Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors

Zi-Hong Yan; Hai-Qiu Wu; Wen-Xue Chen; Yan Wu; Hu-Ri Piao; Qiu-Qin He; Fen-Er Chen; Erik De Clercq; Christophe Pannecouque

doi:10.1016/j.bmc.2014.03.020

Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors

Bioorg Med Chem. 2014 Jun 15;22(12):3220-6. doi: 10.1016/j.bmc.2014.03.020. Epub 2014 Mar 27.

Authors

Zi-Hong Yan¹, Hai-Qiu Wu¹, Wen-Xue Chen¹, Yan Wu², Hu-Ri Piao², Qiu-Qin He³, Fen-Er Chen⁴, Erik De Clercq⁵, Christophe Pannecouque⁵

Affiliations

¹ Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
² College of Pharmacy, Yanbian University, Yanji 133000, People's Republic of China.
³ Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China. Electronic address: qqhe@fudan.edu.cn.
⁴ Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Institute of Biomedical Science, Fudan University, Shanghai 200433, People's Republic of China. Electronic address: rfchen@fudan.edu.cn.
⁵ Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.

PMID: 24794751
DOI: 10.1016/j.bmc.2014.03.020

Abstract

A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC50 values of 0.005 and 0.009 μM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC50 value of 8.2 μM. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated.

Keywords: Antiviral activity; Diarylpyrimidine; HIV-1; NNRTIs; SAR.

Publication types

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

MeSH terms

Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / pharmacology*
Benzamides / chemical synthesis*
Benzamides / pharmacology*
Cell Survival / drug effects
Cells, Cultured
Drug Design*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV-1 / drug effects
Humans
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Nitriles
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Precursor Cell Lymphoblastic Leukemia-Lymphoma / virology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
Virus Replication / drug effects

Substances

4-((4-((3-bromophenyl)chloromethyl)pyrimidin-2-yl)amino)benzonitrile
4-((4-(chloro(3-chlorophenyl)methyl)pyrimidin-2-yl)amino)benzonitrile
Anti-HIV Agents
Benzamides
Nitriles
Pyrimidines
Reverse Transcriptase Inhibitors
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase