Open AccessDiscovery 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
Author(s) -
Dongwei Kang,
Francesc Xavier Ruiz,
Du Feng,
Alyssa Pilch,
Tong Zhao,
Fenju Wei,
Zhao Wang,
Yun Sun,
Zengjun Fang,
Erik De Clercq,
Christophe Pannecouque,
Eddy Arnold,
Xinyong Liu,
Peng Zhan
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01769
Subject(s) - herg , chemistry , stereochemistry , trifluoromethyl , etravirine , combinatorial chemistry , fluorine , cytotoxicity , in vitro , biophysics , organic chemistry , biochemistry , potassium channel , reverse transcriptase , rna , alkyl , gene , biology
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 (EC 50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC 50 = 155 μM), and reduced hERG inhibition (IC 50 > 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.