Synthesis of omeprazole analogues and evaluation of these as potential inhibitors of the multidrug efflux pump NorA of Staphylococcus aureus.

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 microg/ml, and by the checkerboard method, compound 1e (MIC decrease, 16-fold; fractional inhibitory concentration index [SigmaFIC], 0.

Probing the role of the covalent linkage of ferrocene into a chloroquine template.

A new therapeutic approach to malaria led to the discovery of ferroquine (FQ, SR97276). To assess the importance of the linkage of the ferrocenyl group to a 4-aminoquinoline scaffold, two series of 4-aminoquinolines, structurally related to FQ, were synthesized. Evaluation of antimalarial activity, physicochemical parameters, and the beta-hematin inhibition property indicate that the ferrocene moiety has to be covalently flanked by a 4-aminoquinoline and an alkylamine.

Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity.

Ferroquine (FQ) is a 4-aminoquinoline antimalarial which contains a quinoline nucleus similar to chloroquine, but a novel ferrocenic group in its side chain. Previous work has demonstrated that this compound has excellent activity against malaria parasites, both in vitro and in vivo, with especially good activity against chloroquine-resistant parasites, but details of its mechanism of action have not previously been reported. In this study, we have investigated the physicochemical properties of FQ for comparison with chloroquine (CQ).

Development of a rapid RP-HPLC method for the determination of clonazepam in human plasma.

A rapid and sensitive high-performance liquid chromatography method with UV detection was developed for the determination of clonazepam in human plasma using 3-methylclonazepam, as internal standard. A one-step extraction of both compounds was performed with a mixture of hexane/ethyl acetate (90:10, v/v). The HPLC analysis was carried out on a Nova Pak((R)) C(18) reversed-phase column with a mobile phase of acetonitrile-0.

Synthesis, antimalarial activity, and molecular modeling of new pyrrolo[1,2-a]quinoxalines, bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines.

Three pyrrolo[1,2-a]quinoxalines, 15 bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines were synthesized from various substituted nitroanilines or nitropyridines and tested for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. Bispyrrolo[1,2-a]quinoxalines showed superior antimalarial activity with respect to monopyrrolo[1,2-a]quinoxalines. The best activity was observed with bispyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine.