Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors

• Published in: Journal of medicinal chemistry Vol. 64; no. 8; pp. 4762 - 4786
• Main Authors: Ahmed, S. Kaleem, Haese, Nicole N, Cowan, Jaden T, Pathak, Vibha, Moukha-Chafiq, Omar, Smith, Valerie J, Rodzinak, Kevin J, Ahmad, Fahim, Zhang, Sixue, Bonin, Kiley M, Streblow, Aaron D, Streblow, Cassilyn E, Kreklywich, Craig N, Morrison, Clayton, Sarkar, Sanjay, Moorman, Nathaniel, Sander, Wes, Allen, Robbie, DeFilippis, Victor, Tekwani, Babu L, Wu, Mousheng, Hirsch, Alec J, Smith, Jessica L, Tower, Nichole A, Rasmussen, Lynn, Bostwick, Robert, Maddry, Joseph A, Ananthan, Subramaniam, Gerdes, John M, Augelli-Szafran, Corinne E, Suto, Mark J, Morrison, Thomas E, Heise, Mark T, Streblow, Daniel N, Pathak, Ashish K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.04.2021; Amer Chemical Soc
• Subjects: Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Benzene Derivatives - chemistry; Benzene Derivatives - metabolism; Benzene Derivatives - pharmacology; Benzene Derivatives - therapeutic use; Binding Sites; Cell Line; Cell Survival - drug effects; Chemistry, Medicinal; Chikungunya Fever - drug therapy; Chikungunya virus - physiology; Dihydroorotate Dehydrogenase; Disease Models, Animal; Female; Half-Life; Humans; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Microsomes, Liver - metabolism; Molecular Docking Simulation; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Virus Replication - drug effects; DIHYDROOROTATE DEHYDROGENASES; DESIGN; ACTIVATION; COMPOUND; BIOLOGICAL EVALUATION; INFECTION; POTENT INHIBITORS; DENGUE VIRUS; DERIVATIVES; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c02183

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.