@article{66cc40f5fb9e4642ab55c1090addb20f,
title = "Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors",
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.",
author = "Ahmed, {S. Kaleem} and Haese, {Nicole N.} and Cowan, {Jaden T.} and Vibha Pathak and Omar Moukha-Chafiq and Smith, {Valerie J.} and Rodzinak, {Kevin J.} and Fahim Ahmad and Sixue Zhang and Bonin, {Kiley M.} and Streblow, {Aaron D.} and Streblow, {Cassilyn E.} and Kreklywich, {Craig N.} and Clayton Morrison and Sanjay Sarkar and Nathaniel Moorman and Wes Sander and Robbie Allen and Victor Defilippis and Tekwani, {Babu L.} and Mousheng Wu and Hirsch, {Alec J.} and Smith, {Jessica L.} and Tower, {Nichole A.} and Lynn Rasmussen and Robert Bostwick and Maddry, {Joseph A.} and Subramaniam Ananthan and Gerdes, {John M.} and Augelli-Szafran, {Corinne E.} and Suto, {Mark J.} and Morrison, {Thomas E.} and Heise, {Mark T.} and Streblow, {Daniel N.} and Pathak, {Ashish K.}",
note = "Funding Information: This work was supported by grants from the National Institutes of Health 1U19AI109680-01 and 1U19AI142759-01. We also acknowledge Drs. Don Bao and Robert Deimler from the Bioanalytical Core at Southern Research for their assistance with the ADME evaluation of compounds. Publisher Copyright: {\textcopyright} 2021 American Chemical Society. All rights reserved.",
year = "2021",
month = apr,
day = "22",
doi = "10.1021/acs.jmedchem.0c02183",
language = "English (US)",
volume = "64",
pages = "4762--4786",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",
}