Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.
Eur J Med Chem
; 199: 112402, 2020 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-32417538
ABSTRACT
Tuberculosis remains the most deadly infectious disease worldwide due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Hence, there is a great need for more efficient treatment regimens. Herein, we carried out rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) (PDB code 5OIL). Although this compound fulfills all structural requirements to interact with InhA, it does not inhibit the enzyme effectively. With the aim of improving the inhibition value, we synthesized thiourea-based derivatives by one-pot reaction of the amines with corresponding isothiocyanates. After the structural characterization using 1H NMR, 13C NMR, FTIR and HRMS, the obtained compounds were initially tested for their abilities to inhibit Mycobacterium tuberculosis growth. The results revealed that some compounds exhibited promising antitubercular activity, MIC values at 0.78 and 1.56 µg/mL, combined with low cytotoxicity. Moreover, the most active compounds were tested against latent as well as dormant forms of the bacteria utilizing nutrient starvation model and Mycobacterium tuberculosis infected macrophage assay. Enzyme inhibition assay against enoyl-acyl carrier protein reductase identified InhA as the important target of some compounds. Molecular docking studies were performed to correlate InhA inhibition data with in silico results. Finally, theoretical calculations were established to predict the physicochemical properties of the most active compounds.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Oxidorreductasas
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Tiourea
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Proteínas Bacterianas
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Diseño de Fármacos
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Inhibidores Enzimáticos
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Mycobacterium tuberculosis
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Antituberculosos
Límite:
Animals
Idioma:
En
Revista:
Eur J Med Chem
Año:
2020
Tipo del documento:
Article