RESUMO
Being crucial part of plant-based novel discovery of drug from natural resources, a study was done to explore the antibacterial potential of curcumin mimics in combination with antibiotics against multidrug resistant isolates of Pseudomonas aeruginosa. The best candidate Van D, a curcumin mimics reduced the MIC of tetracycline (TET) up to 16 folds against multidrug resistant clinical isolates. VanD further inhibited the efflux pumps as evident by ethidium bromide efflux and by in-silico docking studies. In another experiment, it was also found that Van D inhibits biofilm synthesis. This derivative kills the KG-P2, an isolate of P. aeruginosa in a time dependent manner, the post-antibiotic effect (PAE) of tetracycline was extended as well as mutant prevention concentration (MPC) of TET was also decreased. In Swiss albino mice, Van D reduced the proinflammatory cytokines concentration. In acute oral toxicity study, this derivative was well tolerated and found to be safe up to 1000 mg/kg dose. To the best of our knowledge, this is the first report on curcumin mimics as synergistic agent via inhibition of efflux pump.
Assuntos
Antibacterianos/uso terapêutico , Chalconas/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/toxicidade , Proteínas da Membrana Bacteriana Externa/metabolismo , Biofilmes/efeitos dos fármacos , Chalconas/síntese química , Chalconas/metabolismo , Chalconas/toxicidade , Curcumina/química , Curcumina/farmacologia , Desenho de Fármacos , Sinergismo Farmacológico , Feminino , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ligação Proteica , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Tetraciclina/farmacologiaRESUMO
Prostate cancer is one of the most common cancers in men. Diosgenin and related compounds are potential cytotoxic agents. Twelve diverse analogues of long chain fatty acid/ester of diosgenin-7-ketoxime have been prepared. Six of the analogues exhibited significant anticancer activity against a panel of human cancer cell lines with IC50 ranging from 12 to 35µM. Compound 16, the best representative of the series exerted S phase arrest in DU145 prostate cancer cells and induced apoptosis through caspase pathway. Additionally, these analogues inhibited lipopolysaccharide induced pro-inflammatory cytokines (TNF-α and IL-6) up to 47.7% and 23.3% respectively. Compound 16 was found to be safe in acute oral toxicity in Swiss albino mice up to 300mg/kg dose. The anticancer and antiinflammatory properties of compound 16 are important and can further be optimized for a better anti-prostate cancer candidate.
