2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase

Zhongliang Xu; Mingyu Ba; Hua Zhou; Yingli Cao; Chaojun Tang; Ying Yang; Ricai He; Yu Liang; Xuemei Zhang; Zhenzhong Li; Lihong Zhu; Ying Guo; Changbin Guo

doi:10.1016/j.ejmech.2014.07.072

2,4,5-Trisubstituted thiazole derivatives: a novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase

Eur J Med Chem. 2014 Oct 6:85:27-42. doi: 10.1016/j.ejmech.2014.07.072. Epub 2014 Jul 22.

Authors

Zhongliang Xu¹, Mingyu Ba², Hua Zhou¹, Yingli Cao², Chaojun Tang¹, Ying Yang², Ricai He¹, Yu Liang¹, Xuemei Zhang², Zhenzhong Li¹, Lihong Zhu¹, Ying Guo³, Changbin Guo⁴

Affiliations

¹ Department of Chemistry, Capital Normal University, Beijing 100048, China.
² State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
³ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
⁴ Department of Chemistry, Capital Normal University, Beijing 100048, China. Electronic address: [email protected].

PMID: 25072874
DOI: 10.1016/j.ejmech.2014.07.072

Abstract

Novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among the thirty-eight synthesized target compounds, thirty TSTs showed potent inhibition against HIV-1 replication in wild type HIV-1 at submicromolar concentrations (from 0.046 to 9.59 μM). Compounds 21, 23 and 24 were also tested on seven NNRTI-resistant HIV-1 strains, and all exhibited inhibitory effects with fold changes in IC50 ranging from 2.6 to 111, which were better than those of nevirapine (15.6-fold-371-fold). Docking simulations of compound 24 revealed a reasonable mechanism for the binding mode, and three-dimensional quantitative structure activity relationship (3-DQSAR) studies on this novel series of TST further elucidated the structure-activity relationship (SAR). The results suggested the great potential of TSTs as a novel class of NNRTIs with antiviral efficacy and a good resistance profile.

Keywords: 2,4,5-Trisubstituted thiazole derivatives; HIV-1; Molecular modeling; Non-nucleoside reverse transcriptase inhibitors; Three-dimensional quantitative structure activity relationship.

Publication types

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

MeSH terms

Drug Design*
Drug Resistance, Viral / drug effects
HEK293 Cells
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / chemistry
HIV Reverse Transcriptase / genetics*
HIV-1 / drug effects
HIV-1 / enzymology*
HIV-1 / genetics
Humans
Inhibitory Concentration 50
Models, Molecular
Mutation*
Protein Conformation
Quantitative Structure-Activity Relationship
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology
Thiazoles / chemistry*
Thiazoles / pharmacology*

Substances

Reverse Transcriptase Inhibitors
Thiazoles
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase