2. Academic Validation
  3. Trisubstituted Thieno[3,2-b]pyrrole 5-Carboxamides as Potent Inhibitors of Alphaviruses

Trisubstituted Thieno[3,2-b]pyrrole 5-Carboxamides as Potent Inhibitors of Alphaviruses

  • J Med Chem. 2015 Dec 10;58(23):9196-213. doi: 10.1021/acs.jmedchem.5b01047.
Kuan-Chieh Ching 1 2,  Yiu-Wing Kam 3,  Andres Merits 4,  Lisa F P Ng 3 5,  Christina L L Chai 1 2 6
Affiliations

Affiliations

  • 1 NUS Graduate School for Integrative Sciences and Engineering , Centre for Life Sciences, #05-01, 28 Medical Drive, Singapore 117456.
  • 2 Department of Pharmacy, Faculty of Science, National University of Singapore , Block S4A, Level 3, 18 Science Drive 4, Singapore 117543.
  • 3 Singapore Immunology Network, A*STAR , 8A Biomedical Grove, Immunos Building, Level 4, Singapore 138648.
  • 4 Institute of Technology, University of Tartu , Nooruse 1, Tartu, Estonia 50411.
  • 5 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , Block MD6, Centre for Translational Medicine, 14 Medical Drive, #14-01T, Singapore 117599.
  • 6 Institute of Chemical and Engineering Sciences, A*STAR , 8 Biomedical Grove, Neuros Building, #07-01/02/03, Singapore 138665.
PMID: 26540338 DOI: 10.1021/acs.jmedchem.5b01047
Abstract

Chikungunya virus (CHIKV) is a re-emerging vector-borne alphavirus and is transmitted to humans by Aedes mosquitoes. Despite the re-emergence of CHIKV as an epidemic threat, there is no approved effective Antiviral treatment currently available for CHIKV. Herein, we report the synthesis and structure-activity relationship studies of a class of thieno[3,2-b]pyrroles and the discovery of a trisubstituted thieno[3,2-b]pyrrole 5-carboxamide 15c that exhibits potent inhibitory activity against in vitro CHIKV Infection. Compound 15c displayed low micromolar activity (EC50 value of CA. 2 μM) and limited cytotoxic liability (CC50 > 100 μM) therefore furnishing a selectivity index of greater than 32. Notably, 15c not only controlled viral RNA production, but efficiently inhibited the expression of CHIKV nsP1, nsP3, capsid, and E2 proteins at a concentration as low as 2.5 μM. More importantly, 15c also demonstrated broad spectrum Antiviral activity against Other clinically important alphaviruses such as O'nyong-nyong virus and Sindbis virus.

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