Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV‑1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel

• Published in: Journal of medicinal chemistry 2020-02, Vol.63 (3), p.1298-1312
• Main Authors: Kang, Dongwei, Ruiz, F. Xavier, Feng, Da, Pilch, Alyssa, Zhao, Tong, Wei, Fenju, Wang, Zhao, Sun, Yanying, Fang, Zengjun, De Clercq, Erik, Pannecouque, Christophe, Arnold, Eddy, Liu, Xinyong, Zhan, Peng
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01769

Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60–21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 μM), and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.