Design, synthesis, and biological evaluation of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential anti-HIV-1 agents with reduced cytotoxicity

Boshi Huang; Dongwei Kang; Ye Tian; Dirk Daelemans; Erik De Clercq; Christophe Pannecouque; Peng Zhan; Xinyong Liu

doi:10.1111/cbdd.13760

Design, synthesis, and biological evaluation of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential anti-HIV-1 agents with reduced cytotoxicity

Chem Biol Drug Des. 2021 Jan;97(1):67-76. doi: 10.1111/cbdd.13760. Epub 2020 Aug 3.

Authors

Boshi Huang¹, Dongwei Kang¹, Ye Tian¹, Dirk Daelemans², Erik De Clercq², Christophe Pannecouque², Peng Zhan¹, Xinyong Liu¹

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, China.
² Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U.Leuven, Leuven, Belgium.

PMID: 32725669
DOI: 10.1111/cbdd.13760

Abstract

Taking the previously reported compound BH-7d as the lead, we designed and synthesized a series of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidines, and their anti-HIV activities as well as cytotoxicities were evaluated. Several compounds exhibited moderate anti-HIV (IIIB) potency, among which 2b was the most active one (EC₅₀ = 4.29 μM). Structure-activity relationships derived from the antiretroviral results were analyzed. Additionally, most compounds demonstrated reduced cytotoxicity (CC₅₀ > 200 μM) compared with those of BH-7d and etravirine. Molecular docking study further revealed the binding conformation of 2b in the binding pocket of HIV-1 reverse transcriptase.

Keywords: [1,2,4]Triazolo[1,5-a]pyrimidines; anti-HIV-1 potency; molecular docking; reduced cytotoxicity; reverse transcriptase.

Publication types

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

MeSH terms

Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / metabolism
Anti-HIV Agents / pharmacology
Binding Sites
Cell Line
Cell Survival / drug effects
Drug Design*
HIV Reverse Transcriptase / antagonists & inhibitors
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-1 / enzymology
Humans
Molecular Docking Simulation
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / pharmacology
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / metabolism
Reverse Transcriptase Inhibitors / pharmacology
Structure-Activity Relationship
Triazoles / chemistry*
Triazoles / metabolism
Triazoles / pharmacology

Substances

Anti-HIV Agents
Pyrimidines
Reverse Transcriptase Inhibitors
Triazoles
triazolo(1,5-a)pyrimidine
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase