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Article(id=1200860507742794660, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-1284, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1699891200000, receivedDateStr=2023-11-14, revisedDate=1706889600000, revisedDateStr=2024-02-03, acceptedDate=null, acceptedDateStr=null, onlineDate=1764237055954, onlineDateStr=2025-11-27, pubDate=1715443200000, pubDateStr=2024-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764237055954, onlineIssueDateStr=2025-11-27, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764237055954, creator=13701087609, updateTime=1764237055954, updator=13701087609, issue=Issue{id=1200860506031518620, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='5', pageStart='1101', pageEnd='1508', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764237055547, creator=13701087609, updateTime=1764241222263, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200877982563824311, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200877982563824312, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1200860506031518620, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1313, endPage=1326, ext={EN=ArticleExt(id=1200860508673930157, articleId=1200860507742794660, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Synthesis and antimicrobial activity of sulfonamide derivatives of spectinomycin, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Microsporidia is a group of intracellular parasitic eukaryotic microorganisms that pose threats to livestock fish production and human health, but there is no special chemo-therapeutic drug available for the treatment of microsporidia currently. In this study, sulfonamide derivatives of spectinomycin were designed by taking into consideration the low toxicity of spectinomycin and the favorable pharmaceutical properties of sulfonamides. Through the exploration of reaction conditions, a total of 21 target molecules were synthesized with a yield of 52%-74% and their chemical structures were confirmed by 1H NMR, 13C NMR, and high resolution mass spectrometry (HR MS). By screening in vitro, the host cell cytotoxicity and biological activity of target molecules to Encephalitozoon hellem, a representative of vertebrates infecting microsporidia, were studied. It was found that four target molecules each could inhibit or promote the proliferation of E. hellem. In this study, the synthesis method of sulfonamide derivatives of spectinomycin was established, and new compounds effective against E. hellem were discovered, which provided a new idea for the further derivatization of spectinomycin and the development of therapeutic drugs targeting microsporidia.

, correspAuthors=Jun-hong WEI, Da-cheng YANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 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, authorCompany=null, fund=null, authors=null, authorsList=Yong-qing LI, Li FAN, Wei WANG, Hong-lin ZHU, Jun-hong WEI, Da-cheng YANG), CN=ArticleExt(id=1200860519461679425, articleId=1200860507742794660, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=大观霉素磺酰化衍生物的合成及抗微生物活性研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

微孢子虫是一类威胁畜牧渔生产与人类健康的胞内寄生真核微生物, 但目前尚无专用微孢子虫化学治疗药物。基于大观霉素的低毒性和磺酰胺的良好药学性质, 作者设计了大观霉素的磺酰胺类衍生物; 通过反应条件探索, 以52%~74%的收率合成了21个目标分子, 并通过氢谱、碳谱、高分辨质谱等确证了分子结构; 通过体外筛选, 研究了目标分子的宿主细胞毒性和对脊椎动物微孢子虫代表-海伦脑炎微孢子虫的生物活性, 发现各有4个目标分子能抑制或促进海伦脑炎微孢子虫增殖。本研究建立了大观霉素的磺酰胺类衍生物的合成方法, 发现了对海伦脑炎微孢子虫有效的新型化合物, 为大观霉素的进一步衍生及微孢子虫治疗药物的发现提供了新的思路。

, correspAuthors=韦俊宏, 杨大成, authorNote=null, correspAuthorsNote=
*韦俊宏, E-mail: ;
杨大成, E-mail:
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State Key Laboratory of Resource Insects, Southwest University, Chongqing 400715, China), AuthorCompanyExt(id=1201106663379001734, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, companyId=1201106663353835906, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.西南大学, 资源昆虫高效养殖与利用全国重点实验室, 重庆 400715)])], figs=[ArticleFig(id=1201106669800481551, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=MM2yFAd3Ma9URVGA2YZISA==, figureFileBig=07t0DFkOIJj3jotpofBGlg==, tableContent=null), ArticleFig(id=1201106669930504985, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Figure 1, caption= Some listed sulfonamide drugs , figureFileSmall=MM2yFAd3Ma9URVGA2YZISA==, figureFileBig=07t0DFkOIJj3jotpofBGlg==, tableContent=null), ArticleFig(id=1201106670165386018, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=K6kOwpw3eDUhQsZl6kXkcg==, figureFileBig=loSLNTszCjsPSDtvvmsxFw==, tableContent=null), ArticleFig(id=1201106670442210094, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Figure 2, caption= Molecular structure and stereoconformation of spectinomycin , figureFileSmall=K6kOwpw3eDUhQsZl6kXkcg==, figureFileBig=loSLNTszCjsPSDtvvmsxFw==, tableContent=null), ArticleFig(id=1201106670660313907, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=n/oGNOrE59yZwerrZK1I8g==, figureFileBig=VqZ185BJnjTG0m6ctJAEnA==, tableContent=null), ArticleFig(id=1201106671914410818, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Figure 3, caption= Selected sulfonyl chlorides for the project , figureFileSmall=n/oGNOrE59yZwerrZK1I8g==, figureFileBig=VqZ185BJnjTG0m6ctJAEnA==, tableContent=null), ArticleFig(id=1201106672040239943, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=vj2BjL+0eB7xhbZxNzGGTg==, figureFileBig=eXTJL55fK1ZA4tQ1ONxsDg==, tableContent=null), ArticleFig(id=1201106672161874764, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Scheme 1, caption= Design of target molecule <strong>TM1</strong> , figureFileSmall=vj2BjL+0eB7xhbZxNzGGTg==, figureFileBig=eXTJL55fK1ZA4tQ1ONxsDg==, tableContent=null), ArticleFig(id=1201106672270926674, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=GANiGzx6X/Tbm6gUSiFAYw==, figureFileBig=XP6mNpJ3cZbIbxt9+pI1vQ==, tableContent=null), ArticleFig(id=1201106672430310231, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Scheme 2, caption= Synthetic strategies (A, B) of spectinomycin derivative <strong>TM1</strong> , figureFileSmall=GANiGzx6X/Tbm6gUSiFAYw==, figureFileBig=XP6mNpJ3cZbIbxt9+pI1vQ==, tableContent=null), ArticleFig(id=1201106672526779229, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=sWUEJEhZW4w0aQinP7KNnA==, figureFileBig=eVhL4t3svWiWJDGi20H8/w==, tableContent=null), ArticleFig(id=1201106672606471012, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Figure 4, caption= Inhibitory effect of target compounds on <i>E. hellem</i> proliferation. A-E: The <i>in vitro</i> evaluation of inhibitory effect of spectinomycin (A), <strong>TM1a</strong> (B), <strong>TM1e</strong> (C), <strong>TM1l</strong> (D), and <strong>TM1o</strong> (E). In all experiments, after drug treatment for 6–8 h, <i>E. hellem</i> was added for infection, and the number of parasitophorous vacuoles was counted by fluorescent brightener 28 staining on the 3rd and 6th days for statistics. <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=sWUEJEhZW4w0aQinP7KNnA==, figureFileBig=eVhL4t3svWiWJDGi20H8/w==, tableContent=null), ArticleFig(id=1201106672723911532, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=4I1+Q4jTszmNqoIkSZy0+Q==, figureFileBig=K5rw4ChUUzaQoRguMPmoiw==, tableContent=null), ArticleFig(id=1201106672828769136, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Figure 5, caption= Promotion effect of target compounds on <i>E. hellem</i> proliferation. A-D: The <i>in vitro</i> evaluation of promotion effect of <strong>TM1c</strong> (A), <strong>TM1d</strong> (B), <strong>TM1h</strong> (C), and <strong>TM1j</strong> (D). In all experiments, after drug treatment for 6-8 h, <i>E. hellem</i> was added for infection, and the number of parasitophorous vacuoles was counted by fluorescent brightener 28 staining on the 3rd and 6th days after infection for statistics. <i>n</i> = 3, <i><span class="mag-xml-overline" style="border-top:1px solid black">x</span></i> ± <i>s</i>. <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=4I1+Q4jTszmNqoIkSZy0+Q==, figureFileBig=K5rw4ChUUzaQoRguMPmoiw==, tableContent=null), ArticleFig(id=1201106672929432433, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=aU4tDQL7qnmDTtpGMRDWPQ==, figureFileBig=+McQUJ5YJej1uZ8O6N0rHg==, tableContent=null), ArticleFig(id=1201106673097204602, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Figure 6, caption= CLogP and total energy of <strong>TM1a</strong>, <strong>TM1e</strong>, <strong>TM1o</strong> and <strong>TM1l</strong> , figureFileSmall=aU4tDQL7qnmDTtpGMRDWPQ==, figureFileBig=+McQUJ5YJej1uZ8O6N0rHg==, tableContent=null), ArticleFig(id=1201106673223033728, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=Ji8+58JoMkuh0LNmIMRZUg==, figureFileBig=kazrPLiiu4GA16Af5gZjLw==, tableContent=null), ArticleFig(id=1201106673353057161, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Figure 7, caption= CLogP and total energy of <strong>TM1c</strong>, <strong>TM1d</strong>, <strong>TM1h</strong> and <strong>TM1j</strong> , figureFileSmall=Ji8+58JoMkuh0LNmIMRZUg==, figureFileBig=kazrPLiiu4GA16Af5gZjLw==, tableContent=null), ArticleFig(id=1201106673470497682, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
EntrySpe/mgArSO2ClArSO2Cl/mgTime/hTemp./℃Weight/mgYield/%
TM1a101156416-2011674.3
TM1b100156416-2010265.8
TM1c99113515-218264.1
TM1d99114415-217760.3
TM1e99128415-217052.4
TM1f99133415-218158.1
TM1g99142516-2510370.2
TM1h99116416-257759.7
TM1i99117516-258867.5
TM1j99128511-187756.3
TM1k99126411-188462.1
TM1l99127511-187957.9
TM1m99126411-187152.4
TM1n99155412-1910769.7
TM1o99153412-199561.6
TM1p99157512-198555.4
TM1q99146512-198757.9
TM1r9910648-158165.8
TM1s9913158-157754.8
TM1t9913748-158862.9
TM1u9910948-157660.9
), ArticleFig(id=1201106673579549588, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Table 1, caption=

Synthetic results of sulfonylated derivatives of spectinomycin (Spe) in DMF solvent

, figureFileSmall=null, figureFileBig=null, tableContent=
EntrySpe/mgArSO2ClArSO2Cl/mgTime/hTemp./℃Weight/mgYield/%
TM1a101156416-2011674.3
TM1b100156416-2010265.8
TM1c99113515-218264.1
TM1d99114415-217760.3
TM1e99128415-217052.4
TM1f99133415-218158.1
TM1g99142516-2510370.2
TM1h99116416-257759.7
TM1i99117516-258867.5
TM1j99128511-187756.3
TM1k99126411-188462.1
TM1l99127511-187957.9
TM1m99126411-187152.4
TM1n99155412-1910769.7
TM1o99153412-199561.6
TM1p99157512-198555.4
TM1q99146512-198757.9
TM1r9910648-158165.8
TM1s9913158-157754.8
TM1t9913748-158862.9
TM1u9910948-157660.9
), ArticleFig(id=1201106673709573020, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
EntryCell viability/%
50 μg·mL-120 μg·mL-11 μg·mL-1
TM1a34.8982.6289.02
TM1b82.4683.2288.06
TM1c82.2681.4287.60
TM1d84.9283.5984.83
TM1e75.7786.2089.41
TM1f58.4056.3670.51
TM1g21.6852.2676.28
TM1h83.3187.2385.71
TM1i86.1386.9784.71
TM1j82.6885.1384.53
TM1k57.9775.6177.28
TM1l40.2280.6880.26
TM1m74.0377.9378.61
TM1n25.9161.6477.41
TM1o24.2980.5681.05
TM1p70.7883.9390.07
TM1q18.0966.5982.91
TM1r82.7393.2796.15
TM1s81.3980.5778.55
TM1t83.9886.4787.34
TM1u78.7892.0486.93
), ArticleFig(id=1201106673881539494, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Table 2, caption=

Impact of target compounds on host cells assayed by cell counting kit-8 (CCK-8)

, figureFileSmall=null, figureFileBig=null, tableContent=
EntryCell viability/%
50 μg·mL-120 μg·mL-11 μg·mL-1
TM1a34.8982.6289.02
TM1b82.4683.2288.06
TM1c82.2681.4287.60
TM1d84.9283.5984.83
TM1e75.7786.2089.41
TM1f58.4056.3670.51
TM1g21.6852.2676.28
TM1h83.3187.2385.71
TM1i86.1386.9784.71
TM1j82.6885.1384.53
TM1k57.9775.6177.28
TM1l40.2280.6880.26
TM1m74.0377.9378.61
TM1n25.9161.6477.41
TM1o24.2980.5681.05
TM1p70.7883.9390.07
TM1q18.0966.5982.91
TM1r82.7393.2796.15
TM1s81.3980.5778.55
TM1t83.9886.4787.34
TM1u78.7892.0486.93
), ArticleFig(id=1201106674049311659, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
EntryAssay (c)/μg·mL-1ResultEntryAssay (c)/μg·mL-1Result
TM1a20InhibitionTM1l20Inhibition
TM1b50No influenceTM1mHigh toxicity
TM1c50ProliferationTM1nHigh toxicity
TM1d50ProliferationTM1o20Inhibition
TM1e20InhibitionTM1p20No influence
TM1fHigh toxicityTM1q1No influence
TM1gHigh toxicityTM1r50No influence
TM1h50ProliferationTM1s50No influence
TM1i50No influenceTM1t50No influence
TM1j50ProliferationTM1u20No influence
TM1kHigh toxicity
), ArticleFig(id=1201106674179335087, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Table 3, caption=

Effect of target compound TM1 on the proliferation of E. hellem

, figureFileSmall=null, figureFileBig=null, tableContent=
EntryAssay (c)/μg·mL-1ResultEntryAssay (c)/μg·mL-1Result
TM1a20InhibitionTM1l20Inhibition
TM1b50No influenceTM1mHigh toxicity
TM1c50ProliferationTM1nHigh toxicity
TM1d50ProliferationTM1o20Inhibition
TM1e20InhibitionTM1p20No influence
TM1fHigh toxicityTM1q1No influence
TM1gHigh toxicityTM1r50No influence
TM1h50ProliferationTM1s50No influence
TM1i50No influenceTM1t50No influence
TM1j50ProliferationTM1u20No influence
TM1kHigh toxicity
), ArticleFig(id=1201106674288386996, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.Inhibitory activity (MIC)/μg·mL-1
E. coli
ATCC25922		S. enteritidis
ATCC13076		A. baumannii
ATCC19606		P. aeruginosa
ATCC27853		M. luteusS. aureus
ATCC25129ATCC14125
TM1a256256256> 256> 256> 256> 256
TM1b> 256256256> 256> 256> 256> 256
TM1c> 256> 256> 256> 256256> 256> 256
TM1d> 256256256> 256256> 256> 256
TM1e> 256256256> 256256> 256> 256
TM1f> 256256256> 256256> 256> 256
TM1g> 256> 256256> 256> 256> 256> 256
TM1h> 256> 256256> 256> 256> 256> 256
TM1i> 256> 256256> 256> 256> 256> 256
TM1j> 256> 256256> 256> 256> 256> 256
TM1k> 256> 256> 256> 256> 256> 256> 256
TM1l> 256> 256> 256> 256> 256> 256> 256
TM1m> 256256> 256> 256> 256> 256> 256
TM1n> 256> 256> 256256> 256> 256> 256
TM1o> 256256256> 256> 256> 256> 256
TM1p> 256256256> 256> 256> 256> 256
TM1q> 256> 256256> 256> 256> 256> 256
TM1r> 256> 256> 256> 256> 256> 256> 256
TM1s> 256256> 256> 256> 256> 256> 256
TM1t> 256256> 256> 256> 256> 256> 256
TM1u> 256> 256> 256> 256> 256> 256> 256
Spe> 256> 256256> 2561664256
), ArticleFig(id=1201106674430993339, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1200860507742794660, language=CN, label=Table 4, caption=

Inhibitory activity of the synthesized molecules against human pathogenic bacteria

, figureFileSmall=null, figureFileBig=null, tableContent=
Compd.Inhibitory activity (MIC)/μg·mL-1
E. coli
ATCC25922		S. enteritidis
ATCC13076		A. baumannii
ATCC19606		P. aeruginosa
ATCC27853		M. luteusS. aureus
ATCC25129ATCC14125
TM1a256256256> 256> 256> 256> 256
TM1b> 256256256> 256> 256> 256> 256
TM1c> 256> 256> 256> 256256> 256> 256
TM1d> 256256256> 256256> 256> 256
TM1e> 256256256> 256256> 256> 256
TM1f> 256256256> 256256> 256> 256
TM1g> 256> 256256> 256> 256> 256> 256
TM1h> 256> 256256> 256> 256> 256> 256
TM1i> 256> 256256> 256> 256> 256> 256
TM1j> 256> 256256> 256> 256> 256> 256
TM1k> 256> 256> 256> 256> 256> 256> 256
TM1l> 256> 256> 256> 256> 256> 256> 256
TM1m> 256256> 256> 256> 256> 256> 256
TM1n> 256> 256> 256256> 256> 256> 256
TM1o> 256256256> 256> 256> 256> 256
TM1p> 256256256> 256> 256> 256> 256
TM1q> 256> 256256> 256> 256> 256> 256
TM1r> 256> 256> 256> 256> 256> 256> 256
TM1s> 256256> 256> 256> 256> 256> 256
TM1t> 256256> 256> 256> 256> 256> 256
TM1u> 256> 256> 256> 256> 256> 256> 256
Spe> 256> 256256> 2561664256
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大观霉素磺酰化衍生物的合成及抗微生物活性研究
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李永清 1 , 范莉 1 , 王巍 2 , 朱洪林 2 , 韦俊宏 2, * , 杨大成 1, *
药学学报 | 研究论文 2024,59(5): 1313-1326
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药学学报 | 研究论文 2024, 59(5): 1313-1326
大观霉素磺酰化衍生物的合成及抗微生物活性研究
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李永清1, 范莉1, 王巍2, 朱洪林2, 韦俊宏2, * , 杨大成1, *
作者信息
  • 1.西南大学化学化工学院, 重庆市高校应用化学重点实验室, 重庆 400715
  • 2.西南大学, 资源昆虫高效养殖与利用全国重点实验室, 重庆 400715

通讯作者:

*韦俊宏, E-mail: ;
杨大成, E-mail:
Synthesis and antimicrobial activity of sulfonamide derivatives of spectinomycin
Yong-qing LI1, Li FAN1, Wei WANG2, Hong-lin ZHU2, Jun-hong WEI2, * , Da-cheng YANG1, *
Affiliations
  • 1. Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
  • 2. State Key Laboratory of Resource Insects, Southwest University, Chongqing 400715, China
出版时间: 2024-05-12 doi: 10.16438/j.0513-4870.2023-1284
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微孢子虫是一类威胁畜牧渔生产与人类健康的胞内寄生真核微生物, 但目前尚无专用微孢子虫化学治疗药物。基于大观霉素的低毒性和磺酰胺的良好药学性质, 作者设计了大观霉素的磺酰胺类衍生物; 通过反应条件探索, 以52%~74%的收率合成了21个目标分子, 并通过氢谱、碳谱、高分辨质谱等确证了分子结构; 通过体外筛选, 研究了目标分子的宿主细胞毒性和对脊椎动物微孢子虫代表-海伦脑炎微孢子虫的生物活性, 发现各有4个目标分子能抑制或促进海伦脑炎微孢子虫增殖。本研究建立了大观霉素的磺酰胺类衍生物的合成方法, 发现了对海伦脑炎微孢子虫有效的新型化合物, 为大观霉素的进一步衍生及微孢子虫治疗药物的发现提供了新的思路。

大观霉素  /  磺酰氯  /  磺酰胺  /  海伦脑炎微孢子虫  /  生物活性

Microsporidia is a group of intracellular parasitic eukaryotic microorganisms that pose threats to livestock fish production and human health, but there is no special chemo-therapeutic drug available for the treatment of microsporidia currently. In this study, sulfonamide derivatives of spectinomycin were designed by taking into consideration the low toxicity of spectinomycin and the favorable pharmaceutical properties of sulfonamides. Through the exploration of reaction conditions, a total of 21 target molecules were synthesized with a yield of 52%-74% and their chemical structures were confirmed by 1H NMR, 13C NMR, and high resolution mass spectrometry (HR MS). By screening in vitro, the host cell cytotoxicity and biological activity of target molecules to Encephalitozoon hellem, a representative of vertebrates infecting microsporidia, were studied. It was found that four target molecules each could inhibit or promote the proliferation of E. hellem. In this study, the synthesis method of sulfonamide derivatives of spectinomycin was established, and new compounds effective against E. hellem were discovered, which provided a new idea for the further derivatization of spectinomycin and the development of therapeutic drugs targeting microsporidia.

spectinomycin  /  sulfonyl chloride  /  sulfonamide  /  Encephalitozoon hellem  /  biological activity
李永清, 范莉, 王巍, 朱洪林, 韦俊宏, 杨大成. 大观霉素磺酰化衍生物的合成及抗微生物活性研究. 药学学报, 2024 , 59 (5) : 1313 -1326 . DOI: 10.16438/j.0513-4870.2023-1284
Yong-qing LI, Li FAN, Wei WANG, Hong-lin ZHU, Jun-hong WEI, Da-cheng YANG. Synthesis and antimicrobial activity of sulfonamide derivatives of spectinomycin[J]. Acta Pharmaceutica Sinica, 2024 , 59 (5) : 1313 -1326 . DOI: 10.16438/j.0513-4870.2023-1284
正文
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微孢子虫(microsporidia) 是一类典型的专性细胞内寄生的单细胞真核生物, 其分类地位存在争议, 目前认为其属于真菌或者真菌的姊妹枝。微孢子虫具有独特的侵染装置, 孢子发芽时弹出极丝, 将具有感染性的孢原质运输至宿主细胞内[1, 2]。微孢子虫中的脑炎微孢子虫属(Encephalitozoon) 可以感染许多哺乳动物, 最近也发现它可感染昆虫[3, 4]。该属中的海伦脑炎微孢子虫(E. hellem)、兔脑炎微孢子虫(E. cuniculi) 和肠脑炎微孢子虫(E. intestinalis), 与哺乳动物的致病感染息息相关。脑炎微孢子虫可以造成宿主播散性感染疾病, 几乎可涉及所有的器官系统[5, 6]。脑炎微孢子虫病伴随大量的临床综合征, 包括肠胃炎、角膜炎、鼻窦炎、细支气管炎、肾炎、膀胱炎-输尿管炎、尿道炎、前列腺炎、肝炎、腹膜炎、脑炎和全身播散感染[7-12]。
微孢子虫病目前还没有很好的治疗方法, 临床上主要使用高效广谱驱虫药阿苯达唑, 然而该药在治疗时偶有复发的现象, 且对毕氏肠道微孢子虫等的治疗效果不佳[13]。烟曲霉素及其衍生物对包括毕氏肠道微孢子虫和蜜蜂微孢子虫在内的多种微孢子虫的治疗效果较好, 但因其不良反应已经被欧盟禁用, 目前我国也没有批准该药使用。多菌灵等苯并咪唑类药物对家蚕微粒子虫具有较好防效, 被批准用于蚕种生产, 但是多菌灵及其类似物对哺乳动物具有生殖毒性, 因此无法应用于人类微孢子虫病治疗[14]。此外, 还有一些多胺类、核苷类和喹诺酮类化合物也表现出一定的微孢子虫抑制能力, 但缺乏临床数据支持[15]。因此, 亟待开发出高效安全的特效药物, 用于经济动物和人类微孢子虫病的防控。
大观霉素(spectinomycin, Spe) 是由链霉菌产生的氨基糖苷类化合物, 没有其他氨基糖苷类药物的肾毒性或耳毒性, 具有较高的安全范围, 其盐酸盐是临床治疗淋病的二线药物[16]。大观霉素对常见细菌病原体的抗菌活性较弱, 具有良好的选择性。在研究已上市药物对微孢子虫的拮抗作用时发现, 靶向30S亚基的大观霉素能抑制海伦脑炎微孢子虫及家蚕微粒子虫的增殖, 但是活性不够强且活性不稳定。为了寻找活性增强的稳定分子, 选择大观霉素作为母体分子进行衍生。相较于其他母体分子, 大观霉素分子中含有2个甲胺基、3个羟基和1个羰基, 便于合成不同类型的衍生物和引入不同个数的修饰基团, 具有明显的结构优势。
磺胺类药物是较早出现并使用至今的抗菌药物, 拥有抗菌谱广、性质稳定、价格便宜等优点[17], 是目前仅次于抗生素的常用抗菌药物。磺酰胺类分子还有很多非抗菌性活性, 诸如格列美脲的降糖、呋塞米的利尿、西地那非可解决勃起功能障碍、塞米昔布能解热镇痛、贝利司他可治疗复发或难治性外周T细胞淋巴瘤、替拉那韦能治疗HIV等(图 1), 因而吸引和鼓励众多研究人员从事磺酰胺类化合物的药物研发。
磺胺类药物分子和PABA的结构相似, 可以取代PABA抑制二氢蝶酸合成酶, 阻断二氢叶酸的生物合成, 从而阻断后续的四氢叶酸及辅酶F的合成。人体可以从食物中摄取四氢叶酸, 因此磺胺类药物不影响人体正常的叶酸代谢, 而微生物靠自身合成四氢叶酸, 一旦叶酸代谢受阻, 生命不能继续, 因此微生物对磺胺类药物敏感。本研究针对人病原菌、微孢子虫相关疾病开展分子设计, 正是利用微生物对磺胺类药物的敏感性和安全性。为了接近常见磺胺药物的结构和便于分子检测, 目标分子(TM) 进一步设计为大观霉素的芳基磺酰化衍生物TM1 (路线图 1)。
大观霉素为三环分子, 在优势构象状态, 2个NHMe处于直立键, 甲胺基周围的立体位阻较大, 见图 2。
鉴于仲胺基旁边较大的空间位阻, 选取的磺酰氯分子的体积越小越有利于磺酰化反应; 为了研究构效关系, 磺酰氯芳环上的取代基最好分布于芳环的不同位置、带有吸电子基或给电子基。据此, 作者选择了下列21种磺酰氯(图 3) 合成大观霉素的磺酰胺衍生物。
通过反应条件探索, 合成了21个尚未报道的新分子, 发现了对海伦脑炎微孢子虫的增殖具有抑制或促进效果的多个化合物。
结果与讨论
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1 化学部分
大观霉素的研究及其应用成果丰硕, 但是大观霉素的衍生仅在C环的羰基和甲基衍生化有所报道[18, 19], 本研究对其A环的甲胺基进行磺酰化。大观霉素A环含有甲胺基和羟基, 如果与磺酰氯反应, 预计甲胺基优先反应, 但有单磺酰化和双磺酰化两种可能。为了实现双磺酰化反应, 可以选取一步法(路线图 2A) 和两步法(路线图 2B) 两种合成策略。
综合考虑, 一步法优于二步法。主要原料盐酸大观霉素五水合物和磺酰氯可分别加入水中、水溶性溶剂或非水溶性溶剂中充分溶解。若进行水相反应, 必须快速搅拌, 让不溶于水的磺酰氯尽可能与水相中的大观霉素碰撞进而发生反应; 同时水相法要低温加料、室温反应, 尽可能减少磺酰氯的水解。而有机相反应, 则需要探索盐酸大观霉素溶解性最好的溶剂, 尽量增大其溶解性; 也可加入碱性物质去掉盐酸大观霉素的HCl, 增加大观霉素在有机溶剂中的溶解性, 解决溶解性矛盾的分子之间的充分反应问题。
加料方式, 可以采用顺加法(先加盐酸大观霉素制成水溶液、然后分批加入磺酰氯或滴加其有机溶液) 或反加法(磺酰氯制成高浓度有机溶液, 分批加入盐酸大观霉素或滴加其水溶液)。前者大观霉素过量, 适于两步法或者两步一锅法; 后者磺酰氯过量, 有利于一次完成两个磺酰基的引入, 适于一步法合成[20, 21]。经过长时间尝试, 寻找到较佳的合成及纯化方法, 实现了大观霉素的双磺酰化, 其结果见表 1。
表 1实验结果显示, 在优化的反应条件下, 大观霉素可以与选定的磺酰氯在甲胺基发生反应并生成双磺酰化产物, 纯品收率52%~74%, 实现了合成目标。
比较TM1k~TM1m和TM1n~TM1p发现, 反应收率为对位 > 间位 > 邻位, 显示位阻越大收率越低。此外, 当取代基为供电子基时, 如TM1a~TM1g, 收率为52.4%~74.3%, 当取代基为吸电子基时, 如TM1h~TM1q、TM1s、TM1t, 收率为52.4%~69.7%, 表明电子效应对反应收率也有影响。再则, 供电子效应越强, 收率越高, 例如TM1a (4-CF3O) 和TM1g (4-tBu); 苯环上供电子基团增多但有邻位取代基时收率反而降低, 例如TM1e、TM1f, 收率仅为50%左右; 当对位为吸电子取代基时, 如TM1h、TM1k、TM1n、TM1q、TM1s, 吸电子效应越强, 收率越低。但是比较TM1h和TM1i、TM1s和TM1t, 邻位吸电子取代基的收率却要高于对位吸电子取代基, 可能是氟原子、硝基为强吸电子基团, 邻位取代的磺酰氯的反应性更强, 导致反应更彻底收率更高。
2 抗微生物活性评价
微孢子虫是一类宿主域相当广泛的单细胞胞内寄生病原, 严重威胁畜牧水产和人类健康。目前应用的微孢子虫病治疗药物有较高的复发风险和较强的毒副作用, 微孢子虫病仍没有针对性的特效药物。本研究以海伦脑炎微孢子虫作为测试病原初步评估大观霉素衍生物的体外抑制活性, 筛选有活性的微孢子虫抑制剂, 以用于后续药物开发。
由于微孢子虫是严格胞内寄生病原, 对其抑制作用的评估需要使用被感染的宿主或者宿主细胞系来进行。通过与西南大学资源昆虫高效养殖与利用全国重点实验室合作, 选取可以感染哺乳动物细胞的海伦脑炎微孢子虫作为研究对象进行微孢子虫拮抗能力测试。
2.1 目标化合物对宿主细胞的毒性测试
采用CCK-8试剂(cell counting kit-8) 检测TM1系列目标化合物对宿主细胞的毒性, 实验结果见表 2。
表 2数据表明, 部分化合物即使在1 μg·mL-1的浓度下对宿主细胞也表现出很强的细胞毒性, 包括TM1f、TM1g、TM1k、TM1m和TM1n。这些化合物因对宿主细胞毒性过大而难以测试其微孢子虫拮抗活性, 而其他化合物则在一定浓度下对细胞活性影响较小, 可以选择相应浓度测试其微孢子虫拮抗活性。
2.2 抗微孢子虫活性实验研究
挑选低毒性的化合物测试其对海伦脑炎微孢子虫增殖能力的影响, 抑制海伦脑炎微孢子虫增殖的实验结果见图 4, 促进海伦脑炎微孢子虫增殖的实验结果见图 5, 实验结果总结见表 3。
表 3数据表明, 有的目标化合物对宿主细胞表现为较强的细胞毒性, 低细胞毒性化合物对海伦脑炎微孢子虫的增殖能力则分别表现为抑制性、促进性或无影响三类。化合物TM1a、TM1e、TM1l、TM1o以安全浓度20 μg·mL-1处理均对海伦脑炎微孢子虫的增殖有显著的抑制效果(图 4)。化合物TM1a处理组在第3天时微孢子虫寄生囊数量与对照组相比差异较小, 但在第6天时抑制效果更为明显。化合物TM1e和TM1o处理组在第3天海伦脑炎微孢子虫的寄生囊数量就显著少于对照组, 且第6天抑制效果仍很明显。化合物TM1l与上述3个化合物略有不同, 第3天时TM1l处理组海伦脑炎微孢子虫的寄生囊数量极显著地低于对照组, 在第6天时海伦脑炎微孢子虫的寄生囊数量虽然仍少于对照组但差异相对较小。
出乎意料地, 化合物TM1c、TM1d、TM1h、TM1j以安全浓度50 μg·mL-1处理均对海伦脑炎微孢子虫的增殖表现出了促进效果(图 5)。其中化合物TM1c与TM1h处理组在第3天就开始显现出促进海伦脑炎微孢子虫增殖的效果, 第6天时处理组的海伦脑炎微孢子虫增殖促进效果更为明显; 而化合物TM1d与TM1j处理组促进海伦脑炎微孢子虫增殖的效果从第6天才开始显现, 表现为海伦脑炎微孢子虫寄生囊的数量显著多于对照组。
此外, TM1b、TM1i、TM1p~TM1u以安全浓度处理均对海伦脑炎微孢子虫的增殖无明显影响; TM1f、TM1g、TM1k、TM1m和TM1n表现为较强的细胞毒性。
从化合物TM1a、TM1e、TM1l、TM1o结构来看, 它们的仲胺基分别连接4-三氟甲氧基苯磺酰基、2, 5-二甲基苯磺酰基、3-氯苯磺酰基、3-溴苯磺酰基, 苯环上的取代基要么为给电子的4-CF3O-和2, 5-diMe, 要么为吸电子的3-Cl和3-Br, 未表现出明显规律。
采用ChemDraw软件计算TM1a、TM1e、TM1o和TM1l的脂水分配系数(lipid water partition coefficients, CLogP) 和最优构象下的分子内能(total energy), 结果见图 6。
从上述数据看出, 这几个分子的总能量顺序为TM1a > TM1e > TM1l ≈ TM1o, ClogP值为TM1a > TM1e > TM1o > TM1l; 从抑制海伦脑炎微孢子虫的数据来看, 亲脂性最小的化合物TM1l在第3天时抑制海伦脑炎微孢子虫的能力达到顶峰, 但在第6天时抑制效果已很微弱; 反观另外3个化合物, 在处理第3天时与对照组的差异相对较小, 其抑制效果在第6天更为显著。也许化合物亲脂性越高, 越容易同时穿过宿主细胞与微孢子虫的细胞膜, 到达微孢子虫内的核糖体靶点并抑制其增殖。
化合物TM1c、TM1h、TM1d、TM1j对海伦脑炎微孢子虫的增殖表现为促进效果, 化合物TM1c与TM1h的仲胺基分别连接4-甲苯磺酰基和4-氟苯磺酰基, 而TM1d与TM1j分别连接2-甲苯磺酰基和2, 6-二氟苯磺酰基, 前者磺酰基的对位存在取代基, 后者邻位存在取代基。计算每个化合物的参数, 结果见图 7。
化合物TM1c与TM1h的内能相对较低, TM1d与TM1j内能相对较高, 但它们的促微孢子虫增殖活性和脂溶性的关系没有明显规律。关于微孢子虫增殖的相关研究很少, 推测这几个化合物有可能激活了微孢子虫的蛋白表达, 例如分泌蛋白EH7108或者己糖激酶等的表达[22, 23], 直接促进微孢子虫的增殖。也有可能刺激了宿主的细胞代谢, 间接激活了微孢子虫的增殖。
微孢子虫的孢子阶段是微孢子虫存活于宿主体外的主要形式, 所有微孢子虫的孢子中都具有一套独特的侵染装置。在适当的环境刺激下, 孢子发芽弹出极管穿刺宿主细胞膜, 将具有感染性的孢原质注入宿主细胞, 并开始在细胞内增殖[24, 25]。孢原质在细胞中快速分化进入裂殖增殖期产生裂殖子, 随后裂殖子继续分裂增殖或发育为母孢子进入孢子增殖期, 此时开始形成孢壁并逐渐增厚, 最终发育为成熟孢子并从宿主细胞中释放出来。与其他真核微生物相比, 微孢子虫具有一些独特的结构特征, 包括几丁质内壁、退化的线粒体、因精简而导致沉降系数仅为70S的核糖体以及缺乏过氧化物酶体等[26, 27]。可以根据微孢子虫这些独特的性质, 选择相应化合物去抑制其增殖。例如靶向几丁质合成酶的多氧菌素与尼可霉素, 就被证明同样具有抑制微孢子虫增殖的能力[27]。大观霉素属于氨基糖苷抗生素, 带有正电荷的氨基与16S rRNA中带负电荷的结合位点特异性结合, 从而干扰蛋白质合成。合成的大观霉素衍生物可能也是通过与微孢子虫具有独特结构的核糖体结合, 进而抑制微孢子虫的增殖。
2.3 抗人致病菌活性研究
本课题选取了3株G-菌株、4株G+菌株, 用于目标化合物TM1系列分子的抑菌能力测试, 相关结果见表 4。
表 4测试结果表明, 大观霉素对藤黄微球菌显示较好的抑制活性(MIC = 16 μg·mL-1)、对金葡菌ATCC 25129有抑制活性(MIC = 64 μg·mL-1), TM1系列的目标分子对测试的7株人致病菌未表现出明显抑制作用。
小结
收起
大观霉素的衍生难度较大, 本研究尝试了大观霉素A环甲胺基的衍生, 克服了溶解性、选择性和稳定性等困难, 建立了相应的合成方法, 以中等至良好的收率获得了21个大观霉素磺酰化衍生物。目标分子的结构以 1H NMR、13C NMR和HR-MS进行了确证。细胞毒性测试表明, 5个目标分子对测试的宿主细胞显示毒性; 抑菌试验表明, 各有4个目标分子对海伦脑炎微孢子虫的增殖具有抑制或促进作用, 但对人或动物致病菌几乎没有抑制活性, 显示了优良的选择性。本研究发现了活性和选择性均强于大观霉素的新衍生物, 为后续研究奠定了基础。
实验部分
收起
盐酸大观霉素(上海麦克林生化科技有限公司, > 98%); 4-三氟甲氧基苯磺酰氯、2-三氟甲氧基苯磺酰氯、4-甲苯磺酰氯、2-甲苯磺酰氯、2, 5-二甲基苯磺酰氯、2, 4, 6-三甲基苯磺酰氯、4-叔丁基苯磺酰酰氯、4-氟苯磺酰氯、2-氟苯磺酰氯、2, 6-二氟苯磺酰氯、4-氯苯磺酰氯、3-氯苯磺酰氯、2-氯苯磺酰氯、4-溴苯磺酰氯、3-溴苯磺酰氯、2-溴苯磺酰氯、4-三氟甲基苯磺酰氯、苯磺酰氯、4-硝基苯磺酰氯、2-硝基苯磺酰氯、2-噻吩磺酰氯(上海麦克林生化科技有限公司, AR); 其余试剂均为市售化学纯或分析纯产品, 未经纯化直接使用。
核磁共振仪(Bruker, ADVANCE ⅢTM 600 MHz, TMS为内标, Switzerland); 高分辨质谱仪(QTOF-MS, Bruker Impact Ⅱ, Germany); 自动旋光仪(WZZ-2S, 上海精密科学仪器有限公司); 熔点测定仪(X-6, 北京福凯仪器有限公司)。
1 化合物的合成
合成方法为DMF低温反应法。在100 mL圆底烧瓶中依次加入原料五水盐酸大观霉素(0.2 mmol)、DMF (0.5 mL)、DIPEA (0.144 mL, 0.8 mmol), 搅拌10 min后, 冰浴, 加入磺酰氯(0.6 mmol), 冰浴下快速搅拌。TLC监测反应进程。反应结束后, 加入自来水4 mL, 析出白色絮状物或白色粉末。加入饱和碳酸钠水溶液6 mL, 调节pH 8~9, 室温下搅拌30 min, 抽滤, 滤饼依次用自来水(1 mL×3)、石油醚(PE, 1 mL×3) 润洗。滤饼转移至干燥的圆底烧瓶中, 加入DCM 1 mL, 溶解后加入2 mol·L-1 HCl调节pH 1~2, 室温下搅拌15 min, 分液, 有机相中继续加入饱和碳酸钠溶液, 调节pH 7~8, 分液, 干燥, 39 ℃旋除溶剂, 加入DCM 1 mL, 溶解后加入乙醚1 mL、石油醚8 mL, 析出白色固体, 抽滤, 干燥, 乙酸乙酯(EA) 和PE混合溶剂柱层析(PE∶EA = 5∶1~1∶1) 得纯品, 实验结果见表 1。
TM1系列化合物的表征数据如下:
TM1a: 白色固体, mp 210.9~212.7 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +30.2º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.95 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.86 (s, 1H), 6.07 (d, J = 6.2 Hz, 1H), 5.09 (d, J = 4.9 Hz, 1H), 4.52 (s, 1H), 4.12 (t, J = 10.5 Hz, 1H), 4.02 (s, 1H), 3.86 (t, J = 9.3 Hz, 1H), 3.77 (d, J = 11.7 Hz, 1H), 3.73 (d, J = 10.9 Hz, 2H), 3.68~3.61 (m, 1H), 2.89 (d, J = 9.8 Hz, 6H, ), 2.13 (s, 2H), 1.25 (d, J = 5.7 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.09, 151.24, 138.95, 138.50, 130.37, 130.08, 121.29, 121.03, 96.21, 91.30, 77.67, 73.29, 67.10, 64.97, 64.40, 60.75, 57.44, 45.36, 31.71, 21.53; HR MS calcd for C28H30F6N2O13S2, [M+H]+: 781.116 6, found: 781.116 9。
TM1b: 白色固体, mp 159.8~161.2 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +35.3º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 8.00 (d, J = 7.8 Hz, 1H), 7.96~7.92 (m, 1H), 7.73 (dd, J = 13.9, 6.4 Hz, 2H), 7.52 (dd, J = 13.3, 5.9 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 6.11 (d, J = 6.4 Hz, 1H), 5.22 (d, J = 4.6 Hz, 1H), 4.53 (s, 1H), 4.18 (d, J = 10.8 Hz, 1H), 4.14 (dd, J = 7.6, 4.3 Hz, 1H), 3.73~3.67 (m, 2H), 3.63 (t, J = 9.3 Hz, 1H), 3.55 (dd, J = 11.6, 2.0 Hz, 1H), 3.46 (dd, J = 10.6, 1.7 Hz, 1H), 3.02 (s, 3H), 2.95 (s, 3H), 2.16 (d, J = 13.0 Hz, 1H), 1.89 (t, J = 12.9 Hz, 1H), 1.18 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.07, 145.75, 145.40, 135.13, 134.93, 132.74, 132.46, 131.50, 131.29, 127.58, 127.52, 121.46, 121.23, 96.08, 91.43, 77.00, 73.46, 67.00, 64.78, 64.09, 60.36, 57.42, 45.48, 32.07, 32.02, 21.54; HR MS calcd for C28H30F6N2O13S2, [M+H]+: 781.116 6, found: 781.116 7。
TM1c: 白色固体, mp 235.9~236.7 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +33.6º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.70 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.78 (s, 1H), 5.95 (d, J = 6.4 Hz, 1H), 5.02 (d, J = 4.4 Hz, 1H), 4.50 (s, 1H), 4.14~4.09 (m, 1H), 4.02 (d, J = 6.3 Hz, 1H), 3.80 (t, J = 9.0 Hz, 1H), 3.70 (d, J = 10.4 Hz, 1H), 3.67 (d, J = 1.8 Hz, 2H), 3.61 (dd, J = 11.6, 2.0 Hz, 1H), 2.85 (d, J = 4.2 Hz, 6H), 2.37 (d, J = 11.4 Hz, 6H), 2.16 (d, J = 12.7 Hz, 1H), 2.08~2.01 (m, 1H), 1.25 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.13, 142.89, 142.77, 137.45, 136.90, 129.70, 129.63, 127.78, 127.44, 96.19, 91.32, 77.54, 73.54, 67.11, 64.95, 64.36, 60.67, 57.43, 45.27, 31.83, 31.42, 21.58, 21.44; HR MS calcd for C28H36N2O11S2, [M+H]+: 641.183 3, found: 641.183 2。
TM1d: 白色固体, mp 170.9~172.1 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +32.4º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.99 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.06 (s, 1H), 6.08 (d, J = 6.3 Hz, 1H), 5.42 (d, J = 5.3 Hz, 1H), 4.62 (s, 1H), 4.28 (d, J = 9.4 Hz, 2H), 3.84~3.76 (m, 3H), 3.51 (d, J = 10.7 Hz, 1H), 3.42 (d, J = 11.4 Hz, 1H), 2.97 (s, 3H), 2.93 (s, 3H), 2.60~2.56 (m, 6H), 2.26 (d, J = 13.0 Hz, 1H), 2.11~2.05 (m, 1H), 1.19 (d, J = 6.1 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.57, 138.96, 138.79, 137.55, 137.42, 132.96, 132.77, 129.49, 129.41, 126.44, 126.18, 96.11, 91.45, 76.90, 73.73, 67.08, 64.95, 64.07, 60.15, 57.19, 45.53, 31.90, 31.65, 21.56, 20.67, 20.59; HR MS calcd for C28H36N2O11S2, [M+Na]+: 663.165 3, found: 663.164 8。
TM1e: 白色固体, mp 172.3~173.7 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +39.2º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.60 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.4 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.02 (d, J = 6.6 Hz, 1H), 5.46 (d, J = 5.3 Hz, 1H), 4.60 (s, 1H), 4.29 (d, J = 11.2 Hz, 1H), 4.25 (d, J = 7.0 Hz, 1H), 3.84 (dd, J = 15.4, 10.0 Hz, 1H), 3.75 (dd, J = 17.2, 7.8 Hz, 2H), 3.52 (d, J = 10.6 Hz, 1H), 3.42 (d, J = 11.6 Hz, 1H), 2.94 (d, J = 2.9 Hz, 6H), 2.53 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 2.21 (d, J = 13.9 Hz, 1H, H-21), 2.07~2.01 (m, 1H, H-22), 1.20 (d, J = 5.8 Hz, 3H, H-23); 13C NMR (151 MHz, DMSO-d6) δ 201.48, 138.81, 138.43, 135.82, 135.72, 134.28, 134.24, 133.37, 133.24, 132.91, 132.87, 129.94, 129.59, 96.13, 91.57, 76.91, 73.77, 67.09, 65.12, 63.99, 60.21, 57.06, 45.62, 31.85, 31.67, 21.62, 20.84, 20.78, 20.29, 20.17; HR MS calcd for C30H40N2O11S2, [M+Na]+: 691.196 6, found: 691.195 8。
TM1f: 白色固体, mp 186.7~187.9 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +30.6º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.64 (s, 1H), 7.57 (d, J = 3.5 Hz, 1H), 7.46 (s, 1H), 6.83 (s, 1H), 6.01 (d, J = 5.6 Hz, 1H), 5.11 (s, 1H), 4.53 (s, 1H), 4.14 (t, J = 10.4 Hz, 1H), 4.05 (d, J = 6.6 Hz, 1H), 3.88 (t, J = 9.2 Hz, 1H), 3.73 (s, 1H), 3.72 (s, 1H), 3.70 (d, J = 5.6 Hz, 1H), 3.68~3.63 (m, 1H), 2.85 (d, J = 14.3 Hz, 6H), 2.26~2.20 (m, 1H), 2.16 (d, J = 12.8 Hz, 1H), 1.31 (d, J = 3.7 Hz, 18H), 1.28 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.57, 142.32, 142.19, 140.21, 140.14, 133.87, 133.64, 132.13, 132.06, 96.00, 91.37, 75.34, 74.12, 66.98, 64.68, 63.26, 59.84, 56.64, 45.35, 31.08, 30.74, 23.09, 23.06, 22.99, 22.94, 21.60, 20.90, 20.77; HR MS calcd for C32H44N2O11S2, [M+H]+: 697.245 9, found: 697.246 1。
TM1g: 白色固体, mp 204.5~206.7 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +40.2º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.75~7.74 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.4, 3.5 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 6.01 (d, J = 5.6 Hz, 1H), 5.11 (s, 1H), 4.53 (s, 1H), 4.14 (t, J = 10.4 Hz, 1H), 4.05 (d, J = 6.6 Hz, 1H), 3.88 (t, J = 9.2 Hz, 1H), 3.73 (s, 1H), 3.72 (s, 1H), 3.71~3.63 (m, 2H), 2.85 (d, J = 14.3 Hz, 6H), 2.26~2.20 (m, 1H), 2.16 (d, J = 12.8 Hz, 1H), 1.31 (d, J = 3.7 Hz, 18H), 1.28 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 200.99, 155.50, 155.45, 137.55, 136.96, 127.69, 127.48, 126.02, 125.87, 96.23, 91.40, 77.92, 73.56, 67.16, 64.93, 64.38, 60.74, 57.63, 45.85, 35.25, 35.17, 31.66, 31.42, 31.32, 21.62; HR MS calcd for C34H48N2O11S2, [M+Na]+: 747.259 2, found: 747.258 6。
TM1h: 白色固体, mp 237.5~236.4 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +44.3º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.88 (d, J = 7.8 Hz, 2H), 7.81~7.77 (m, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.28 (t, J = 8.7 Hz, 2H), 6.83 (s, 1H), 6.01 (d, J = 6.2 Hz, 1H), 5.06 (d, J = 4.7 Hz, 1H), 4.52 (s, 1H), 4.14~4.08 (m, 1H), 4.00 (d, J = 6.1 Hz, 1H), 3.83 (t, J = 9.2 Hz, 1H), 3.70 (d, J = 11.9 Hz, 3H), 3.67~3.61 (m, 1H), 2.87 (d, J = 7.5 Hz, 6H), 2.16 (dd, J = 22.5, 12.1 Hz, 2H), 1.26 (d, J = 5.8 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.16, 165.45, 163.77, 136.46 (s), 136.01, 130.77, 130.71, 130.42, 130.35, 116.34, 116.19, 96.23, 91.29, 77.57, 73.37, 67.11, 64.95, 64.45, 60.67, 57.35, 45.43, 31.79, 31.54, 21.59; HR MS calcd for C26H30F2N2O11S2, [M+Na]+: 671.115 1, found: 671.114 5。
TM1i: 白色固体, mp 170.2~171.5 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +47.6º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.85 (dd, J = 13.0, 6.9 Hz, 2H), 7.65 (s, 2H), 7.37 (dd, J = 16.3, 7.7 Hz, 2H), 7.32 (dd, J = 15.9, 7.8 Hz, 2H), 6.95 (s, 1H), 6.12 (d, J = 5.5 Hz, 1H), 5.17 (s, 1H), 4.51 (s, 1H), 4.16 (t, J = 10.5 Hz, 1H), 4.11 (d, J = 6.0 Hz, 1H), 3.69 (dd, J = 14.7, 9.4 Hz, 2H), 3.63 (t, J = 9.3 Hz, 1H), 3.52~3.49 (m, 1H), 3.47 (d, J = 10.6 Hz, 1H), 2.99 (d, J = 17.0 Hz, 6H), 2.11 (d, J = 13.4 Hz, 1H), 1.83 (t, J = 12.9 Hz, 1H), 1.18 (d, J = 5.9 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.05, 159.62, 157.93, 135.55, 135.35, 130.94, 130.79, 127.97, 127.63, 124.85, 117.57, 117.42, 96.13, 91.40, 77.08, 73.47, 67.04, 64.79, 64.13, 60.49, 57.47, 45.58, 31.85, 21.61; HR MS calcd for C26H30F2N2O11S2, [M+H]+: 649.133 2, found: 649.133 4。
TM1j: 白色固体, mp 187.2~188.5 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +44.9º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.70~7.64 (m, 2H), 7.24 (t, J = 9.2 Hz, 2H), 7.19 (t, J = 9.2 Hz, 2H), 7.00 (s, 1H), 6.22 (d, J = 5.6 Hz, 1H), 5.23 (d, J = 3.7 Hz, 1H), 4.53 (s, 1H), 4.19 (t, J = 10.5 Hz, 1H), 4.09 (d, J = 3.1 Hz, 1H), 3.70 (dt, J = 15.5, 8.6 Hz, 2H), 3.61 (t, J = 9.3 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.49 (d, J = 10.5 Hz, 1H), 3.03 (s, 3H), 2.99 (s, 3H), 2.14 (d, J = 14.0 Hz, 1H), 1.91 (t, J = 13.0 Hz, 1H), 1.22 (d, J = 5.9 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.05, 149.95, 149.84, 145.30, 144.65, 129.37, 129.02, 124.47, 124.44, 96.21, 91.05, 77.56, 73.10, 66.96, 64.87, 64.53, 60.80, 57.38, 45.37, 31.92, 31.84, 21.52; HR MS calcd for C26H28F4N2O11S2, [M+H]+: 685.114 3, found: 685.113 7。
TM1k: 白色固体, mp 243.5~244.9 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +42.3º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.82 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 6.80 (s, 1H), 6.00 (d, J = 6.1 Hz, 1H), 5.04 (d, J = 4.5 Hz, 1H), 4.51 (s, 1H), 4.15~4.08 (m, 1H), 4.01 (s, 1H), 3.83 (t, J = 9.2 Hz, 1H), 3.71 (s, 1H), 3.69 (s, 1H), 3.65 (dd, J = 11.0, 4.9 Hz, 2H), 2.88 (d, J = 2.3 Hz, 6H), 2.19 (d, J = 13.8 Hz, 1H), 2.08 (t, J = 12.8 Hz, 1H), 1.26 (d, J = 5.8 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.14, 138.88, 138.40, 137.81, 137.56, 129.71, 129.32, 96.20, 91.26, 77.49, 73.30, 67.09, 64.96, 64.39, 60.69, 57.33, 45.29, 31.88, 31.58, 21.60; HR MS calcd for C26H30Cl2N2O11S2, [M+H]+: 681.074 1, found: 681.074 5。
TM1l: 白色固体, mp 170.8~172.1 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +44.9º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.86 (s, 2H), 7.78 (t, J = 8.6 Hz, 2H), 7.70 (dd, J = 13.1, 8.6 Hz, 2H), 7.58 (td, J = 7.9, 2.0 Hz, 2H), 6.71 (s, 1H), 6.14 (d, J = 6.5 Hz, 1H), 5.13 (d, J = 5.8 Hz, 1H), 5.09 (t, J = 10.7 Hz, 1H), 4.98 (s, 1H), 4.20 (d, J = 10.9 Hz, 1H), 4.08~4.00 (m, 3H), 3.84 (dd, J = 10.6, 1.8 Hz, 1H), 3.78 (t, J = 10.0 Hz, 1H), 2.92 (s, 3H), 2.88 (s, 3H), 2.03 (dd, J = 13.2, 8.6 Hz, 2H), 1.18 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 170.06, 141.88, 141.16, 134.29, 133.91, 133.05, 132.66, 131.34, 131.13, 127.42, 127.26, 126.43, 126.28, 103.91, 87.14, 78.66, 77.00, 73.41, 70.60, 61.77, 60.60, 57.67, 44.18, 31.72, 20.52; HR MS calcd for C26H30Cl2N2O11S2, [M+Na]+: 703.056 0, found: 703.055 7。
TM1m: 白色固体, mp 179.8~181.1 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +41.8º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 8.12 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.1 Hz, 2H), 7.58 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.00 (s, 1H), 6.10 (d, J = 6.5 Hz, 1H), 5.36 (d, J = 5.2 Hz, 1H), 4.58 (s, 1H), 4.28 (d, J = 5.6 Hz, 1H), 4.25 (d, J = 11.1 Hz, 1H), 3.79 (dd, J = 10.1, 5.5 Hz, 1H), 3.74 (t, J = 9.2 Hz, 2H), 3.56 (dd, J = 17.1, 5.6 Hz, 2H), 3.04 (s, 3H), 3.02 (s, 3H), 2.21 (d, J = 13.0 Hz, 1H), 2.10~2.04 (m, 1H), 1.19 (d, J = 6.0 Hz, 3H, H-21); 13C NMR (151 MHz, DMSO-d6) δ 201.31, 138.37, 137.89, 134.18, 134.10, 132.41, 131.56, 131.40, 131.35, 131.32, 127.82, 127.55, 96.16, 91.52, 76.76, 73.48, 67.12, 64.86, 64.09, 60.33, 57.46, 45.52, 32.49, 32.29, 21.60; HR MS calcd for C26H30Cl2N2O11S2, [M+Na]+: 703.056 0, found: 703.055 9。
TM1n: 白色固体, mp 255.9~257.0 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +40.5º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.76 (d, J = 3.7 Hz, 4H), 7.66 (s, 4H), 6.86 (s, 1H), 6.04 (d, J = 6.2 Hz, 1H), 5.07 (d, J = 4.7 Hz, 1H), 4.51 (s, 1H), 4.11 (t, J = 10.5 Hz, 1H), 4.00 (d, J = 5.8 Hz, 1H), 3.82 (t, J = 9.3 Hz, 1H), 3.70 (d, J = 13.2 Hz, 2H), 3.68~3.60 (m, 2H), 2.89 (s, 6H), 2.21 (d, J = 13.8 Hz, 1H), 2.08 (t, J = 12.9 Hz, 1H), 1.27 (d, J = 5.8 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.12, 139.29, 138.82, 132.25, 129.82, 129.45, 126.80, 126.52, 96.19, 91.28, 77.48, 73.29, 67.10, 64.97, 64.38, 60.70, 57.33, 45.34, 31.90, 31.58, 21.61; HR MS calcd for C26H30Br2N2O11S2, [M+Na]+: 790.955 0, found: 790.955 2。
TM1o: 白色固体, mp 167.5~169.1 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +47.6º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.92 (s, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 6.86 (s, 1H), 6.05 (d, J = 6.4 Hz, 1H), 5.11 (d, J = 5.5 Hz, 1H), 4.51 (s, 1H), 4.15~4.10 (m, 1H), 4.04~4.01 (m, 1H), 3.91 (t, J = 9.3 Hz, 1H), 3.81 (dd, J = 10.8, 2.3 Hz, 1H), 3.79~3.77 (m, 1H), 3.71 (dd, J = 11.7, 6.0 Hz, 1H), 3.66 (dd, J = 10.0, 5.8 Hz, 1H), 2.91 (d, J = 4.2 Hz, 6H), 2.13 (d, J = 13.0 Hz, 1H), 2.05 (t, J = 9.7 Hz, 1H), 1.28 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.11, 142.14, 141.64, 135.60, 135.53, 131.45, 130.03, 129.76, 126.95, 126.41, 122.33, 122.14, 96.20, 91.49, 77.62, 73.10, 67.11, 65.15, 64.42, 60.65, 57.23, 45.76, 31.96, 31.66, 21.66; HR MS calcd for C26H30Br2N2O11S2, [M+Na]+: 790.955 0, found: 790.954 6。
TM1p: 白色固体, mp 180.5~181.7 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +41.7º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 8.19 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.56~7.48 (m, 3H), 7.43 (t, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.12 (d, J = 6.6 Hz, 1H), 5.45 (d, J = 4.4 Hz, 1H), 4.62 (s, 1H), 4.31 (dd, J = 23.6, 8.6 Hz, 2H), 3.82 (dd, J = 16.5, 7.5 Hz, 2H), 3.78 (dd, J = 8.9, 6.1 Hz, 1H), 3.68 (d, J = 11.5 Hz, 1H), 3.60 (d, J = 9.1 Hz, 1H), 3.05 (s, 3H), 3.03 (s, 3H), 2.28~2.18 (m, 2H), 1.22 (d, J = 5.9 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.44, 140.23, 139.74, 136.00, 135.97, 134.10, 134.03, 131.43, 131.21, 128.37, 128.03, 119.73, 119.67, 96.17, 91.55, 76.84, 73.47, 67.16, 64.96, 64.21, 60.40, 57.51, 45.54, 32.61, 32.40, 21.59; HR MS calcd for C26H30Br2N2O11S2, [M+Na]+: 790.955 0, found: 790.954 3。
TM1q: 白色固体, mp 178.5~180.1 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +42.8º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 8.04 (d, J = 8.2 Hz, 2H), 7.95 (t, J = 9.3 Hz, 4H), 7.84 (d, J = 8.2 Hz, 2H), 6.84 (s, 1H), 6.10 (d, J = 6.6 Hz, 1H), 5.07 (d, J = 5.4 Hz, 1H), 4.50 (s, 1H), 4.14~4.09 (m, 1H), 4.06~4.03 (m, 1H), 3.85 (t, J = 9.3 Hz, 1H), 3.80~3.75 (m, 2H), 3.69 (dd, J = 10.7, 5.4 Hz, 1H), 3.66~3.61 (m, 1H), 2.93 (d, J = 8.7 Hz, 6H), 2.05 (d, J = 13.1 Hz, 1H), 2.01~1.96 (m, 1H), 1.24 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 200.88, 143.76, 143.27, 128.74, 128.47, 126.35, 96.17, 91.27, 77.60, 73.17, 67.02, 64.95, 64.41, 60.78, 57.39, 45.51, 31.92, 31.69, 21.52; HR MS calcd for C28H30F6N2O11S2, [M+H]+: 749.126 8, found: 749.127 0。
TM1r: 白色固体, mp 255.5~256.7 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +43.5º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.83 (d, J = 7.5 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.65~7.59 (m, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 6.83 (s, 1H), 6.01 (d, J = 6.3 Hz, 1H), 5.07 (d, J = 4.3 Hz, 1H), 4.52 (s, 1H), 4.15 (t, J = 10.5 Hz, 1H), 4.07~4.03 (m, 1H), 3.84 (t, J = 9.2 Hz, 1H), 3.71 (t, J = 11.7 Hz, 4H), 2.89 (s, 6H), 2.15 (d, J = 12.7 Hz, 1H), 2.13~2.06 (m, 1H), 1.26 (d, J = 5.9 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.14, 140.21, 139.79, 132.71, 132.67, 129.23, 129.16, 127.71, 127.39, 96.21, 91.43, 77.59, 73.50, 67.15, 64.96, 64.38, 60.71, 57.49, 45.65, 31.83, 31.49, 21.62; HR MS calcd for C26H32N2O11S2, [M+H]+: 613.152 0, found: 613.152 1。
TM1s: 白色固体, mp 213.5~215.7 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +42.3º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 8.38 (d, J = 8.8 Hz, 2H), 8.30 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H), 6.14 (d, J = 6.5 Hz, 1H), 5.07 (d, J = 5.4 Hz, 1H), 4.50 (s, 1H), 4.08 (dd, J = 11.1, 9.9 Hz, 1H), 4.05~4.02 (m, 1H), 3.85 (d, J = 9.3 Hz, 1H), 3.83~3.81 (m, 1H), 3.74 (dd, J = 10.8, 2.3 Hz, 1H), 3.68 (dd, J = 10.0, 7.2 Hz, 1H), 3.63 (dd, J = 9.5, 4.7 Hz, 1H), 2.96 (s, 3H), 2.92 (s, 3H), 2.07 (d, J = 11.4 Hz, 1H), 2.04~2.00 (m, 1H), 1.25 (d, J = 6.1 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 200.88, 160.42, 160.10, 158.72, 158.40, 135.74, 135.43, 113.74, 113.58, 96.12, 91.44, 76.80, 73.66, 67.06, 64.70, 64.06, 60.84, 57.58, 45.63, 31.81, 31.73, 21.64; HR MS calcd for C26H30N4O15S2, [M+H]+: 703.122 2, found: 703.122 7。
TM1t: 白色固体, mp 179.6~181.5 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +37.7º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 8.21~8.18 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.93~7.90 (m, 2H), 7.83 (d, J = 7.9 Hz, 2H), 7.82~7.78 (m, 2H), 7.05 (s, 1H), 6.21 (d, J = 6.6 Hz, 1H), 5.47 (d, J = 4.6 Hz, 1H), 4.61 (s, 1H), 4.27~4.23 (m, 1H), 4.10 (d, J = 6.4 Hz, 1H), 3.97 (t, J = 8.9 Hz, 1H), 3.85 (dd, J = 11.4, 2.3 Hz, 1H), 3.80~3.75 (m, 3H), 3.01 (s, 3H), 3.00 (s, 3H), 2.18 (d, J = 12.5 Hz, 1H), 2.10 (t, J = 10.0 Hz, 1H), 1.25 (d, J = 6.0 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.32, 148.48, 148.25, 134.51, 134.38, 132.41, 132.31, 132.07, 131.76, 130.65, 130.37, 124.26, 124.18, 96.17, 91.49, 77.10, 73.23, 67.15, 65.06, 64.22, 60.86, 57.42, 45.52, 32.23, 32.07, 21.62; HR MS calcd for C26H30N4O15S2, [M+H]+: 703.122 2, found: 703.122 1。
TM1u: 白色固体, mp 179.7~181.0 ℃, [α]$ {}_{\mathrm{D}}^{21} $ +38.9º (c 0.2, DMSO)。1H NMR (600 MHz, DMSO-d6) δ 7.91 (d, J = 4.8 Hz, 1H), 7.87 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 2.6 Hz, 1H), 7.19~7.16 (m, 1H), 7.10 (t, J = 3.9 Hz, 1H), 6.88 (s, 1H), 6.04 (d, J = 6.2 Hz, 1H), 5.16 (s, 1H), 4.54 (s, 1H), 4.15 (t, J = 10.5 Hz, 1H), 4.02 (d, J = 5.0 Hz, 1H), 3.84 (t, J = 8.6 Hz, 1H), 3.73 (d, J = 9.2 Hz, 1H), 3.67 (t, J = 9.4 Hz, 3H), 2.94 (s, 3H), 2.90 (s, 3H), 2.29~2.18 (m, 2H), 1.27 (d, J = 5.8 Hz, 3H); 13C NMR (151 MHz, DMSO-d6) δ 201.19, 132.62, 132.32, 127.96, 127.85, 96.20, 91.47, 77.08, 73.45, 67.20, 64.93, 64.38, 60.97, 57.74, 45.68, 31.84, 31.62, 21.66; HR MS calcd for C22H28N2O11S4, [M+Na]+: 647.046 8, found: 647.046 2。
2 化合物的生物活性测试
2.1 抗海伦脑炎微孢子虫增殖活性
测试工作由西南大学资源昆虫高效养殖与利用全国重点实验室主持完成。化合物的细胞毒性使用CCK-8试剂盒(重庆葆光生物技术有限公司) 进行分析, 相关结果见表 2。与DMSO对照组比较, 细胞存活率为100% 时视为无毒性, 细胞存活率在80%以上时视为低毒性, 选取相应化合物表现为低毒性的浓度作为安全浓度用作后续实验。
化合物的抗微孢子虫增殖活性利用海伦脑炎微孢子虫感染的RK13细胞进行评估[28], 相关结果见表 3。通过荧光增白剂28 (fluorescent brightener 28) 对微孢子虫的几丁质外壳进行染色, 在荧光显微镜下观察微孢子虫形成的寄生囊, 对每个孔进行拍照, 统计视野中细胞内微孢子虫寄生囊数量。视野中寄生囊数量相对于同批次对照组中显著减少的测试组即可认为该化合物对微孢子虫增殖具有抑制效果, 而视野中寄生囊数量相对于同批次对照组中显著增加的测试组即可认为该化合物对微孢子虫增殖具有促进效果。相关结果见图 4、5。
2.2 抗人致病菌活性
按照美国国家临床实验室标准化委员会(NCCLS) 推荐的微量稀释法, 采用本实验室常用的测试方法[29-31], 测定了目标分子对金葡菌ATCC25129及ATCC14125、藤黄微球菌、大肠杆菌ATCC25922、鲍曼不动杆菌ATCC19606、沙门氏菌ATCC13076、铜绿假单胞菌ATCC27853的MIC的作用, 相关结果见表 4。
2.3 统计学分析
GraphPad Prism 6.0.1软件绘图, 组间比较采用student's t-test进行检验分析。数据以平均值±标准差(mean ± SD) 表示, P < 0.05表示结果在统计学上具有显著差异。
致谢: 西南大学药学院中医药学院徐兴然副教授、本学院老师分别在抗人致病菌活性、核磁共振和高分辨质谱测试中提供了支持。
作者贡献: 李永清负责化合物的合成与部分生物活性测试、论文的撰写和校对; 范莉负责文本修改、校对; 王巍、朱洪林负责细胞毒性和微孢子虫活性测试; 韦俊宏负责生物活性测试指导以及文本修改、校对; 杨大成负责课题规划, 指导化合物的设计及合成, 文本的修改、校对。
利益冲突: 无利益冲突。
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  • 中央高校基本科研业务费专项资金(SWU-KR22009)
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doi: 10.16438/j.0513-4870.2023-1284
  • 接收时间：2023-11-14
  • 首发时间：2025-11-27
  • 出版时间：2024-05-12
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  • 收稿日期：2023-11-14
  • 修回日期：2024-02-03
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资源昆虫高效养殖与利用全国重点实验室开放课题(SKLSGB-ORP202203)
中央高校基本科研业务费专项资金(SWU-KR22009)
作者信息
    1.西南大学化学化工学院, 重庆市高校应用化学重点实验室, 重庆 400715
    2.西南大学, 资源昆虫高效养殖与利用全国重点实验室, 重庆 400715

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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
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