Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad 13100 AJK, Pakistan; Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Department of Chemistry, University of Azad Jammu and Kashmir, Muzaffarabad 13100 AJK, Pakistan.
Bioorg Chem. 2020 Mar;96:103567. doi: 10.1016/j.bioorg.2020.103567. Epub 2020 Jan 3.
Direct acting antiviral drugs (DAADs) are becoming therapeutics of choice for the treatment of viral infections. Successful development of anti HIV and HCV drugs by targeting the viral proteases has provided impetus for discovering newer DAADs. Dengue virus (DENV) protease, which is composed of two nonstructural proteins, NS2B and NS3pro, can be likewise exploited for discovering new anti-dengue therapeutics. In this study, we have linked together two pharmaceutically interesting motifs, namely 1,3,4-oxadiazole and benzenesulfonamide in two alternative series to develop novel S-benzylated and S-alkylphthalimidated hybrids. For the first series of hybrids, 4-aminobenzoic acid (1) was reacted with substituted benzenesulfonyl chlorides via its amino group, whereas the carboxylic acid side was elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (6a/b) in three steps. At this stage, the intermediates 6a/b were bifurcated to either S-alkylphthalimidated (8a-j) or S-benzylated (9a-c) hybrids by reacting with corresponding halides. For the alternative series of hybrids, the carboxylic acid group of probenecid (10) was similarly elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (13), and diverged to S-alkylphthalimidated (14a-f) and S-benzylated hybrids (15a-e). Bioactivity assays demonstrated that 8g and 8h are the most potent inhibitors among the synthesized analogs, exhibiting the IC values of 13.9 μM and 15.1 μM, respectively. Computational assessment predicted the binding of the inhibitors at an allosteric site developed in the open conformation of DENV2 NS2B/NS3pro. Taken together these findings point out that the synthesized hybrid inhibitors possess a great potential for further antiviral drug development.
直接作用抗病毒药物 (DAADs) 正成为治疗病毒感染的首选疗法。针对病毒蛋白酶成功开发抗 HIV 和 HCV 药物为发现新型 DAADs 提供了动力。登革热病毒 (DENV) 蛋白酶由两个非结构蛋白 NS2B 和 NS3pro 组成，同样可用于发现新的抗登革热治疗药物。在这项研究中，我们将两个具有药物应用前景的结构模块，即 1,3,4-噁二唑和苯磺酰胺，以两种不同的方式连接在一起，设计并合成了新型 S-苄基化和 S-烷基邻苯二甲酰亚胺化杂合分子。对于第一个系列的杂合分子，4-氨基苯甲酸 (1) 通过其氨基与取代的苯磺酰氯反应，而羧酸侧链则通过三步反应被扩展为磺酰胺基-1,3,4-噁二唑-2-硫醇 (6a/b)。在这一阶段，中间体 6a/b 通过与相应的卤化物反应，分叉为 S-烷基邻苯二甲酰亚胺化 (8a-j) 或 S-苄基化 (9a-c) 杂合分子。对于第二个系列的杂合分子，丙磺舒 (10) 的羧酸基团也被类似地扩展为磺酰胺基-1,3,4-噁二唑-2-硫醇 (13)，并分叉为 S-烷基邻苯二甲酰亚胺化 (14a-f) 和 S-苄基化杂合分子 (15a-e)。生物活性测定表明，8g 和 8h 是合成类似物中最有效的抑制剂，其 IC 值分别为 13.9 μM 和 15.1 μM。计算评估预测抑制剂在 DENV2 NS2B/NS3pro 开放构象中形成的别构位点上的结合。综上所述，这些发现表明合成的杂合抑制剂具有进一步开发抗病毒药物的巨大潜力。
