RESUMO
The discovery of antibiotics around the middle twentieth century led to a decrease in the interest in antimycobacterial fatty acids. In order to re-establish the importance of naturally abundant fatty acid, a series of fatty acid-thiadiazole derivatives were designed and synthesized based on molecular hybridization approach. In vitro antimycobacterial potential was established by a screening of synthesized compounds against Mycobacterium tuberculosis H37Rv strain. Among them, compounds 5a, 5d, 5h, and 5j were the most active, with compound 5j exhibiting minimum inhibitory concentration of 2.34 µg/ml against M.tb H37Rv. Additionally, the compounds were docked to determine the probable binding interactions and understand the mechanism of action of most active molecules on enoyl-acyl carrier protein reductases (InhA), which is involved in the mycobacterium fatty acid biosynthetic pathway.
Assuntos
Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/química , Ácidos Graxos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Tiadiazóis/síntese química , Antituberculosos/farmacologia , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiadiazóis/farmacologiaRESUMO
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become the world's leading killer disease due to a single infectious agent which survives in the host macrophage for the indefinite period. Hence, it is necessary to enhance the efficacy of the clinically existing antitubercular agents or to discover new anti antitubercular agents. Here, we report the synthesis, characterization and antimycobacterial evaluation of protein-drug conjugates. A carrier protein, Transferrin (Tf) was covalently conjugated to isoniazid (INH) utilizing hydrazone and amide linkers. The purity of the reactions was confirmed by SDS-PAGE while conjugation was confirmed by UV-visible spectrophotometry, MALDI-TOF analysis, and FTIR spectrophotometry. The in vitro antitubercular assay result showed that the inhibitory activity of the parent drug was conserved in both the conjugates. The conjugates were effective against intracellular Mtb H37Rv and were devoid of cytotoxic effect at therapeutic concentration.