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.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acridines / chemical synthesis*
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Acridines / pharmacology
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Animals
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Antitubercular Agents / chemical synthesis*
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Antitubercular Agents / pharmacology
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Cell Line
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Cell Survival / drug effects
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Chlorobenzoates / chemistry
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DNA Gyrase / genetics
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DNA Gyrase / metabolism*
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Dose-Response Relationship, Drug
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Embryo, Nonmammalian / drug effects
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Embryo, Nonmammalian / physiology
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Ether-A-Go-Go Potassium Channels / genetics
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Ether-A-Go-Go Potassium Channels / metabolism
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Gene Expression
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Heart Rate / drug effects
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Microbial Sensitivity Tests
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Mycobacterium tuberculosis
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Piperidines / chemical synthesis*
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Piperidines / pharmacology
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Quinolines / chemical synthesis*
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Quinolines / pharmacology
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Structure-Activity Relationship
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Topoisomerase II Inhibitors / chemical synthesis*
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Topoisomerase II Inhibitors / pharmacology
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Zebrafish
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Zebrafish Proteins / antagonists & inhibitors
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism
Substances
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Acridines
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Antitubercular Agents
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Bacterial Proteins
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Chlorobenzoates
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Erg protein, zebrafish
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Ether-A-Go-Go Potassium Channels
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Piperidines
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Quinolines
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Topoisomerase II Inhibitors
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Zebrafish Proteins
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2-chlorobenzoic acid
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DNA Gyrase