Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis.

doi:10.1021/acs.jmedchem.5b00608

Paper

Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis.

Published Mar 15, 2016 · Galina Karabanovich, Júlia Zemanová, T. Smutny

Journal of medicinal chemistry

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91

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1

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Abstract

Herein, we report the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011-0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.

In Vitro Study

Highly Cited

Study Snapshot

The new class of antitubercular agents, 3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles and 1,3,4-thiadiazoles, show promising activity against Mycobacterium tuberculosis, with low toxicity and no mutagenic

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis.

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References

Bioluminescence for Assessing Drug Potency against Nonreplicating Mycobacterium tuberculosis

The luminescent M. tuberculosis 18b strain, 18b-Lux, effectively assesses drug potency against nonreplicating bacteria, highlighting potential for future applications.

Tetrazole regioisomers in the development of nitro group-containing antitubercular agents

2-alkyl-5-[(3,5-dinitrobenzyl)sulfanyl]-2H-tetrazole derivatives show higher antimycobacterial activity and lower toxicity compared to 1-alkyl isomers, suggesting potential for antitubercular drug development.

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1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles show high potency against drug-susceptible and multidrug-resistant mycobacteria, with low toxicity in mammalian cells.

Bedaquiline for the treatment of resistant tuberculosis: promises and pitfalls.

Bedaquiline shows promise for treating pulmonary MDR-TB, but further clinical trials and data analysis are needed to assess its risk benefit profile and potential benefits.

Towards a new combination therapy for tuberculosis with next generation benzothiazinones

PBTZ169, a next-generation benzothiazinone, shows improved potency, safety, and efficacy in tuberculosis models, making it an attractive drug candidate for human treatment.

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DprE1 and Ddn as promising therapeutic targets in the development of novel anti-tuberculosis nitroaromatic drugs.

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