Diaryl-substituted thiosemicarbazone: A potent scaffold for the development of New Delhi metallo-ß-lactamase-1 inhibitors.
Bioorg Chem
; 107: 104576, 2021 02.
Article
em En
| MEDLINE
| ID: mdl-33383326
ABSTRACT
The superbug infection caused by New Delhi metallo-ß-lactamase (NDM-1) has become an emerging public health threat. Inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. A potent scaffold, diaryl-substituted thiosemicarbazone, was constructed and assayed with metallo-ß-lactamases (MßLs). The obtained twenty-six molecules specifically inhibited NDM-1 with IC50 0.038-34.7 µM range (except 1e, 2e, and 3d), and 1c is the most potent inhibitor (IC50 = 0.038 µM). The structure-activity relationship of synthetic thiosemicarbazones revealed that the diaryl-substitutes, specifically 2-pyridine and 2-hydroxylbenzene improved inhibitory activities of the inhibitors. The thiosemicarbazones exhibited synergistic antimycobacterial actions against E. coli-NDM-1, resulted a 2-512-fold reduction in MIC of meropenem, while 1c restored 16-256-, 16-, and 2-fold activity of the antibiotic on clinical isolates ECs, K. pneumonia and P. aeruginosa harboring NDM-1, respectively. Also, mice experiments showed that 1c had a synergistic antibacterial ability with meropenem, reduced the bacterial load clinical isolate EC08 in the spleen and liver. This work provided a highly promising scaffold for the development of NDM-1 inhibitors.
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Base de dados:
MEDLINE
Assunto principal:
Tiossemicarbazonas
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Beta-Lactamases
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Inibidores Enzimáticos
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Antibacterianos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article