Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives

Subhash Chander; Ping Wang; Penta Ashok; Liu-Meng Yang; Yong-Tang Zheng; Murugesan Sankaranarayanan

doi:10.1016/j.bmcl.2016.11.030

Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives

Bioorg Med Chem Lett. 2017 Jan 1;27(1):61-65. doi: 10.1016/j.bmcl.2016.11.030. Epub 2016 Nov 14.

Authors

Subhash Chander¹, Ping Wang², Penta Ashok¹, Liu-Meng Yang², Yong-Tang Zheng³, Murugesan Sankaranarayanan⁴

Affiliations

¹ Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India.
² Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China.
³ Laboratory of Molecular Immunopharmacology, Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, PR China. Electronic address: zhengyt@mail.kiz.ac.cn.
⁴ Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India. Electronic address: murugesan@pilani.bits-pilani.ac.in.

PMID: 27894873
DOI: 10.1016/j.bmcl.2016.11.030

Abstract

In this study, using molecular hybridization approach, fourteen novel 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives (7a-n) were designed as inhibitor of HIV-1 RT. The binding affinity of the designed compounds with HIV-1 RT as well as their drug-likeness behavior was predicted using in-silico studies. All the designed compounds were synthesized, characterized and in-vitro evaluated for HIV-1 RT inhibitory activity, in which tested compounds displayed significant to weak potency against the selected target. Moreover, best active compounds of the series, 7k and 7m inhibited the activity of RT with IC₅₀ values 14.18 and 12.26μM respectively. Structure Activity Relationship (SAR) studies were also performed in order to predict the influence of substitution pattern on the RT inhibitory potency. Anti-HIV-1 and cytotoxicity studies of best five RT inhibitor (7a, 7d, 7k, 7L and 7m) revealed that, except compound 7d other compounds retained significant anti-HIV-1 potency with good safety index. Best scoring pose of compound 7m was analysed in order to predict its putative binding mode with wild HIV-1 RT.

Keywords: Cytotoxicity; Docking; Enzymatic assay; Reverse transcriptase; Wild strain.

Publication types

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

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
CD4-Positive T-Lymphocytes / drug effects*
Dose-Response Relationship, Drug
Drug Design*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects*
Humans
Microbial Sensitivity Tests
Molecular Structure
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology*
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Anti-HIV Agents
Piperazines
Reverse Transcriptase Inhibitors
HIV Reverse Transcriptase