2. Academic Validation
  3. 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

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

  • J Med Chem. 2020 Feb 13;63(3):1298-1312. doi: 10.1021/acs.jmedchem.9b01769.
Dongwei Kang 1 2,  F Xavier Ruiz 3 4,  Da Feng 1,  Alyssa Pilch 3 4,  Tong Zhao 1,  Fenju Wei 1,  Zhao Wang 1,  Yanying Sun 1,  Zengjun Fang 5,  Erik De Clercq 6,  Christophe Pannecouque 6,  Eddy Arnold 3 4,  Xinyong Liu 1,  Peng Zhan 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , 44 West Culture Road , 250012 Jinan , Shandong , PR China.
  • 2 Suzhou Research Institute , Shandong University , Room522, Building H of NUSP, NO.388 Ruoshui Road, SIP , Suzhou , 215123 Jiangsu , P.R. China.
  • 3 Center for Advanced Biotechnology and Medicine , Rutgers University , Piscataway , New Jersey 08854 , United States.
  • 4 Department of Chemistry and Chemical Biology , Rutgers University , Piscataway , New Jersey 08854 , United States.
  • 5 The Second Hospital , Shandong University , No. 247 Beiyuan Avenue , Jinan 250033 , China.
  • 6 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy , K.U. Leuven , Herestraat 49 Postbus 1043 (09.A097) , B-3000 Leuven , Belgium.
PMID: 31935327 DOI: 10.1021/acs.jmedchem.9b01769
Abstract

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.

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