Design, Synthesis and Biological Evaluation of FABP4/5 Inhibitors Based on Quinoline Scaffold

doi:10.6023/cjoc202207001

Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (2): 636-645.DOI: 10.6023/cjoc202207001 Previous Articles Next Articles

作为FABP4/5抑制剂喹啉类化合物的设计合成与生物活性研究

高建飞^a,c,†, 李瞬依^b,†, 何玉龙^c, 李英霞^c, 王贺瑶^b, 黄二芳^a^,^*(), 胡春^a^,^*()

a 沈阳药科大学教育部基于靶点的药物设计与研究重点实验室沈阳 110015
b 中国科学院上海药物研究所上海 201203
c 复旦大学药学院上海 201203

收稿日期:2022-07-02 修回日期:2022-09-14 发布日期:2022-11-07
作者简介:
†共同第一作者
基金资助:
国家自然科学基金(21342006); 教育部创新团队(IRT_14R36)

Design, Synthesis and Biological Evaluation of FABP4/5 Inhibitors Based on Quinoline Scaffold

Jianfei Gao^a,c,†, Shunyi Li^b,†, Yulong He^c, Yingxia Li^c, Heyao Wang^b, Erfang Huang^a(), Chun Hu^a()

a Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110015
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
c School of Pharmacy, Fudan University, Shanghai 201203

Received:2022-07-02 Revised:2022-09-14 Published:2022-11-07
Contact: *E-mail: erfanghuang@syphu.edu.cn;chunhu@syphu.edu.cn
About author:
†(The authors contributed equally to this work).
Supported by:
National Natural Science Foundation of China(21342006); Program for Innovative Research Team of the Ministry of Education(IRT_14R36)

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Abstract

Taking the dual FABP 4/5 inhibitor RO6806051 and FABP4 inhibitor XU17 as the lead compounds, twenty new quinoline derivatives as dual FABP4/5 inhibitors were designed and synthesized according to the reported RO6806051/FABP5 crystal complex and XU17/FABP4 crystal complex, then confirmed by ¹H NMR, ¹³C NMR and high-resolution mass spectra (HRMS). All the target compounds were evaluated for their inhibitory activity against FABP4 and FABP5 via the 8-anilino- naphthalene-1-sulfonic acid (1,8-ANS) displacement assay. The results showed that the target compound 2-(2-(6-chloro- 4-(2-chlorophenyl)quinolin-2-yl)phenyl)acetic acid (11a) exhibited strong inhibitory activity against FABP4 (IC₅₀: 4.50 μmol/L) and FABP5 (IC₅₀: 3.90 μmol/L).

Key words: FABP4/5 inhibitors, fusion strategy, quinoline, synthesis

Cite this article

Jianfei Gao, Shunyi Li, Yulong He, Yingxia Li, Heyao Wang, Erfang Huang, Chun Hu. Design, Synthesis and Biological Evaluation of FABP4/5 Inhibitors Based on Quinoline Scaffold[J]. Chinese Journal of Organic Chemistry, 2023, 43(2): 636-645.

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References 23

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Compd.	FABP4		FABP5
Compd.	Inhibition^a/%	IC₅₀/(μmol•L^-1)	Inhibition^a/%	IC₅₀/(μmol•L^-1)
4a	-	N.d	-	N.d
4b	24	N.d	-	N.d
4c	17	N.d	16	N.d
4d	31	N.d	44	N.d
4e	27	N.d	17	N.d
4f	37	N.d	48	N.d
4g	86	4.4	53	N.d
4h	24	N.d	59	N.d
4i	15	N.d	59	N.d
4j	30	N.d	33	N.d
4k	85	5.92	59	N.d
4l	78	13.3	56	N.d
4m	41	N.d	40	N.d
4n	71	14	54	N.d
11a	88	4.5	73	3.9
11b	7	N.d	21	N.d
11c	85	5.09	52	N.d
11d	58	N.d	33	N.d
11e	82	7.58	51	N.d
11f	83	6.03	47	N.d
BMS309403	98	2.16	-	N.d
XU17	99	1.62	62	3.38
RO6806051	80	1.77	29	N.d

Compd.	FABP4		FABP5
Compd.	Inhibition^a/%	IC₅₀/(μmol•L^-1)	Inhibition^a/%	IC₅₀/(μmol•L^-1)
4a	-	N.d	-	N.d
4b	24	N.d	-	N.d
4c	17	N.d	16	N.d
4d	31	N.d	44	N.d
4e	27	N.d	17	N.d
4f	37	N.d	48	N.d
4g	86	4.4	53	N.d
4h	24	N.d	59	N.d
4i	15	N.d	59	N.d
4j	30	N.d	33	N.d
4k	85	5.92	59	N.d
4l	78	13.3	56	N.d
4m	41	N.d	40	N.d
4n	71	14	54	N.d
11a	88	4.5	73	3.9
11b	7	N.d	21	N.d
11c	85	5.09	52	N.d
11d	58	N.d	33	N.d
11e	82	7.58	51	N.d
11f	83	6.03	47	N.d
BMS309403	98	2.16	-	N.d
XU17	99	1.62	62	3.38
RO6806051	80	1.77	29	N.d

作为FABP4/5抑制剂喹啉类化合物的设计合成与生物活性研究

Design, Synthesis and Biological Evaluation of FABP4/5 Inhibitors Based on Quinoline Scaffold

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