2. Academic Validation
  3. Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors

Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors

  • J Med Chem. 2021 Apr 22;64(8):4762-4786. doi: 10.1021/acs.jmedchem.0c02183.
S Kaleem Ahmed 1,  Nicole N Haese 2,  Jaden T Cowan 1,  Vibha Pathak 1,  Omar Moukha-Chafiq 1,  Valerie J Smith 1,  Kevin J Rodzinak 1,  Fahim Ahmad 1,  Sixue Zhang 1,  Kiley M Bonin 2,  Aaron D Streblow 2,  Cassilyn E Streblow 2,  Craig N Kreklywich 2,  Clayton Morrison 3,  Sanjay Sarkar 3,  Nathaniel Moorman 4,  Wes Sander 4,  Robbie Allen 5,  Victor DeFilippis 2,  Babu L Tekwani 1,  Mousheng Wu 1,  Alec J Hirsch 2,  Jessica L Smith 2,  Nichole A Tower 1,  Lynn Rasmussen 1,  Robert Bostwick 1,  Joseph A Maddry 1,  Subramaniam Ananthan 1,  John M Gerdes 1,  Corinne E Augelli-Szafran 1,  Mark J Suto 1,  Thomas E Morrison 6,  Mark T Heise 3,  Daniel N Streblow 2,  Ashish K Pathak 1
Affiliations

Affiliations

  • 1 Drug Discovery 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 Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, United States.
  • 4 Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, United States.
  • 5 Oregon Translational Research and Development Institute, Portland, Oregon 97239, United States.
  • 6 Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 E. 19th Avenue, Aurora, Colorado 80045, United States.
PMID: 33835811 DOI: 10.1021/acs.jmedchem.0c02183
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z