797-5801.
[34]
Zhang J , Zhang J , Hao G et al . Design, synthesis, and structure-activity relationship of 7-propanamide benzoxaboroles as potent anticancer agents[J]. J Med Chem, 2019, 62: 6765-6784.
2019年第54卷第11期
PDF下载
405
178
引用本文
BibTeX
文章信息
doi: 10.16438/j.0513-4870.2019-0577
  • 接收时间：2019-07-20
  • 首发时间：2026-01-26
  • 出版时间：2019-11-12
补充材料
相关文章
文章信息
作者
出版历史
  • 收稿日期：2019-07-20
  • 修回日期：2019-08-13
基金
国家自然科学基金资助项目(21672127)
作者信息
    山东大学药学院药物化学研究所, 山东 济南 250012

通讯作者:

*方浩, Tel: 86-531-88382019, E-mail:
参考文献
分享链接
https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2019-0577
分享至
全文二维码

扫描看全文

引用本文
BibTeX
本文的引用情况
2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
关闭全屏
相关链接
论文
最新文章
热读文章
热点专题
内参
蓝皮书
产业发展报告
传播力报告
期刊分级目录
资讯
学术新闻
行业新闻
学术会议
行业会议
关于
关于我们
联系我们
北京市海淀区学院南路86号
100081
010-62199257（仅加盟咨询）
qkjq@cast.org.cn

中国科学技术协会版权所有 京ICP 备10216604号-4 海淀分局备案 1101084647
科技导报社主办 中国科协信息中心技术支持