2. Academic Validation
  3. 4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses

4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses

  • J Med Chem. 2024 Dec 12;67(23):20858-20878. doi: 10.1021/acs.jmedchem.4c01073.
Atefeh Garzan 1,  S Kaleem Ahmed 1,  Nicole N Haese 2,  Gauthami Sulgey 2,  Samuel Medica 2,  Jessica L Smith 2,  Sixue Zhang 1,  Fahim Ahmad 1,  Shuklendu Karyakarte 1,  Lynn Rasmussen 1,  Victor DeFilippis 2,  Babu Tekwani 1,  Robert Bostwick 1,  Mark J Suto 1,  Alec J Hirsch 2,  Thomas E Morrison 3,  Mark T Heise 4,  Corinne E Augelli-Szafran 1,  Daniel N Streblow 2,  Ashish K Pathak 1,  Omar Moukha-Chafiq 1
Affiliations

Affiliations

  • 1 Scientific Platforms Division, Southern Research, 2000 ninth Avenue South, Birmingham, Alabama 35205, United States.
  • 2 Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, United States.
  • 3 Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 E. 19th Avenue, Aurora, Colorado 80045, United States.
  • 4 Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, United States.
PMID: 39621435 DOI: 10.1021/acs.jmedchem.4c01073
Abstract

2-(Methylthio)-N-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide 1 was identified as an inhibitor against Chikungunya virus (CHIKV) with good Antiviral activity [EC50 = 0.6 μM; EC90 = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC50 = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure-activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of 1 led to the discovery of a new potent inhibitor N-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide 26, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC90 of 0.45 μM with considerably improved MLM stability (t1/2 = 74 min) as compared to 1. Mechanism of action studies show that 26 inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The in vivo efficacy studies of compound 26 on CHIKV Infection in mice are reported.

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