9-fluorenone-based synthetic sulfonamide compounds as dual inhibitors of SARS-CoV-2 Main-Protease and Papain-like Protease.

IF 3.8 2区 化学 Q2 CHEMISTRY, APPLIED
Sudesna Das, Prasad Sunnapu, Mohammed Rafi, Yasmin Begum, Sudip Dey, Akshay Joshi, Nittu Singh, Krishan Gopal Thakur, Parasuraman Jaisankar, Umesh Prasad Singh
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引用次数: 0

Abstract

Tilorone, a 9-fluorenone scaffold-based molecule, is a known broad-spectrum antiviral with an IC50 of 180 nM against SARS-CoV-2, but its mechanism is not known. In the present study, we found it to have weak activity against PLpro (IC50 = 30.7 ± 7.5 μM) and was inactive against Mpro. Several sulfonamide derivatives of 9-fluorenone, having the same scaffold as tilorone, were synthesized based on our in-silico studies to enhance their protease activity. They were evaluated for their inhibitory potential for targeting SARS-CoV-2 Mpro (main protease) and PLpro (papain-like protease) using FRET-based high-throughput screening and gel-based assays. Among the derivatives, 3e exhibited dual inhibition against Mpro (IC50 = 23 ± 3.4 μM) and PLpro (IC50 = 6.33 ± 0.5 μM), while 3h selectively inhibited PLpro (IC50= 5.94 ± 1.0 μM). Both 3e and 3h suppressed SARS-CoV-2 replication with IC50 values of 13.4 ± 0.28 μM and 18.2 ± 3.2 μM, respectively. Molecular docking and dynamics studies revealed that the NO2 group in 3h enhances the rigidity of the BL2 loop of PLpro, contributing to its higher PLpro activity. Both 3e and 3h showed antiviral activity comparable with standard alpha-ketoamide inhibitor (13b-K) in cell-based assays and were non-cytotoxic with acceptable selectivity indices (S.I. > 5.5). These findings suggest that 9-fluorenone-based sulfonamides, particularly 3e and 3h, may be promising candidates as dual or selective protease inhibitors against SARS-CoV-2.

基于9-芴酮的合成磺胺类化合物作为SARS-CoV-2主蛋白酶和木瓜蛋白酶的双重抑制剂
Tilorone是一种基于9-芴酮支架的分子,是一种已知的广谱抗病毒药物,对SARS-CoV-2的IC50为180 nM,但其作用机制尚不清楚。在本研究中,我们发现它对PLpro具有弱活性(IC50 = 30.7±7.5 μM),对Mpro无活性。为了提高9-芴酮的蛋白酶活性,我们合成了几种与替洛酮具有相同支架的9-芴酮磺酰胺衍生物。利用基于fret的高通量筛选和凝胶试验,评估了它们对SARS-CoV-2 Mpro(主要蛋白酶)和PLpro(木瓜蛋白酶样蛋白酶)的抑制潜力。其中3e对Mpro (IC50= 23±3.4 μM)和PLpro (IC50= 6.33±0.5 μM)具有双重抑制作用,3h对PLpro (IC50= 5.94±1.0 μM)具有选择性抑制作用。3e和3h抑制SARS-CoV-2复制的IC50值分别为13.4±0.28 μM和18.2±3.2 μM。分子对接和动力学研究表明,3h NO2基团增强了PLpro BL2环的刚性,使其具有较高的PLpro活性。在基于细胞的实验中,3e和3h都显示出与标准α -酮酰胺抑制剂(13b-K)相当的抗病毒活性,并且具有可接受的选择性指数(S.I. > 5.5),无细胞毒性。这些发现表明,基于9-芴酮的磺胺类药物,特别是3e和3h,可能是抗SARS-CoV-2的双重或选择性蛋白酶抑制剂的有希望的候选者。
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来源期刊
Molecular Diversity
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;
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