Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors

S. Kaleem Ahmed, Nicole N. Haese, Jaden T. Cowan, Vibha Pathak, Omar Moukha-Chafiq, Valerie J. Smith, Kevin J. Rodzinak, Fahim Ahmad, Sixue Zhang, Kiley M. Bonin, Aaron D. Streblow, Cassilyn E. Streblow, Craig N. Kreklywich, Clayton Morrison, Sanjay Sarkar, Nathaniel Moorman, Wes Sander, Robbie Allen, Victor Defilippis, Babu L. TekwaniMousheng Wu, Alec J. Hirsch, Jessica L. Smith, Nichole A. Tower, Lynn Rasmussen, Robert Bostwick, Joseph A. Maddry, Subramaniam Ananthan, John M. Gerdes, Corinne E. Augelli-Szafran, Mark J. Suto, Thomas E. Morrison, Mark T. Heise, Daniel N. Streblow, Ashish K. Pathak

Research output: Contribution to journalArticlepeer-review

Abstract

A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 μM and viral titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity (CC50 = 169 μM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC90 = 270 nM and VTR of 4.5 log at 10 μM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway.

Original languageEnglish (US)
Pages (from-to)4762-4786
Number of pages25
JournalJournal of Medicinal Chemistry
Volume64
Issue number8
DOIs
StatePublished - Apr 22 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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