药学学报

Compd.	Yield/%	mp/℃	HR-MS m/z [M+H]⁺ or [M+Na]⁺ Calcd. (Found)	¹H NMR (400 MHz, CDCl₃) δ
7a	89.5	140-141	C₁₅H₁₃ClNO₂S₂ 338.007 6 (338.007 7)	8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.81-6.77 (m, 2H), 4.46 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H), 3.77 (s, 3H)
7b	90.8	148-149	C₁₄H₁₀ClFNOS₂ 325.987 6 (325.986 9)	8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.13-7.07 (m, 2H), 6.98-6.91 (m, 2H), 4.48 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H)
7c	93.5	176-177	C₁₆H₁₃ClNO₃S₂ 366.002 5 (366.002 0)	8.01 (d, J = 8.8 Hz, 1H), 7.95-7.89 (m, 3H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.22-7.17 (m, 2H), 4.56 (d, J = 13.1 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 3.90 (s, 3H)
7d	92.5	186.5-188.0	C₁₅H₁₀ClN₂OS₂ 332.992 3 (332.991 5)	8.01 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.58-7.51 (m, 3H), 7.24-7.19 (m, 2H), 4.55 (d, J = 13.2 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H)
7e	90.9	171-172	C₁₄H₁₀BrClNOS₂ 385.907 5 (385.907 4)	8.00 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.02-6.97 (m, 2H), 4.46 (d, J = 13.3 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H)
8a	90.6	187.5-189.0	C₁₅H₁₂ClNNaO₃S₂ 375.983 4 (375.983 0)	8.16 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.18-7.14 (m, 2H), 6.82-6.77 (m, 2H), 4.69 (s, 2H), 3.77 (s, 3H)
8b	89.7	154-155	C₁₄H₁₀ClFNO₂S₂ 341.982 5 (341.981 6)	8.16 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.28-7.21 (m, 2H), 7.01-6.95 (m, 2H), 4.72 (s, 2H)
8c	91.4	200-201	C₁₆H₁₃ClNO₄S₂ 381.996 9 (381.996 7)	8.17 (d, J = 8.8 Hz, 1H), 7.97-7.92 (m, 3H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.36-7.32 (m, 2H), 4.80 (s, 2H), 3.90 (s, 3H)
8d	83.3	201-202	C₁₅H₁₀ClN₂O₂S₂ 348.987 2 (348.986 5)	8.16 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.66-7.58 (m, 3H), 7.44-7.40 (m, 2H), 4.80 (s, 2H)
8e	94.0	190-191	C₁₄H₁₀BrClNO₂S₂ 401.902 4 (401.902 0)	8.16 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.9, 2.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.16-7.11 (m, 2H), 4.70 (s, 2H)
9a	93.3	160.5-162.0	C₁₆H₁₆ClN₂O₂S 335.062 1 (335.061 6)	7.82 (s, 1H), 7.35 (dd, J = 8.7, 1.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.97-6.90 (m, 2H), 6.79-6.73 (m, 2H), 4.59 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 3.77 (s, 3H), 3.48 (s, 3H)
9b	82.7	168-169	C₁₅H₁₃ClFN₂OS 323.042 1 (323.042 1)	7.86 (s, 1H), 7.39 (dd, J = 8.7, 1.3 Hz, 1H), 7.29-7.24 (m, 1H), 7.09-7.02 (m, 2H), 6.98-6.91 (m, 2H), 4.66 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H), 3.56 (s, 3H)
9c	80.0	176.5-177.5	C₁₇H₁₆ClN₂O₃S 363.057 0 (363.056 1)	7.95-7.89 (m, 2H), 7.82 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.16-7.12 (m, 2H), 4.71 (d, J = 12.9 Hz, 1H), 4.55 (d, J = 13.0 Hz, 1H), 3.91 (s, 3H), 3.50 (s, 3H)
10a	93.1	156.5-158.0	C₁₆H₁₆ClN₂O₃S 351.056 0 (351.055 7)	7.91 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.8, 1.5 Hz, 1H), 7.31-7.23 (m, 1H), 7.12-7.07 (m, J = 8.5 Hz, 2H), 6.81-6.76 (m, J = 8.6 Hz, 2H), 4.73 (s, 2H), 3.77 (s, 3H), 3.61 (s, 3H)
10b	90.7	150-151	C₁₅H₁₃ClFN₂O₂S 339.037 0 (339.036 3)	7.89 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.8, 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.01-6.94 (m, 2H), 4.80 (s, 2H), 3.71 (s, 3H)
10c	91.4	176.5-178.0	C₁₇H₁₆ClN₂O₄S 379.051 9 (379.051 3)	7.98-7.93 (m, 2H), 7.89 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35-7.28 (m, 3H), 4.88 (s, 2H), 3.90 (s, 3H), 3.68 (s, 3H)

Compd.	Yield/%	mp/℃	HR-MS m/z [M+H]⁺ or [M+Na]⁺ Calcd. (Found)	¹H NMR (400 MHz, CDCl₃) δ
7a	89.5	140-141	C₁₅H₁₃ClNO₂S₂ 338.007 6 (338.007 7)	8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.81-6.77 (m, 2H), 4.46 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H), 3.77 (s, 3H)
7b	90.8	148-149	C₁₄H₁₀ClFNOS₂ 325.987 6 (325.986 9)	8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.13-7.07 (m, 2H), 6.98-6.91 (m, 2H), 4.48 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H)
7c	93.5	176-177	C₁₆H₁₃ClNO₃S₂ 366.002 5 (366.002 0)	8.01 (d, J = 8.8 Hz, 1H), 7.95-7.89 (m, 3H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.22-7.17 (m, 2H), 4.56 (d, J = 13.1 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 3.90 (s, 3H)
7d	92.5	186.5-188.0	C₁₅H₁₀ClN₂OS₂ 332.992 3 (332.991 5)	8.01 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.58-7.51 (m, 3H), 7.24-7.19 (m, 2H), 4.55 (d, J = 13.2 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H)
7e	90.9	171-172	C₁₄H₁₀BrClNOS₂ 385.907 5 (385.907 4)	8.00 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.02-6.97 (m, 2H), 4.46 (d, J = 13.3 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H)
8a	90.6	187.5-189.0	C₁₅H₁₂ClNNaO₃S₂ 375.983 4 (375.983 0)	8.16 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.18-7.14 (m, 2H), 6.82-6.77 (m, 2H), 4.69 (s, 2H), 3.77 (s, 3H)
8b	89.7	154-155	C₁₄H₁₀ClFNO₂S₂ 341.982 5 (341.981 6)	8.16 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.28-7.21 (m, 2H), 7.01-6.95 (m, 2H), 4.72 (s, 2H)
8c	91.4	200-201	C₁₆H₁₃ClNO₄S₂ 381.996 9 (381.996 7)	8.17 (d, J = 8.8 Hz, 1H), 7.97-7.92 (m, 3H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.36-7.32 (m, 2H), 4.80 (s, 2H), 3.90 (s, 3H)
8d	83.3	201-202	C₁₅H₁₀ClN₂O₂S₂ 348.987 2 (348.986 5)	8.16 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.66-7.58 (m, 3H), 7.44-7.40 (m, 2H), 4.80 (s, 2H)
8e	94.0	190-191	C₁₄H₁₀BrClNO₂S₂ 401.902 4 (401.902 0)	8.16 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.9, 2.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.16-7.11 (m, 2H), 4.70 (s, 2H)
9a	93.3	160.5-162.0	C₁₆H₁₆ClN₂O₂S 335.062 1 (335.061 6)	7.82 (s, 1H), 7.35 (dd, J = 8.7, 1.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.97-6.90 (m, 2H), 6.79-6.73 (m, 2H), 4.59 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 3.77 (s, 3H), 3.48 (s, 3H)
9b	82.7	168-169	C₁₅H₁₃ClFN₂OS 323.042 1 (323.042 1)	7.86 (s, 1H), 7.39 (dd, J = 8.7, 1.3 Hz, 1H), 7.29-7.24 (m, 1H), 7.09-7.02 (m, 2H), 6.98-6.91 (m, 2H), 4.66 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H), 3.56 (s, 3H)
9c	80.0	176.5-177.5	C₁₇H₁₆ClN₂O₃S 363.057 0 (363.056 1)	7.95-7.89 (m, 2H), 7.82 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.16-7.12 (m, 2H), 4.71 (d, J = 12.9 Hz, 1H), 4.55 (d, J = 13.0 Hz, 1H), 3.91 (s, 3H), 3.50 (s, 3H)
10a	93.1	156.5-158.0	C₁₆H₁₆ClN₂O₃S 351.056 0 (351.055 7)	7.91 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.8, 1.5 Hz, 1H), 7.31-7.23 (m, 1H), 7.12-7.07 (m, J = 8.5 Hz, 2H), 6.81-6.76 (m, J = 8.6 Hz, 2H), 4.73 (s, 2H), 3.77 (s, 3H), 3.61 (s, 3H)
10b	90.7	150-151	C₁₅H₁₃ClFN₂O₂S 339.037 0 (339.036 3)	7.89 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.8, 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.01-6.94 (m, 2H), 4.80 (s, 2H), 3.71 (s, 3H)
10c	91.4	176.5-178.0	C₁₇H₁₆ClN₂O₄S 379.051 9 (379.051 3)	7.98-7.93 (m, 2H), 7.89 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35-7.28 (m, 3H), 4.88 (s, 2H), 3.90 (s, 3H), 3.68 (s, 3H)

Compd.	R	% inhibition at 50 μmol·L^-1		IC₅₀/μmol·L^-1
7a	CH₃O	33	28	43		> 100	> 100	> 100
7b	F	57	45	39	76.8	> 100	> 100
7c	CH₃OCO	51	39	34	85.1	> 100	> 100
7d	CN	45	38	41	> 100	> 100	> 100
7e	Br	43	33	26	> 100	> 100	> 100
8a	CH₃O	36	31	35	> 100	> 100	> 100
8b	F	56	45	36	80.7	> 100	> 100
8c	CH₃OCO	53	26	33	82.3	> 100	> 100
8d	CN	43	33	36	> 100	> 100	> 100
8e	Br	44	34	33	> 100	> 100	> 100
9a	CH₃O	33	71	38	> 100	21.2	> 100
9b	F	20	84	27	> 100	10.6	> 100
9c	CH₃OCO	30	87	39	> 100	5.2	> 100
10a	CH₃O	20	90	31	> 100	7.7	> 100
10b	F	68	87	72	31.9	3.9	21.2
10c	CH₃OCO	20	96	35	> 100	2.8	> 100
Tenovin-6	-	66	84	38	37.5	15.3	> 100
AGK2	-	35	100	58	> 100	1.56	52.8

Compd.	R	% inhibition at 50 μmol·L^-1		IC₅₀/μmol·L^-1
7a	CH₃O	33	28	43		> 100	> 100	> 100
7b	F	57	45	39	76.8	> 100	> 100
7c	CH₃OCO	51	39	34	85.1	> 100	> 100
7d	CN	45	38	41	> 100	> 100	> 100
7e	Br	43	33	26	> 100	> 100	> 100
8a	CH₃O	36	31	35	> 100	> 100	> 100
8b	F	56	45	36	80.7	> 100	> 100
8c	CH₃OCO	53	26	33	82.3	> 100	> 100
8d	CN	43	33	36	> 100	> 100	> 100
8e	Br	44	34	33	> 100	> 100	> 100
9a	CH₃O	33	71	38	> 100	21.2	> 100
9b	F	20	84	27	> 100	10.6	> 100
9c	CH₃OCO	30	87	39	> 100	5.2	> 100
10a	CH₃O	20	90	31	> 100	7.7	> 100
10b	F	68	87	72	31.9	3.9	21.2
10c	CH₃OCO	20	96	35	> 100	2.8	> 100
Tenovin-6	-	66	84	38	37.5	15.3	> 100
AGK2	-	35	100	58	> 100	1.56	52.8

苯并咪唑和苯并噻唑类衍生物的合成及其sirtuins抑制活性评价

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周玉美 ¹^,²^,³ , 崔华清 ³ , 俞晓明 ³ , 张首国 ² , 彭涛 ² , 王刚 ² , 温晓雪 ² , 孙云波 ² , 刘曙晨 ² , 王林 ¹^,²^,^*

药学学报 | 研究论文 2017,52(5): 773-778

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药学学报 | 研究论文 2017, 52(5): 773-778

苯并咪唑和苯并噻唑类衍生物的合成及其sirtuins抑制活性评价

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周玉美¹^,²^,³, 崔华清³, 俞晓明³, 张首国², 彭涛², 王刚², 温晓雪², 孙云波², 刘曙晨², 王林¹^,²^,^*

作者信息

1.北京工业大学生命科学与生物工程学院, 北京 100124

2.军事医学科学院放射与辐射医学研究所, 北京 100850

3.中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

* 王林, Tel:86-10-66932239, E-mail:wanglin07@sina.com

Synthesis of benzimidazole and benzothiazole derivatives as a sirtuins 2 inhibitor

Yu-mei ZHOU¹^,²^,³, Hua-qing CUI³, Xiao-ming YU³, Shou-guo ZHANG², Tao PENG², Gang WANG², Xiao-xue WEN², Yun-bo SUN², Shu-chen LIU², Lin WANG¹^,²^,^*

Affiliations

1. College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China

2. Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China

3. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2017-05-12 doi: 10.16438/j.0513-4870.2017-0180

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摘要

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设计合成新型结构sirtuins抑制剂并评价其对SIRT1~SIRT3的抑制活性。基于已报道的sirtuins抑制剂结构和药效团特征，设计了一系列苯并咪唑和苯并噻唑类化合物。以乙基黄原酸钾为起始原料，经3步反应合成了16个未见文献报道的目标化合物，目标化合物的结构经¹H NMR、HR-MS确证。对目标化合物进行SIRT1~SIRT3的抑制活性评价，其中苯并咪唑类化合物对SIRT2具有选择性的抑制活性。

关键词

设计合成 / 苯并咪唑 / 苯并噻唑 / sirtuins抑制剂

Abstract

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A series of novel benzimidazole and benzothiazole derivatives were designed and synthesized as inhibitors of SIRT1-SIRT3. The target compounds were synthesized from potassium O-ethyldithiocarbonate through a three-step route. The structures of the obtained compounds were elucidated by ¹H NMR and HR-MS. Of all compounds, six showed potent SIRT2-inhibitory activities with IC₅₀ values ranging from 2.8 to 21.2 μmol·L^-1. Among them, compound 10c displayed the most potent SIRT2-inhibitory activities (IC₅₀ = 2.8 μmol·L^-1), with more than 35-fold selectivity over SIRT1 and SIRT3 (IC₅₀ > 100 μmol·L^-1).

Key words

design and synthesis / benzimidazole / benzothiazole / sirtuins inhibitor

引用本文

周玉美, 崔华清, 俞晓明, 张首国, 彭涛, 王刚, 温晓雪, 孙云波, 刘曙晨, 王林. 苯并咪唑和苯并噻唑类衍生物的合成及其sirtuins抑制活性评价. 药学学报, 2017 , 52 (5) : 773 -778 . DOI: 10.16438/j.0513-4870.2017-0180

Yu-mei ZHOU, Hua-qing CUI, Xiao-ming YU, Shou-guo ZHANG, Tao PENG, Gang WANG, Xiao-xue WEN, Yun-bo SUN, Shu-chen LIU, Lin WANG. Synthesis of benzimidazole and benzothiazole derivatives as a sirtuins 2 inhibitor[J]. Acta Pharmaceutica Sinica, 2017 , 52 (5) : 773 -778 . DOI: 10.16438/j.0513-4870.2017-0180

正文

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Sirtuins家族是一类依赖NAD⁺的组蛋白去乙酰化酶, 属于组蛋白去乙酰化酶的第Ⅲ亚族^[1]。人类sirtuins家族有7个成员: SIRT1~SIRT7, 其中: SIRT1和SIRT2的去乙酰化酶活性最强, 生理功能最为重要。已有研究表明, SIRT1和SIRT2在多种生理和病理过程中发挥重要作用^[2]。

在过去的几年中, sirtuins已成为热门治疗靶点, 大量文献报道, 通过抑制sirtuins可以治疗包括2型糖尿病、心血管疾病、神经退行性疾病、炎症和肿瘤等多种疾病。但到目前为止, 高活性小分子抑制剂仍较少, 部分结构见图 1^{[3, 4]}。其中, 化合物1、cambinol、和tenovin-6是非选择性sirtuins抑制剂, EX-527和AGK2、AK-1是已报道的活性较好的小分子选择性抑制剂, 然而在动物实验中, Tenovin-6是抗肿瘤活性最显著的化合物^{[5, 6]}。

本文设计了一系列新结构类型的苯并咪唑和苯并噻唑衍生物, 期望能够获得高活性的sirtuins抑制剂。目标化合物的合成见合成路线1^{[7, 8]}:分别以2-氨基-5-氯苯硫酚或N-甲基-4-氯-2-氨基苯胺与乙基黄原酸钾为起始原料, 在微波条件下反应生成中间体3、4, 再经取代反应得到5a~5e和6a~6c, 然后经间氯过氧苯甲酸 (m-CPBA) 在适宜条件下氧化得到16个目标化合物7a~7e、8a~8e与9a~9c、10a~10c。

结果与讨论

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1 目标化合物的结构确证

合成了16个目标化合物, 结构均经¹H NMR和HR-MS确证且未见文献报道, 其理化性质和谱学数据见表 1。

2 目标化合物的SIRT1~SIRT3抑制活性及初步结果讨论

以Tenovin-6和AGK2为阳性对照, 测定了16个目标化合物对SIRT1~SIRT3的抑制活性, 结果显示, 目标化合物对SIRT1~SIRT3均有一定抑制作用 (表 2)。

对于苯并噻唑类衍生物 (7a~7e、8a~8e):当R为氟和甲氧羰基时, 化合物7b、7c和8b、8c对SIRT1抑制活性高于SIRT2和SIRT3, 其IC₅₀值分别为76.8、85.1和80.7、82.3 μmol·L^-1; 当R相同时, 苯并噻唑的2-位为砜和亚砜的化合物对SIRT1~SIRT3的抑制活性没有明显区别。

对于苯并咪唑类衍生物 (9a~9c、10a~10c):所有化合物对SIRT2抑制活性高于SIRT1和SIRT3, 有一定选择性。其中化合物10c对SIRT2的抑制活性最为显著, IC₅₀值为2.8 μmol·L^-1, 活性高于阳性对照Tenovin-6;化合物9a~9c的活性结果表明, 苯环上取代基R对活性的影响如下: CH₃OCO > F > CH₃O, 提示取代基R的电性效应及体积大小均可能影响抑酶活性, 化合物10a~10c呈现相似的构效关系; 当R相同时, 苯并咪唑环的2-位为砜的化合物比对应的亚砜化合物活性略高。

为预测苯并咪唑类新化合物的结合模式, 将活性最好的化合物10c对接到SIRT2的晶体结构中 (PDB code: 3ZGV, X-ray resolution = 2.30 Å)^[9], 采用文献报道的方法进行计算。依据计算得到的结合能和结合方式的合理性, 选择最优结合模式。化合物10c与SIRT2的结合方式见图 2。化合物10c苯并咪唑环上的氮与Arg97形成氢键, 同时苯并咪唑环与Tyr104形成π-π相互作用; 砜基的两个氧原子均与Ser263、Thr262和Ala85形成氢键; 亚砜因为少一个氧原子, 减少了氢键的形成, 导致抑制活性没有对应的含砜化合物活性高; 其他的氢键 (3.5 Å内) 包括与His187、Asn286和Thr262相互作用。上述氢键, 与SIRT2和底物ADPr复合物对接形成的氢键的结合模式是一致的^[9], 与其他的SIRT2抑制剂如化合物1、salermide和NF-675报道的结合模式亦相似^{[6, 10]}。

3 小结

基于已报道的sirtuins抑制剂结构和药效团特征, 设计了一系列结构新颖的苯并咪唑和苯并噻唑类化合物, 评价了它们对SIRT1~SIRT3的抑制活性, 获得了6个有显著SIRT2选择性抑制活性的新化合物。初步探讨了目标化合物抑制SIRT1~SIRT3活性的构效关系, 并通过分子对接研究了苯并咪唑类化合物10c与SIRT2可能的结合模式, 为此类化合物的进一步结构优化提供了参考。

实验部分

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熔点采用MP-J3熔点测定仪测定, 温度未校正; ¹H NMR谱采用Varian 400 MHz Plus核磁共振仪测定 (TMS为内标); HR-MS采用ThermoExactivePlus质谱仪测定。所用试剂均为市售化学纯或分析纯。

1 化学合成

1.1 中间体3和4的合成通法 (以化合物3为例)

2-巯基-6-氯苯并噻唑 (3) 的合成 将310 mg (1.94 mmol) 2-氨基-5-氯苯硫酚和790 mg (4.93 mmol) 乙基黄原酸钾置于10 mL微波管中, 加入3 mL DMF, 搅拌至全溶, 放入微波中, 在150 psi压力、45 W、155 ℃反应5 min。停止反应, 用30 mL水稀释, 用醋酸调pH至3~4, 析出灰色固体, 抽滤, 得到灰色固体 (3) 350 mg。用乙醇重结晶, 得到白色絮状固体 (3) 290 mg, 收率74%; mp 231~232 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 13.86 (s, 1H), 7.86 (s, 1H), 7.44 (d, J= 8.6 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H)。通法合成4。

5-氯-2-巯基-N-甲基苯并咪唑 (4) 白色絮状固体; 收率66.4%; mp 239.5~241 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.87 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.19 (s, 1H), 3.64 (s, 3H)。

1.2 中间体5a~5e和6a~6c的合成通法 (以化合物5a为例)

6-氯-2-[(4-甲氧基苄基) 硫基]苯并[d]噻唑 (5a) 的合成 将400 mg (2.0 mmol) 化合物3置于反应瓶中, 加入15 mL CH₂Cl₂、1 mL DMF, 加入0.3 mL (2.1 mmol) 4-甲氧基氯苄, 缓慢滴加0.39 mL (2.8 mmol) Et₃N, 室温反应3 h。停止反应, 蒸出CH₂Cl₂, 加10 mL水, 析出固体, 抽滤, 得到浅褐色固体581 mg, 乙醇重结晶, 得到白色晶体 (5a) 430 mg, 收率67%; mp 103~104 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.17 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.7, 2.0 Hz, 1H), 7.45~7.39 (m, 2H), 6.93~6.87 (m, 2H), 4.60 (s, 2H), 3.73 (s, 3H)。通法合成5b~5e, 以4代替3通法合成6a~6c。

6-氯-2-[(4-氟基苄基) 硫基]苯并[d]噻唑 (5b) 白色晶体; 收率54.8%; mp 84~85 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (d, J = 8.6 Hz, 1H), 7.73 (d, J= 1.4 Hz, 1H), 7.45~7.36 (m, 3H), 7.05~6.97 (m, 2H), 4.57 (s, 2H)。

6-氯-2-[(4-甲氧羰基苄基) 硫基]苯并[d]噻唑 (5c) 白色晶体; 收率80%; mp 121~122 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.03~7.97 (m, 2H), 7.79 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.54~7.50 (m, 2H), 7.39 (dd, J= 8.7, 2.0 Hz, 1H), 4.63 (s, 1H), 3.90 (s, 3H)。

6-氯-2-[(4-氰基苄基) 硫基]苯并[d]噻唑 (5d) 白色絮状固体; 收率84%; mp 125~126 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.64~7.55 (m, 4H), 7.40 (dd, J = 8.7, 2.0 Hz, 1H), 4.63 (s, 2H)。

6-氯-2-[(4-溴基苄基) 硫基]苯并[d]噻唑 (5e) 白色晶体; 收率77%; mp 95~96 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.47~7.43 (m, 2H), 7.39 (dd, J = 8.7, 2.0 Hz, 1H), 7.35~7.31 (m, 2H), 4.54 (s, 2H)。

5-氯-2-[(4-甲氧基苄基) 硫基]-1-甲基-1H-苯并[d]咪唑 (6a) 白色晶体; 收率89%; mp 117~118 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.75 (s, 1H), 7.37~7.32 (m, 2H), 7.22 (d, J= 8.7 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.86~6.81 (m, 2H), 4.63 (s, 2H), 3.78 (s, 3H), 3.61 (s, 3H)。

5-氯-2-[(4-氟基苄基) 硫基]-1-甲基-1H-苯并[d]咪唑 (6b) 白色晶体; 收率79%; mp 85~86 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.81 (s, 1H), 7.47~7.39 (m, 2H), 7.30~7.24 (m, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.03~6.95 (m, 2H), 4.74 (s, 2H), 3.66 (s, 3H)。

5-氯-2-[(4-甲氧羰基苄基) 硫基]-1-甲基-1H-苯并[d]咪唑 (6c) 白色絮状固体; 收率82%; mp 122~123 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.00~7.94 (m, 2H), 7.79 (s, 1H), 7.55~7.50 (m, 2H), 7.27~7.25 (m, 1H), 7.18 (d, J = 8.6 Hz, 1H), 4.77 (s, 2H), 3.90 (s, 3H), 3.64 (s, 3H)。

1.3 目标化合物7a~7e和9a~9c的合成通法 (以化合物7a为例)

6-氯-2-[(4-甲氧基苄基) 亚磺酰基]苯并[d]噻唑 (7a) 的合成 冰浴条件下, 将200 mg (0.62 mmol) 5a置于氩气保护的单口瓶中, 加入10 mL CH₂Cl₂, 搅拌10 min后, 加85%的m-CPBA 126 mg (0.62 mmol)。冰浴条件下反应30 min, 反应完全 (TLC跟踪)。用饱和碳酸氢钠溶液 (8 mL)、饱和氯化钠溶液 (8 mL) 洗涤, 无水硫酸钠干燥, 过滤, 浓缩, 柱色谱 (石油醚-乙酸乙酯, 体积比5:1) 纯化, 得白色晶体 (7a) 188 mg, 收率90%。通法合成目标物7b~7e和9a~9c。

1.4 目标化合物8a~8e和10a~10c的合成通法 (以化合物8a为例)

6-氯-2-[(4-甲氧基苄基) 磺酰基]苯并[d]噻唑 (8a) 的合成 将310 mg (0.963 mmol) 5a置于氩气保护的单口瓶中, 加入20 mL二氯甲烷, 加85%的m-CPBA 782 mg (3.853 mmol)。室温搅拌反应1 h, 反应完全。用饱和碳酸氢钠溶液 (12 mL×3)、饱和氯化钠溶液 (12 mL) 洗涤, 无水硫酸镁干燥, 过滤, 浓缩, 柱色谱 (石油醚-乙酸乙酯, 体积比20:1) 纯化, 得白色晶体 (8a) 309 mg, 收率90.6%。通法合成目标物8b~8e和10a~10c。

2 SIRT1~SIRT3体外抑制活性实验

参照文献^[11]方法, 采用大肠杆菌表达纯化的SIRT1、SIRT2和SIRT3重组蛋白用于活性检测。底物肽段为: Ac-Arg-His-Lys-[Lys-(Ac)]-AMC。催化反应在60 μL的反应液中进行 (75 μmol·L^-1 NAD⁺、25 μmol·L^-1底物肽段、SIRT蛋白和不同浓度的待测化合物), 37 ℃放置1 h后向反应溶液中加入60 μL的样品处理液 (50 mmol·L^-1 Tris-HCl, pH 8.0、100 mmol·L^-1 NaCl、60 000 unit Trypsin和4 mmol·L^-1 nicotinamide), 37 ℃放置20 min。将酶标仪设置为激发光355 nm, 吸收光为460 nm, 测定吸收强度。通过计算获得小分子化合物对于各个酶的抑制活性。

基金

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国家自然科学基金资助项目(81273431)

参考文献

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Sumit SM, Michele S, Smitha S, et al. Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors [J]. J Med Chem, 2014, 57, 3283-3294.

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Yeong KY, Mohamed AA, Ang CW, et al. Benzimidazoles as new scaffold of sirtuin inhibitors: green synthesis, in vitro studies, molecular docking analysis and evaluation of their anti-cancer properties [J]. Eur J Med Chem, 2014, 83: 448-454.

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2017年第52卷第5期

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doi: 10.16438/j.0513-4870.2017-0180

接收时间：2017-02-28
首发时间：2026-01-14
出版时间：2017-05-12

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收稿日期：2017-02-28
修回日期：2017-03-17

基金

国家自然科学基金资助项目(81273431)

作者信息

1.北京工业大学生命科学与生物工程学院, 北京 100124

2.军事医学科学院放射与辐射医学研究所, 北京 100850

3.中国医学科学院、北京协和医学院药物研究所, 北京 100050

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* 王林, Tel:86-10-66932239, E-mail:wanglin07@sina.com

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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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Compd.	Yield/%	mp/℃	HR-MS m/z [M+H]⁺ or [M+Na]⁺ Calcd. (Found)	¹H NMR (400 MHz, CDCl₃) δ
7a	89.5	140-141	C₁₅H₁₃ClNO₂S₂ 338.007 6 (338.007 7)	8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.81-6.77 (m, 2H), 4.46 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H), 3.77 (s, 3H)
7b	90.8	148-149	C₁₄H₁₀ClFNOS₂ 325.987 6 (325.986 9)	8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.13-7.07 (m, 2H), 6.98-6.91 (m, 2H), 4.48 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H)
7c	93.5	176-177	C₁₆H₁₃ClNO₃S₂ 366.002 5 (366.002 0)	8.01 (d, J = 8.8 Hz, 1H), 7.95-7.89 (m, 3H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.22-7.17 (m, 2H), 4.56 (d, J = 13.1 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 3.90 (s, 3H)
7d	92.5	186.5-188.0	C₁₅H₁₀ClN₂OS₂ 332.992 3 (332.991 5)	8.01 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.58-7.51 (m, 3H), 7.24-7.19 (m, 2H), 4.55 (d, J = 13.2 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H)
7e	90.9	171-172	C₁₄H₁₀BrClNOS₂ 385.907 5 (385.907 4)	8.00 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.02-6.97 (m, 2H), 4.46 (d, J = 13.3 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H)
8a	90.6	187.5-189.0	C₁₅H₁₂ClNNaO₃S₂ 375.983 4 (375.983 0)	8.16 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.18-7.14 (m, 2H), 6.82-6.77 (m, 2H), 4.69 (s, 2H), 3.77 (s, 3H)
8b	89.7	154-155	C₁₄H₁₀ClFNO₂S₂ 341.982 5 (341.981 6)	8.16 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.28-7.21 (m, 2H), 7.01-6.95 (m, 2H), 4.72 (s, 2H)
8c	91.4	200-201	C₁₆H₁₃ClNO₄S₂ 381.996 9 (381.996 7)	8.17 (d, J = 8.8 Hz, 1H), 7.97-7.92 (m, 3H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.36-7.32 (m, 2H), 4.80 (s, 2H), 3.90 (s, 3H)
8d	83.3	201-202	C₁₅H₁₀ClN₂O₂S₂ 348.987 2 (348.986 5)	8.16 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.66-7.58 (m, 3H), 7.44-7.40 (m, 2H), 4.80 (s, 2H)
8e	94.0	190-191	C₁₄H₁₀BrClNO₂S₂ 401.902 4 (401.902 0)	8.16 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.9, 2.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.16-7.11 (m, 2H), 4.70 (s, 2H)
9a	93.3	160.5-162.0	C₁₆H₁₆ClN₂O₂S 335.062 1 (335.061 6)	7.82 (s, 1H), 7.35 (dd, J = 8.7, 1.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.97-6.90 (m, 2H), 6.79-6.73 (m, 2H), 4.59 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 3.77 (s, 3H), 3.48 (s, 3H)
9b	82.7	168-169	C₁₅H₁₃ClFN₂OS 323.042 1 (323.042 1)	7.86 (s, 1H), 7.39 (dd, J = 8.7, 1.3 Hz, 1H), 7.29-7.24 (m, 1H), 7.09-7.02 (m, 2H), 6.98-6.91 (m, 2H), 4.66 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H), 3.56 (s, 3H)
9c	80.0	176.5-177.5	C₁₇H₁₆ClN₂O₃S 363.057 0 (363.056 1)	7.95-7.89 (m, 2H), 7.82 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.16-7.12 (m, 2H), 4.71 (d, J = 12.9 Hz, 1H), 4.55 (d, J = 13.0 Hz, 1H), 3.91 (s, 3H), 3.50 (s, 3H)
10a	93.1	156.5-158.0	C₁₆H₁₆ClN₂O₃S 351.056 0 (351.055 7)	7.91 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.8, 1.5 Hz, 1H), 7.31-7.23 (m, 1H), 7.12-7.07 (m, J = 8.5 Hz, 2H), 6.81-6.76 (m, J = 8.6 Hz, 2H), 4.73 (s, 2H), 3.77 (s, 3H), 3.61 (s, 3H)
10b	90.7	150-151	C₁₅H₁₃ClFN₂O₂S 339.037 0 (339.036 3)	7.89 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.8, 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.01-6.94 (m, 2H), 4.80 (s, 2H), 3.71 (s, 3H)
10c	91.4	176.5-178.0	C₁₇H₁₆ClN₂O₄S 379.051 9 (379.051 3)	7.98-7.93 (m, 2H), 7.89 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35-7.28 (m, 3H), 4.88 (s, 2H), 3.90 (s, 3H), 3.68 (s, 3H)

Compd.

Yield/%

mp/℃

HR-MS m/z [M+H]⁺ or [M+Na]⁺ Calcd. (Found)

¹H NMR (400 MHz, CDCl₃) δ

89.5

140-141

C₁₅H₁₃ClNO₂S₂
338.007 6 (338.007 7)

8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.81-6.77 (m, 2H), 4.46 (d, J = 13.2 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H), 3.77 (s, 3H)

90.8

148-149

C₁₄H₁₀ClFNOS₂
325.987 6 (325.986 9)

8.00 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.8, 2.0 Hz, 1H), 7.13-7.07 (m, 2H), 6.98-6.91 (m, 2H), 4.48 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H)

93.5

176-177

C₁₆H₁₃ClNO₃S₂
366.002 5 (366.002 0)

8.01 (d, J = 8.8 Hz, 1H), 7.95-7.89 (m, 3H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.22-7.17 (m, 2H), 4.56 (d, J = 13.1 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H), 3.90 (s, 3H)

92.5

186.5-188.0

C₁₅H₁₀ClN₂OS₂
332.992 3 (332.991 5)

8.01 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.58-7.51 (m, 3H), 7.24-7.19 (m, 2H), 4.55 (d, J = 13.2 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H)

90.9

171-172

C₁₄H₁₀BrClNOS₂
385.907 5 (385.907 4)

8.00 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.02-6.97 (m, 2H), 4.46 (d, J = 13.3 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H)

90.6

187.5-189.0

C₁₅H₁₂ClNNaO₃S₂
375.983 4 (375.983 0)

8.16 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 8.8, 2.0 Hz, 1H), 7.18-7.14 (m, 2H), 6.82-6.77 (m, 2H), 4.69 (s, 2H), 3.77 (s, 3H)

89.7

154-155

C₁₄H₁₀ClFNO₂S₂
341.982 5 (341.981 6)

8.16 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.28-7.21 (m, 2H), 7.01-6.95 (m, 2H), 4.72 (s, 2H)

91.4

200-201

C₁₆H₁₃ClNO₄S₂
381.996 9 (381.996 7)

8.17 (d, J = 8.8 Hz, 1H), 7.97-7.92 (m, 3H), 7.62 (dd, J = 8.8, 2.0 Hz, 1H), 7.36-7.32 (m, 2H), 4.80 (s, 2H), 3.90 (s, 3H)

83.3

201-202

C₁₅H₁₀ClN₂O₂S₂
348.987 2 (348.986 5)

8.16 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.66-7.58 (m, 3H), 7.44-7.40 (m, 2H), 4.80 (s, 2H)

94.0

190-191

C₁₄H₁₀BrClNO₂S₂
401.902 4 (401.902 0)

8.16 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.9, 2.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.16-7.11 (m, 2H), 4.70 (s, 2H)

93.3

160.5-162.0

C₁₆H₁₆ClN₂O₂S
335.062 1 (335.061 6)

7.82 (s, 1H), 7.35 (dd, J = 8.7, 1.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 6.97-6.90 (m, 2H), 6.79-6.73 (m, 2H), 4.59 (d, J = 13.1 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 3.77 (s, 3H), 3.48 (s, 3H)

82.7

168-169

C₁₅H₁₃ClFN₂OS
323.042 1 (323.042 1)

7.86 (s, 1H), 7.39 (dd, J = 8.7, 1.3 Hz, 1H), 7.29-7.24 (m, 1H), 7.09-7.02 (m, 2H), 6.98-6.91 (m, 2H), 4.66 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H), 3.56 (s, 3H)

80.0

176.5-177.5

C₁₇H₁₆ClN₂O₃S
363.057 0 (363.056 1)

7.95-7.89 (m, 2H), 7.82 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.16-7.12 (m, 2H), 4.71 (d, J = 12.9 Hz, 1H), 4.55 (d, J = 13.0 Hz, 1H), 3.91 (s, 3H), 3.50 (s, 3H)

10a

93.1

156.5-158.0

C₁₆H₁₆ClN₂O₃S
351.056 0 (351.055 7)

7.91 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.8, 1.5 Hz, 1H), 7.31-7.23 (m, 1H), 7.12-7.07 (m, J = 8.5 Hz, 2H), 6.81-6.76 (m, J = 8.6 Hz, 2H), 4.73 (s, 2H), 3.77 (s, 3H), 3.61 (s, 3H)

10b

90.7

150-151

C₁₅H₁₃ClFN₂O₂S
339.037 0 (339.036 3)

7.89 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.8, 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.01-6.94 (m, 2H), 4.80 (s, 2H), 3.71 (s, 3H)

10c

91.4

176.5-178.0

C₁₇H₁₆ClN₂O₄S
379.051 9 (379.051 3)

7.98-7.93 (m, 2H), 7.89 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.35-7.28 (m, 3H), 4.88 (s, 2H), 3.90 (s, 3H), 3.68 (s, 3H)

Compd.	R	% inhibition at 50 μmol·L^-1		IC₅₀/μmol·L^-1
7a	CH₃O	33	28	43		> 100	> 100	> 100
7b	F	57	45	39	76.8	> 100	> 100
7c	CH₃OCO	51	39	34	85.1	> 100	> 100
7d	CN	45	38	41	> 100	> 100	> 100
7e	Br	43	33	26	> 100	> 100	> 100
8a	CH₃O	36	31	35	> 100	> 100	> 100
8b	F	56	45	36	80.7	> 100	> 100
8c	CH₃OCO	53	26	33	82.3	> 100	> 100
8d	CN	43	33	36	> 100	> 100	> 100
8e	Br	44	34	33	> 100	> 100	> 100
9a	CH₃O	33	71	38	> 100	21.2	> 100
9b	F	20	84	27	> 100	10.6	> 100
9c	CH₃OCO	30	87	39	> 100	5.2	> 100
10a	CH₃O	20	90	31	> 100	7.7	> 100
10b	F	68	87	72	31.9	3.9	21.2
10c	CH₃OCO	20	96	35	> 100	2.8	> 100
Tenovin-6	-	66	84	38	37.5	15.3	> 100
AGK2	-	35	100	58	> 100	1.56	52.8

Compd.

% inhibition at 50 μmol·L^-1

IC₅₀/μmol·L^-1

SIRT1

SIRT2

SIRT3

SIRT1

SIRT2

SIRT3

CH₃O

> 100

76.8

> 100

CH₃OCO

85.1

> 100

CH₃O

> 100

80.7

> 100

CH₃OCO

82.3

> 100

CH₃O

> 100

21.2

> 100

10.6

> 100

CH₃OCO

> 100

5.2

> 100

10a

CH₃O

> 100

7.7

> 100

10b

31.9

3.9

21.2

10c

CH₃OCO

> 100

2.8

> 100

Tenovin-6

37.5

15.3

> 100

AGK2

100

> 100

1.56

52.8