Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides

Ziwei Hu; Janardhan Banothu; Mallesh Beesu; Collin J Gustafson; Michael J H Brush; Kathryn L Trautman; Alex C D Salyer; Balaji Pathakumari; Sunil A David

doi:10.1021/acsmedchemlett.8b00540

Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides

ACS Med Chem Lett. 2018 Dec 20;10(1):132-136. doi: 10.1021/acsmedchemlett.8b00540. eCollection 2019 Jan 10.

Authors

Ziwei Hu¹, Janardhan Banothu¹, Mallesh Beesu¹, Collin J Gustafson¹, Michael J H Brush¹, Kathryn L Trautman¹, Alex C D Salyer¹, Balaji Pathakumari¹, Sunil A David¹

Affiliation

¹ Department of Medicinal Chemistry, University of Minnesota, Sixth Street SE, Minneapolis, Minnesota 55455, United States.

Abstract

Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification of analogues that induce chemokines and cytokines in a TLR2-dependent manner. These results represent new leads for the development of vaccine adjuvants.