Isoxazole carboxylic acid methyl ester-based urea and thiourea derivatives as promising antitubercular agents.
Drug resistance
In silico ADME/T
Isoxazole
MmpL3
Mycobacterium
Ureido/thioureido derivative
Journal
Molecular diversity
ISSN: 1573-501X
Titre abrégé: Mol Divers
Pays: Netherlands
ID NLM: 9516534
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
received:
06
07
2022
accepted:
28
09
2022
medline:
26
9
2023
pubmed:
26
10
2022
entrez:
25
10
2022
Statut:
ppublish
Résumé
In our continued efforts to find potential chemotherapeutics active against drug-resistant (DR) Mycobacterium tuberculosis (Mtb), causative agent of Tuberculosis (TB) and to curb the current burdensome treatment regimen, herein we describe the synthesis and biological evaluation of urea and thiourea variants of 5-phenyl-3-isoxazolecarboxylic acid methyl esters as promising anti-TB agent. Majority of the tested compounds displayed potent in vitro activity not only against drug-susceptible (DS) Mtb H37Rv but also against drug-resistant (DR) Mtb. Cell viability test against Vero cells deemed these compounds devoid of significant toxicity. 3,4-Dichlorophenyl derivative (MIC 0.25 µg/mL) and 4-chlorophenyl congener (MIC 1 µg/mL) among urea and thiourea libraries respectively exhibited optimum potency. Lead optimization resulted in the identification of 1,4-linked analogue of 3,4-dichlorophenyl urea derivative demonstrating improved selectivity. Further, in silico study complemented with previously proposed prodrug like attributes of isoxazole esters. Taken together, this molecular hybridization approach presents a new chemotype having potential to be translated into an alternate anti-Mtb agent.
Identifiants
pubmed: 36282413
doi: 10.1007/s11030-022-10543-0
pii: 10.1007/s11030-022-10543-0
pmc: PMC9592870
doi:
Substances chimiques
Antitubercular Agents
0
Urea
8W8T17847W
Carboxylic Acids
0
Esters
0
Thiourea
GYV9AM2QAG
Isoxazoles
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2037-2052Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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