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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
G. Karabanovich, V. Fabiánová, A. Vocat, J. Dušek, L. Valášková, J. Stolaříková, RRA. Kitson, P. Pávek, K. Vávrová, K. Djaout, K. Mikušová, AR. Baulard, ST. Cole, J. Korduláková, J. Roh
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Odkazy
PubMed
38157261
DOI
10.1021/acs.jmedchem.3c00925
Knihovny.cz E-zdroje
- MeSH
- antituberkulotika farmakologie chemie MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis MeSH
- nitroreduktasy MeSH
- oxadiazoly farmakologie chemie MeSH
- savci MeSH
- tetrazoly farmakologie chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
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