Development of acridine derivatives as selective Mycobacterium tuberculosis DNA gyrase inhibitors

Brahmam Medapi; Nikhila Meda; Pushkar Kulkarni; Perumal Yogeeswari; Dharmarajan Sriram

doi:10.1016/j.bmc.2016.01.011

Development of acridine derivatives as selective Mycobacterium tuberculosis DNA gyrase inhibitors

Bioorg Med Chem. 2016 Feb 15;24(4):877-85. doi: 10.1016/j.bmc.2016.01.011. Epub 2016 Jan 7.

Authors

Brahmam Medapi¹, Nikhila Meda¹, Pushkar Kulkarni², Perumal Yogeeswari¹, Dharmarajan Sriram³

Affiliations

¹ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India.
² Dr Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
³ Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad 500078, India. Electronic address: dsriram@hyderabad.bits-pilani.ac.in.

PMID: 26787274
DOI: 10.1016/j.bmc.2016.01.011

Abstract

In this study we have designed p-phenylene diamine linked acridine derivative from our earlier reported quinoline-aminopiperidine hybrid MTB DNA gyrase inhibitors with aiming more potency and less cardiotoxicity. We synthesized thirty six compounds using four step synthesis from 2-chloro benzoic acid. Among them compound 4-chloro-N-(4-((2-methylacridin-9-yl)amino)phenyl)benzenesulphonamide (6) was found to be more potent with MTB DNA gyrase super coiling IC50 of 5.21±0.51μM; MTB MIC of 6.59μM and no zHERG cardiotoxicity at 30μM and 11.78% inhibition at 50μM against mouse macrophage cell line RAW 264.7.

Keywords: Acridine derivatives; DNA gyrase; Tuberculosis.

Publication types

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

MeSH terms

Acridines / chemical synthesis*
Acridines / pharmacology
Animals
Antitubercular Agents / chemical synthesis*
Antitubercular Agents / pharmacology
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Cell Line
Cell Survival / drug effects
Chlorobenzoates / chemistry
DNA Gyrase / genetics
DNA Gyrase / metabolism*
Dose-Response Relationship, Drug
Embryo, Nonmammalian / drug effects
Embryo, Nonmammalian / physiology
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Ether-A-Go-Go Potassium Channels / genetics
Ether-A-Go-Go Potassium Channels / metabolism
Gene Expression
Heart Rate / drug effects
Macrophages / cytology
Macrophages / drug effects
Macrophages / metabolism
Mice
Microbial Sensitivity Tests
Mycobacterium tuberculosis
Piperidines / chemical synthesis*
Piperidines / pharmacology
Quinolines / chemical synthesis*
Quinolines / pharmacology
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis*
Topoisomerase II Inhibitors / pharmacology
Zebrafish
Zebrafish Proteins / antagonists & inhibitors
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism

Substances

Acridines
Antitubercular Agents
Bacterial Proteins
Chlorobenzoates
Erg protein, zebrafish
Ether-A-Go-Go Potassium Channels
Piperidines
Quinolines
Topoisomerase II Inhibitors
Zebrafish Proteins
2-chlorobenzoic acid
DNA Gyrase