Both Nitro Groups Are Essential for High Antitubercular Activity of 3,5-Dinitrobenzylsulfanyl Tetrazoles and 1,3,4-Oxadiazoles through the Deazaflavin-Dependent Nitroreductase Activation Pathway
![Thumbnail](/bitstream/handle/20.500.14178/2175/karabanovich-et-al-both-nitro-groups-are-essential-for-high-antitubercular-activity-of-3-5-dinitrobenzylsulfanyl.pdf.jpg?sequence=5&isAllowed=y)
Author
Fabiánová, Viktória
Vocat, Anthony
Dušek, Jan
Valášková, Lenka
Stolaříková, Jiřina
Kitson, Russell R. A.
Djaout, Kamel
Mikušová, Katarína
Baulard, Alain R.
Cole, Stewart T.
Korduláková, Jana
Publication date
2024Published in
Journal of Medicinal ChemistryVolume / Issue
XXXX (XXX)ISBN / ISSN
ISSN: 0022-2623Metadata
Show full item recordThis publication has a published version with DOI 10.1021/acs.jmedchem.3c00925
Abstract
3,5-Dinitrobenzylsulfanyl tetrazoles and 1,3,4-oxadiazoles, previously identified as having high in vitro activities against both replicating and nonreplicating mycobacteria and favorable cytotoxicity and genotoxicity profiles were investigated. First we demonstrated that these compounds act in a deazaflavin-dependent nitroreduction pathway and thus require a nitro group for their activity. Second, we confirmed the necessity of both nitro groups for antimycobacterial activity through extensive structure-activity relationship studies using 32 structural types of analogues, each in a five-membered series. Only the analogues with shifted nitro groups, namely, 2,5-dinitrobenzylsulfanyl oxadiazoles and tetrazoles, maintained high antimycobacterial activity but in this case mainly as a result of DprE1 inhibition. However, these analogues also showed increased toxicity to the mammalian cell line. Thus, both nitro groups in 3,5-dinitrobenzylsulfanyl-containing antimycobacterial agents remain essential for their high efficacy, and further efforts should be directed at finding ways to address the possible toxicity and solubility issues, for example, by targeted delivery.
Keywords
Tuberculosis
Permanent link
https://hdl.handle.net/20.500.14178/2175License
Full text of this result is licensed under: Creative Commons Uveďte původ 4.0 International