Rational design and Structure-Activity relationship of coumarin derivatives effective on HIV-1 protease and partially on HIV-1 reverse transcriptase

Mei Zhu; Ling Ma; Jiajia Wen; Biao Dong; Yujia Wang; Zhen Wang; Jinming Zhou; Guoning Zhang; Juxian Wang; Ying Guo; Chen Liang; Shan Cen; Yucheng Wang

doi:10.1016/j.ejmech.2019.111900

Rational design and Structure-Activity relationship of coumarin derivatives effective on HIV-1 protease and partially on HIV-1 reverse transcriptase

Eur J Med Chem. 2020 Jan 15:186:111900. doi: 10.1016/j.ejmech.2019.111900. Epub 2019 Nov 20.

Authors

Mei Zhu¹, Ling Ma¹, Jiajia Wen¹, Biao Dong¹, Yujia Wang¹, Zhen Wang², Jinming Zhou¹, Guoning Zhang¹, Juxian Wang¹, Ying Guo³, Chen Liang², Shan Cen⁴, Yucheng Wang⁵

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
² Lady Davis Institute for Medical Research and McGill AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada.
³ Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
⁴ Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: shancen@imb.pumc.edu.cn.
⁵ Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: wangyucheng@imb.pumc.edu.cn.

PMID: 31771827
DOI: 10.1016/j.ejmech.2019.111900

Abstract

Since dual inhibitors may yield lower toxicity and reduce the likelihood of drug resistance, as well as inhibitors of HIV-1 PR and RT constitute the core of chemotherapy for AIDS treatment, we herein designed and synthesized new coumarin derivatives characterized by various linkers that exhibited excellent potency against PR and a weak inhibition of RT. Among which, compounds 6f and 7c inhibited PR with IC₅₀ values of 15.5 and 62.1 nM, respectively, and weakly affected also RT with IC₅₀ values of 241.8 and 188.7 μM, respectively, showing the possibility in the future of developing dual HIV-1 PR/RT inhibitors. Creative stimulation for further research of more potent dual HIV-1 inhibitors was got according to the molecular docking studies.

Keywords: Coumarin; HIV-1 PR inhibitors; HIV-1 RT inhibitors; Pharmacophore fusion types.

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Cell Line
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology*
Dose-Response Relationship, Drug
Drug Design
HIV Infections / drug therapy
HIV Infections / metabolism
HIV Protease / metabolism*
HIV Protease Inhibitors / chemical synthesis
HIV Protease Inhibitors / chemistry
HIV Protease Inhibitors / pharmacology*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects
HIV-1 / enzymology
Humans
Molecular Docking Simulation
Molecular Structure
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Anti-HIV Agents
Coumarins
HIV Protease Inhibitors
Reverse Transcriptase Inhibitors
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
HIV Protease
p16 protease, Human immunodeficiency virus 1