2. Academic Validation
  3. Structure-Based Optimization of 2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Exploiting the Tolerant Regions of the Non-Nucleoside Reverse Transcriptase Inhibitors' Binding Pocket

Structure-Based Optimization of 2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Exploiting the Tolerant Regions of the Non-Nucleoside Reverse Transcriptase Inhibitors' Binding Pocket

  • J Med Chem. 2023 Feb 9;66(3):2102-2115. doi: 10.1021/acs.jmedchem.2c01875.
Fabao Zhao 1,  Heng Zhang 1,  Minghui Xie 1,  Bairu Meng 1,  Na Liu 1,  Caiyun Dun 1,  Yanyang Qin 1,  Shenghua Gao 1,  Erik De Clercq 2,  Christophe Pannecouque 2,  Ya-Jie Tang 3,  Peng Zhan 1 4,  Xinyong Liu 1 4,  Dongwei Kang 1 4
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 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), Leuven B-3000, Belgium.
  • 3 State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
  • 4 China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, Jinan 250012 Shandong, PR China.
PMID: 36700940 DOI: 10.1021/acs.jmedchem.2c01875
Abstract

Although non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) exhibit potent anti-HIV-1 activity and play an important role in the active antiretroviral therapy of AIDS, the emergence of drug-resistant strains has seriously reduced their clinical efficacy. Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 NNRTIs by exploiting the tolerant regions of the NNRTI binding pocket. Compounds 16b and 16c were demonstrated to have excellent activity (EC50 = 3.14-22.1 nM) against wild-type and a panel of mutant HIV-1 strains, being much superior to that of etravirine (EC50 = 3.53-52.2 nM). Molecular modeling studies were performed to illustrate the detailed interactions between RT and 16b, which shed light on the improvement of the drug resistance profiles. Moreover, 16b possessed favorable pharmacokinetic (T1/2 = 1.33 h, F = 31.8%) and safety profiles (LD50 > 2000 mg/kg), making it a promising anti-HIV-1 drug candidate for further development.

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