Design, Synthesis and Anti-HIV-Reverse Transcriptase Activity of Novel Diaryl Thiazolindin-4-one Derivatives Possessing Amide Linkage on N-3 Position

Abstract

A series of thiazolidin-4-one derivatives possessing ester were synthesized under microwave irradiation using amino acid ester as starting material. After ester hydrolysis reaction and amide condensation reaction, the aimed diaryl thiazolindin-4-one derivatives possessing amide linkage on N-3 position were obtained. The compounds were evaluated for their human immunodeficiency virus (HIV-1) reverse transcriptase (RT) inhibitory activities in vitro HIV-1 RT kit assay (colorimetric method). The results showed that some of the compounds, such as 5bb, 5bc, 5cb, and 5cc could effectively inhibit RT activity with the IC 50 values of 4.15, 3.53, 4.61 and 4.06 μmol/L, respectively. Structure activity relationship analysis of these analogues suggested that the introduction of two carbons side chain on N-3 position and lipophilic group like methyl group should be favorable to their anti-HIV-RT activitives. Keywords thiazolidin-4-one; anti-HIV-RT activity; lipophilic group; flexible side chain; amide bond 噻唑烷酮是一类广谱的药效基团, 其衍生物多具有 抗菌﹑抗病毒﹑抗炎和抗癌等生物活性 [1,2]. 其中, 2,3-二芳基-1,3-噻唑烷-4-酮作为非核苷类逆转录酶抑制剂 (NNRTIs) [3] , 因具有高的抗艾滋病毒(HIV)活性和选择 性引起了广泛关注 [4]. 这类化合物以 HIV 逆转录酶(RT, 病 毒 基 因 复 制 中 的 关 键 酶 [5]) 为 靶 点 , 呈 类 蝴 蝶 状 (butterfly-like conformation)构象结合在距酶活性中心 10Å 的变构位点(allosteric binding site) [6] , 从而有效抑制 酶活. 经系统的结构优化, 2-(2,6-二氯苯基)-3-(4,6-二甲 基嘧啶-2-基)噻唑烷-4-酮 1～4 较其它芳基取代具有更 高的抗 HIV 活性(图 1) [7～11]. 因此, 为了增加此类分子的 柔性以提高化合物与 HIV 逆转录酶变构结合位点的构 象适配性, 进一步发现抗 HIV 病毒药物的及构效关系分 析(SAR), 本文设计、合成了一系列在噻唑烷-4-酮 N-3 位上通过柔性侧链连接嘧啶胺的衍生物 5aa～5dc(图 2), 并对其 HIV 逆转录酶的抑制活性进行了评价.