Synthesis and biological evaluation of sulfonamide derivatives containing imidazole moiety as ALK5 inhibitors

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-08-30 DOI:10.1007/s11030-024-10973-y

Shu-Yan Ding, Yu-Xuan Yang, Chuang Liu, Xu-Yin Quan, Zi-Han Zhao, Cheng-Hua Jin

引用次数: 0

Abstract

Four series of sulfonamide derivatives (13a–b, 14a–d, 15a–b, and 16a–d) were synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) inhibitory activities. Of these, compounds 13b (IC₅₀ = 0.130 μM) and 15a (IC₅₀ = 0.130 μM) showed the highest inhibitory activities against ALK5 kinase, with activities similar to the positive control LY-2157299. Notably, we discovered that introduction of sulfonamide group at the 2-position of the central imidazole ring significantly increased ALK5 inhibitory activity. Compounds 13b and 15a did not show toxicity in A549 cells up to the maximum concentration of 50 μM, and effectively inhibited TGF-β1-induced Smad-signaling and cell motility in A549 cells. The results indicate that compounds 13b and 15a are worth of further development as anticancer agents.

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含咪唑分子的磺酰胺衍生物作为 ALK5 抑制剂的合成与生物学评价

研究人员合成了四个系列的磺酰胺衍生物（13a-b、14a-d、15a-b和16a-d），并评估了它们对活化素受体样激酶5（ALK5）的抑制活性。其中，化合物 13b（IC50 = 0.130 μM）和 15a（IC50 = 0.130 μM）对 ALK5 激酶的抑制活性最高，与阳性对照 LY-2157299 的活性相似。值得注意的是，我们发现在中心咪唑环的 2 位引入磺酰胺基团可显著提高 ALK5 的抑制活性。化合物 13b 和 15a 在最大浓度为 50 μM 时对 A549 细胞无毒性，并能有效抑制 TGF-β1 诱导的 A549 细胞 Smad 信号转导和细胞运动。结果表明，化合物 13b 和 15a 值得作为抗癌剂进一步开发。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;