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

9-fluorenone-based synthetic sulfonamide compounds as dual inhibitors of SARS-CoV-2 Main-Protease and Papain-like Protease
type: AcademicArticle
type: Article
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.
date: 2025-09
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

Springer Science and Business Media LLC
type: Organization

Mol. Divers.
type: Collection

Krishan Gopal Thakur
type: Person
given name: Krishan Gopal
family name: Thakur

Sudesna Das
type: Person
given name: Sudesna
family name: Das

Umesh Prasad Singh
type: Person
given name: Umesh Prasad
family name: Singh

Akshay Joshi
type: Person
given name: Akshay
family name: Joshi

Yasmin Begum
type: Person
given name: Yasmin
family name: Begum

Nittu Singh
type: Person
given name: Nittu
family name: Singh

Parasuraman Jaisankar
type: Person
given name: Parasuraman
family name: Jaisankar

Prasad Sunnapu
type: Person
given name: Prasad
family name: Sunnapu

Mohammed Rafi
type: Person
given name: Mohammed
family name: Rafi

Sudip Dey
type: Person
given name: Sudip
family name: Dey

HTML Summary of #3214 9-fluorenone-based synthetic sulfonamide compounds as dual inhibitors of SARS-CoV-2 Main-Protease and Papain-like Protease
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primary topic: 9-fluorenone-based synthetic sulfonamide compounds as dual inhibitors of SARS-CoV-2 Main-Protease and Papain-like Protease