6-Fluorophenylbenzohydrazides inhibit Mycobacterium tuberculosis growth through alteration of tryptophan biosynthesis.
Eur J Med Chem
; 226: 113843, 2021 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-34520959
ABSTRACT
A major constraint in reducing tuberculosis epidemic is the emergence of strains resistant to one or more of clinically approved antibiotics, which emphasizes the need of novel drugs with novel targets. Genetic knockout strains of Mycobacterium tuberculosis (Mtb) have established that tryptophan (Trp) biosynthesis is essential for the bacterium to survive in vivo and cause disease in animal models. An anthranilate-like compound, 6-FABA, was previously shown to synergize with the host immune response to Mtb infection in vivo. Herein, we present a class of anthranilate-like compounds endowed with good antimycobacterial activity and low cytotoxicity. We show how replacing the carboxylic moiety with a hydrazide led to a significant improvement in both activity and cytotoxicity relative to the parent compound 6-FABA. Several new benzohydrazides (compounds 20-31, 33, 34, 36, 38 and 39) showed good activities against Mtb (0.625 ≤ MIC≤6.25 µM) and demonstrated no detectable cytotoxicity against Vero cell assay (CC50 ≥ 1360 µM). The target preliminary studies confirmed the hypothesis that this new class of compounds inhibits Trp biosynthesis. Taken together, these findings indicate that fluorophenylbenzohydrazides represent good candidates to be assessed for drug discovery.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
2_ODS3
Base de dados:
MEDLINE
Assunto principal:
Triptofano
/
Hidrazinas
/
Mycobacterium tuberculosis
/
Antituberculosos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2021
Tipo de documento:
Article