Discovery of novel anti-tuberculosis agents with pyrrolo[1,2-a]quinoxaline-based scaffold

Ting Wang; Yunxiang Tang; Yang Yang; Qi An; Zitai Sang; Tao Yang; Pingxian Liu; Tianyu Zhang; Yong Deng; Youfu Luo

doi:10.1016/j.bmcl.2018.04.043

Discovery of novel anti-tuberculosis agents with pyrrolo[1,2-a]quinoxaline-based scaffold

Bioorg Med Chem Lett. 2018 Jun 15;28(11):2084-2090. doi: 10.1016/j.bmcl.2018.04.043. Epub 2018 May 2.

Authors

Ting Wang¹, Yunxiang Tang², Yang Yang¹, Qi An¹, Zitai Sang¹, Tao Yang¹, Pingxian Liu¹, Tianyu Zhang³, Yong Deng⁴, Youfu Luo⁵

Affiliations

¹ Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
² Institute of Physical Science and Information Technology, Anhui University, Hefei 230039, China.
³ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510000, China.
⁴ Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: dengyong@scu.edu.cn.
⁵ Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: luo_youfu@scu.edu.cn.

PMID: 29748048
DOI: 10.1016/j.bmcl.2018.04.043

Abstract

A series of small molecules with novel pyrrolo[1,2-a]quinoxaline-based scaffold was designed via molecular hybridization of privileged agents active against Mycobacterium tuberculosis. Twenty-three compounds were synthesized and investigated for their antitubercular activities in vitro where ten compounds showed appreciable activities and moderate cytotoxicity. Compound 12g with MIC values of 5 μg/ml as a representative may possess better oral bioavailability and indicated high permeability by the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB). Further, the determination of enzyme inhibition and molecular docking study indicated that InhA may be the biological target of the active compounds. The results suggest the pyrrolo[1,2-a]quinoxaline hybrids as potential antitubercular leads for the development of new antitubercular agents.

Keywords: Antituberculosis; InhA inhibitors; Pyrrolo[1,2-a]quinoxaline; XBBXBJCTTIAVDA-UHFFFAOYSA-N.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Quinoxalines / chemical synthesis
Quinoxalines / chemistry
Quinoxalines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Antitubercular Agents
Pyrroles
Quinoxalines
pyrrolo(1,2-a)quinoxaline