Shukla Manjari, Mali Ghanshyam, Sharma Supriya, Maji Sushobhan, Yadav Vinay Kumar, Mishra Amit, Erande Rohan D, Bhattacharyya Sudipta
Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur 342037, Rajasthan, India.
Department of Chemistry, Indian Institute of Technology, Jodhpur 342037, Rajasthan, India.
ACS Omega. 2024 Oct 21;9(43):43414-43425. doi: 10.1021/acsomega.4c04325. eCollection 2024 Oct 29.
New therapeutic leads are in global demand against multiple drug-resistant , as presently there is no drug of choice left to treat this pathogen. In the present work, we have designed, synthesized, and in vitro validated dimedone-coupled 2,3-dihydrofuran (DDHF)-based inhibitor scaffolds against Staphylococcal thioredoxin reductase (SaTR), a pivotal drug target enzyme of Gram-positive pathogens. Accordingly, a green multicomponent method that is both efficient and one pot has been optimized to synthesize DDHF derivatives. The synthesized DDHF derivatives were found to inhibit a purified SaTR enzyme. The best inhibitor derivative, DDHF20, inhibits SaTR as a competitive inhibitor for the NADPH binding site at low micromolar concentrations. DDHF20-capped silver nanoparticles are synthesized and characterized, and their bactericidal property has been checked in vitro. Furthermore, detailed in silico-based structure-guided functional studies have been carried out to uncover the plausible mode of action of DDHF20 as a potential anti-Staphylococcal therapeutic lead.
针对多重耐药菌的新型治疗先导物在全球范围内都有需求，因为目前已没有可用于治疗这种病原体的首选药物。在本研究中，我们设计、合成并在体外验证了基于二甲双酮偶联2,3-二氢呋喃（DDHF）的抑制剂支架，其针对葡萄球菌硫氧还蛋白还原酶（SaTR），这是革兰氏阳性病原体的一种关键药物靶标酶。相应地，一种高效且一锅法的绿色多组分方法已被优化用于合成DDHF衍生物。所合成的DDHF衍生物被发现能够抑制纯化的SaTR酶。最佳抑制剂衍生物DDHF20在低微摩尔浓度下作为NADPH结合位点的竞争性抑制剂抑制SaTR。合成并表征了DDHF20包覆的银纳米颗粒，并在体外检查了它们的杀菌性能。此外，还进行了详细的基于计算机模拟的结构导向功能研究，以揭示DDHF20作为潜在抗葡萄球菌治疗先导物的可能作用模式。
