2. Academic Validation
  3. 2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

  • J Med Chem. 2021 Apr 8;64(7):4239-4256. doi: 10.1021/acs.jmedchem.1c00268.
Dongwei Kang 1 2,  Francesc X Ruiz 3 4,  Yanying Sun 1,  Da Feng 1,  Lanlan Jing 1,  Zhao Wang 1,  Tao Zhang 1,  Shenghua Gao 1,  Lin Sun 1,  Erik De Clercq 5,  Christophe Pannecouque 5,  Eddy Arnold 3 4,  Peng Zhan 1 2,  Xinyong Liu 1 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, Shandong, PR China.
  • 2 China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, Jinan 250012, Shandong, PR 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 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Katholieke Universiteit Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium.
PMID: 33734714 DOI: 10.1021/acs.jmedchem.1c00268
Abstract

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c. 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c as a promising anti-HIV-1 drug candidate.

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