Details

Autor(en) / Beteiligte

• 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
• Zhan, Peng
• Liu, Xinyong

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2020-01, Vol.63 (3), p.1298-1312

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.