Synthesis of omeprazole analogues and evaluation of these as potential inhibitors of the multidrug efflux pump NorA of Staphylococcus aureus
| Autor: | Daniel-Henri Caignard, Claudine Quentin, Stéphane Moreau, Corinne Arpin, Jean Guillon, Christian Jarry, Jean Grellet, Boubakar B. Ba, Isabelle Forfar-Bares, Céline Vidaillac |
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| Rok vydání: | 2006 |
| Předmět: |
Benzimidazole
Staphylococcus aureus Microbial Sensitivity Tests Pharmacology medicine.disease_cause chemistry.chemical_compound Structure-Activity Relationship Bacterial Proteins Drug Resistance Multiple Bacterial medicine Pharmacology (medical) Enzyme Inhibitors Mechanisms of Action: Physiological Effects Omeprazole Norfloxacin biology Chemistry Reserpine Anti-Bacterial Agents Culture Media Kinetics Infectious Diseases Enzyme inhibitor biology.protein Indicators and Reagents Efflux Multidrug Resistance-Associated Proteins Antibacterial activity medicine.drug |
| Zdroj: | Antimicrobial agents and chemotherapy. 51(3) |
| ISSN: | 0066-4804 |
| Popis: | A series of 11 pyrrolo[1,2- a ]quinoxaline derivatives, 1a to 1k, sharing structural analogies with omeprazole, a eukaryotic efflux pump inhibitor (EPI) used as an antiulcer agent, was synthesized. Their inhibitory effect was evaluated using Staphylococcus aureus strain SA-1199B overexpressing NorA. By determinations of the MIC of norfloxacin in the presence of these EPIs devoid of intrinsic antibacterial activity and used at 128 μg/ml, and by the checkerboard method, compound 1e (MIC decrease, 16-fold; fractional inhibitory concentration index [ΣFIC], 0.18) appeared to be more active than compounds 1b to 1d, reserpine, and omeprazole (MIC decrease, eightfold; ΣFIC, 0.31), followed by compounds 1a and 1f (MIC decrease, fourfold; ΣFIC, 0.37) and 1g to 1k (MIC decrease, twofold; ΣFIC, 0.50 to 0.56). By time-kill curves combining norfloxacin (1/4 MIC) and the most efficient EPIs (128 μg/ml), compound 1e persistently restored the bactericidal activity of norfloxacin (inoculum reduction, 3 log 10 CFU/ml at 8 and 24 h), compound 1f led to a delayed but progressive decrease in the number of viable cells, and compounds 1b to 1d and omeprazole acted synergistically (inoculum reduction, 3 log 10 CFU/ml at 8 h but further regrowth), while compound 1a and reserpine slightly enhanced norfloxacin activity. The bacterial uptake of norfloxacin monitored by high-performance liquid chromatography confirmed that compounds 1a to 1f increased antibiotic accumulation, as did reserpine and omeprazole. Since these EPIs did not disturb the Δψ and ΔpH, they might directly interact with the pump. A structure-activity relationships study identified the benzimidazole nucleus of omeprazole as the main structural element involved in efflux pump inhibition and highlighted the critical role of the chlorine substituents in the stability and efficiency of compounds 1e to 1f. However, further pharmacomodulation is required to obtain therapeutically applicable derivatives. |
| Databáze: | OpenAIRE |
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