Design, synthesis and biological evaluation of substituted (+)-SG-1 derivatives as novel anti-HIV agents

Xiaoyu Liu; Panpan Chen; Xiaoyu Li; Mingyu Ba; Xiaozhen Jiao; Ying Guo; Ping Xie

doi:10.1016/j.bmcl.2018.04.049

Design, synthesis and biological evaluation of substituted (+)-SG-1 derivatives as novel anti-HIV agents

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1699-1703. doi: 10.1016/j.bmcl.2018.04.049. Epub 2018 Apr 20.

Authors

Xiaoyu Liu¹, Panpan Chen², Xiaoyu Li¹, Mingyu Ba², Xiaozhen Jiao³, Ying Guo⁴, Ping Xie¹

Affiliations

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 100050, People's Republic of China.
² State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
³ State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 100050, People's Republic of China. Electronic address: jiaoxz@imm.ac.cn.
⁴ State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China. Electronic address: yingguo6@imm.ac.cn.

PMID: 29699924
DOI: 10.1016/j.bmcl.2018.04.049

Abstract

SG-1 was previously identified as a potent Non-nucleoside reverse transcriptase inhibitors (NNRTI) which works through inhibition of reverse transcriptase (RT) RNA-dependent DNA polymerase activity via a direct binding event. To further investigate the relationship between its structure and activity, four series of novel analogues were designed and synthesized with 12 of them inhibiting HIV-1 replication with IC₅₀s in the range 0.09-6.71 μM. Compound 4b, 4c, 4f, 2 and 6b were further tested on two NNRTI-resistant HIV-1 strains and one NNRTI-resistant superbug. The result showed that RT- E138K/M184V mutant virus conferred 4.7-9.1-fold resistance to 4c, 4f, 2 and 6b, but only showed slight resistance to 4b (2-fold) which was better than SG-1.

Keywords: HIV; NNRTI-resistant; NNRTIs; SG-1; Structure-activity relationship.

Publication types

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

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Resistance, Viral / drug effects
Gangliosides / chemical synthesis
Gangliosides / chemistry
Gangliosides / pharmacology*
HIV-1 / drug effects*
Microbial Sensitivity Tests
Molecular Structure
Stereoisomerism
Structure-Activity Relationship

Substances

Anti-HIV Agents
Gangliosides
sperm ganglioside 1