RESUMEN
BACKGROUND: Hispolons are natural products known to possess cytoprotective, antioxidant and anti-cancer activities. We have found recently anti TB activity in these compounds. Efforts were made to optimize the structure with bioisosteric replacement of 1,3-diketo functional group with the corresponding pyrazole and isoxazole moieties. OBJECTIVE: The goal of this paper is designing new hispolon isoxazole and pyrazole and the evaluation of their biological activities. METHODS: The designed compounds were prepared using classical organic synthesis methods. The anti- TB activity was evaluated using the MABA method. RESULTS: A total of 44 compounds were synthesized (1a- 1v and 2a-2v) and screened for anti TB activity and antibacterial activity. The compounds 1b and 1n showed the highest potency with MIC 1.6µg/mL against M. tuberculosis H37Rv. CONCLUSION: Bioisosteric replacement of 1,3-diketo functional group in hispolons with pyrazole or isoxazole rings have resulted in potent anti TB molecules. Docking simulations of these compounds on mtFabH enzyme resulted in a clear understanding of bioactivity profiles of these compounds. Docking scores are in good agreement with the anti TB activity obtained for these compounds. Computational studies and in vitro screening results indicate mtFabH as the probable target of these compounds.
Asunto(s)
Antituberculosos/farmacología , Catecoles/farmacología , Isoxazoles/farmacología , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Pirazoles/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Catecoles/síntesis química , Catecoles/química , Evaluación Preclínica de Medicamentos , Isoxazoles/síntesis química , Isoxazoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/químicaRESUMEN
A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6µg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25µg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6µg/mL) followed by H13 (6.25µg/mL) and H17 (12.5µg/mL), H19 (3.125µg/ML). Docking simulations gave good insights on the possible interactions between the tested compounds and ß-keto acyl synthase enzyme (mtbFabH). Drug-inhibitor combination studies showed no synergism with the drugs targeting mycolic acid biosynthesis (isoniazid, ethambutol and thiolactomycin, a specific inhibitor of KAS-B enzyme) but showed significant synergism with other drugs including rifampicin and ciprofloxacin ascertaining the drug target for hispolons as inhibition of mycolic acid biosynthesis, probably via mtbFabH.