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
  • 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.