SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity

Abstract

It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC₅₀ of 1 nM, and viral replication of VSV and WSN-Influenza with an EC₅₀ of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.

Keywords: anti-viral; high-throughput screening; human DHODH inhibitor; structure-activity relationship.

Figure 1

SAR starting point.

Chart 1. Conformationally Restricted Analogues

Chart 2. VSV Inhibition with Diaryl Ether Analoguesa

Figure 2

X-ray structure of human DHODH bound to C44 solved to 1.2 Å resolutions. The 4 Å shell around C44 is displayed, and the structure is aligned to the previously reported human DHODH structure complexed with brequinar (1D3G). The protein chain for the C44 structure is shown in orange, and the brequinar structure is shown in turquoise. The bound C44 and brequinar are shown as ball and stick. The bound FMN cofactor and the product orotate are also shown.