Design, synthesis and anti-HIV evaluation of novel 5-substituted diarylpyrimidine derivatives as potent HIV-1 NNRTIs

Ping Gao; Shu Song; Zhao Wang; Lin Sun; Jian Zhang; Christophe Pannecouque; Erik De Clercq; Peng Zhan; Xinyong Liu

doi:10.1016/j.bmc.2021.116195

Design, synthesis and anti-HIV evaluation of novel 5-substituted diarylpyrimidine derivatives as potent HIV-1 NNRTIs

Bioorg Med Chem. 2021 Jun 15:40:116195. doi: 10.1016/j.bmc.2021.116195. Epub 2021 May 5.

Authors

Ping Gao¹, Shu Song², Zhao Wang², Lin Sun², Jian Zhang³, Christophe Pannecouque⁴, Erik De Clercq⁴, Peng Zhan⁵, Xinyong Liu⁶

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China; Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
² Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China.
³ Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, 250033, China.
⁴ Rega Institute for Medical Research, K. U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
⁵ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].
⁶ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: [email protected].

PMID: 33979774
DOI: 10.1016/j.bmc.2021.116195

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. As a continuation of our efforts to discover and develop "me-better" drugs of DAPYs, novel diarylpyrimidine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds demonstrated strong inhibition activity against wide-type HIV-1 strain (III_B) with EC₅₀ values in the range of 2.5 nM ~ 0.93 μM. Among them, compounds IVB-5-4 and IVB-5-8 were the most potent ones which showed anti-HIV-1_IIIB activity much superior than that of Nevirapine, comparable to Efavirenz and Etravirine. What's more, some compounds also showed low nanomole activity against some mutant strains such as K103N and E138K. The selected compound IVB-5-4 was also evaluated for the activity against reverse transcriptase (RT), and exhibited submicromolar IC₅₀ values indicating that this series compounds are specific RT inhibitors. Preliminary structure-activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization.

Keywords: Antiviral; DAPYs; Drug design; Drug resistance; HIV-1; NNRTIs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Design*
HIV / drug effects*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
Humans
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Reverse Transcriptase Inhibitors
Structure-Activity Relationship

Substances

Anti-HIV Agents
Pyrimidines
Reverse Transcriptase Inhibitors
HIV Reverse Transcriptase