设计、合成、分子对接和生物评价新型2,3-二取代苯基-1,3-噻唑烷-4-酮衍生物作为潜在的抗炎和细胞毒素剂。
Design, Synthesis, Molecular docking, and biological evaluation of novel 2,3-diaryl-1,3-thiazolidine-4-one derivatives as potential anti-inflammatory and cytotoxic agents.
发表日期：2023 Feb 09
作者：
Yosra O Mekhlef, Asmaa M AboulMagd, Ahmed M Gouda
来源：
BIOORGANIC CHEMISTRY
摘要：
一系列新的2,3-二芳基-1,3-噻唑啉-4-酮衍生物被设计、合成和评价其细胞毒性和COXs抑制活性。在这些衍生物中，化合物4k和4j对COX-2表现出最高的抑制活性，IC50值分别为0.05和0.06μM。化合物4a、4b、4e、4g、4j、4k、5b和6b对COX-2表现出最高的抑制百分比，被用于评价其在大鼠中的抗炎活性。结果显示，与 celecoxib（抑制百分比=89.51％）相比，试验化合物对爪水肿厚度的抑制率为41.08-82.00％。此外，相比 celecoxib 和 indomethacin，化合物4b、4j、4k和6b表现出更好的 GIT 安全性。这四个化合物还被评价其抗氧化活性。结果显示，4j（IC50=45.27μM）的抗氧化活性最高，与 torolox（IC50=62.03μM）相当。新化合物的抗增殖活性在 HePG-2、HCT-116、MCF-7 和 PC-3 癌细胞系中得到了评价。结果显示，化合物4b、4j、4k和6b（IC50=2.31-27.19μM）具有最高的细胞毒性，其中4j最强。机制研究改变了化合物4j和4k，诱导HePG-2癌细胞显著的凋亡和细胞周期在G1期停滞。这些生物学结果还表明，COX-2抑制在这些化合物的抗增殖活性中扮演着一定的角色。分子对接研究的结果表明，化合物4k和4j能够与COX-2的活性位点良好结合，并与体外COX-2抑制试验的结果相一致。版权所有©2023年Elsevier Inc.。
A new series of 2,3-diaryl-1,3thiazolidin-4-one derivatives was designed, synthesized, and evaluated for their cytotoxicity and COXs inhibitory activities. Among these derivatives, compounds 4 k and 4j exhibited the highest inhibitory activities against COX-2 at IC50 values of 0.05 and 0.06 μM, respectively. Compounds 4a, 4b, 4e, 4 g, 4j, 4 k, 5b, and 6b, which exhibited the highest inhibition% against COX-2, were evaluated for their anti-inflammatory activity in rats. Results showed 41.08-82.00 % inhibition of paw edema thickness by the test compounds compared to celecoxib (inhibition% = 89.51 %). In addition, compounds 4b, 4j, 4 k, and 6b exhibited better GIT safety profiles compared to celecoxib and indomethacin. The four compounds were also evaluated for their antioxidant activity. The results revealed the highest antioxidant activity for 4j (IC50 = 45.27 μM) comparable to torolox (IC50 = 62.03 μM). The antiproliferative activity of the new compounds was evaluated against HePG-2, HCT-116, MCF-7, and PC-3 cancer cell lines. The results showed the highest cytotoxicity for compounds 4b, 4j, 4 k, and 6b (IC50 = 2.31-27.19 μM), with 4j being the most potent. Mechanistic studies revealed the ability of 4j and 4 k by inducing marked apoptosis and cell cycle arrest at the G1 phase in HePG-2 cancer cells. These biological results may also suggest a role for COX-2 inhibition in the antiproliferative activity of these compounds. The results of the molecular docking study for 4 k and 4j into the active site of COX-2 revealed good fitting and correlation with the results of the in vitro COX‑2 inhibition assay.Copyright © 2023 Elsevier Inc. All rights reserved.