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Antimicrobial Agents and Chemotherapy, March 2007, p. 831-838, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01306-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Synthesis of Omeprazole Analogues and Evaluation of These as Potential Inhibitors of the Multidrug Efflux Pump NorA of Staphylococcus aureus ^,

Equipe d'Accueil 2962, Laboratoire de Chimie-Physique et Minérale,¹ Equipe d'Accueil 525, Laboratoire de Microbiologie,² Equipe d'Accueil 525, Laboratoire de Pharmacocinétique et Pharmacie Clinique, Faculté de Pharmacie, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France,³ Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France⁴

Received 6 October 2005/ Returned for modification 8 November 2005/ Accepted 2 November 2006

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 [FIC], 0.18) appeared to be more active than compounds 1b to 1d, reserpine, and omeprazole (MIC decrease, eightfold; FIC, 0.31), followed by compounds 1a and 1f (MIC decrease, fourfold; FIC, 0.37) and 1g to 1k (MIC decrease, twofold; FIC, 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 log₁₀ 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 log₁₀ 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 and pH, 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.

Published ahead of print on 13 November 2006.

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