For several years, our group has been developing quinoxalinic compounds. Two of them, N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine (EAPB0203) and 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503), have emerged as the most promising anticancer drugs. In the present work, we determined metabolism pathways using liver microsomes from four mammalian species including human. We identified the cytochrome P450 isoform(s) involved in the metabolism and then investigated the pharmacokinetics and metabolism of EAPB0203 and EAPB0503 in rat after intravenous and intraperitoneal administration. Biotransformation of the compounds involved demethylation and hydroxylation reactions. Rat and dog metabolized the compounds at a higher rate than mouse and human. In all species, CYP1A1/2 and CYP3A isoforms were the predominant enzymes responsible for the metabolism. From human liver microsomes, unbound intrinsic clearances were approximately 56 ml/(min · g) protein. EAPB0203 and EAPB0503 were extensively bound to human plasma proteins, mainly human serum albumin (HSA) (∼98-99.5%). Thus, HSA could act as carrier of these compounds in human plasma. Scatchard plots showed patterns in which the plots yielded upwardly convex hyperbolic curves. On the basis of the Hill coefficients, there appears to be interaction between the binding sites of HSA, suggesting positive cooperativity. The main in vitro metabolites were identified in vivo. Total clearances of EAPB0203 and EAPB0503 [3.2 and 2.2 l/(h · kg), respectively] were notably lower than the typical cardiac plasma output in rat. The large volumes of distribution of these compounds (4.3 l/kg for EAPB0203 and 2.5 l/kg for EAPB0503) were consistent with extensive tissue binding. After intraperitoneal administration, bioavailability was 22.7% for EAPB0203 and 35% for EAPB0503 and a significant hepatic first-pass effect occurred.

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The synthesis and properties of some new 7-cyclopropyl-4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acids and the 7-tert-butyl analogues, incorporating substituents at positions 2 and 3, are described. The antibacterial activity of these derivatives and of the parent 7-alkyl-2-chloro compounds, unsubstituted at position 3, has been evaluated against an assortment of micro-organisms. 2-Chloro-7-cyclopropyl-4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acid (3a) was found to possess leading in vitro activity among 4-thieno[2,3-b]pridinones known to date. However, none of the 3-nitro- or 3-amino-2-(4-methyl-1-piperazinyl) derivatives (4–6) showed interesting antibacterial activity.

Resume Une etude de relations structure—activite a ete effectuee sur une serie de quinolones et naphtyridines antibacteriennes. Les vecteurs d'autocorrelation ont ete utilises comme descripteurs structuraux. Les variables obtenues ont ete traitees par une analyse en composantes principales, une analyse discriminante et une classification ascendante hierarchique. Sur un echantillon de 122 composes les molecules actives et inactives sont correctement discriminees par deux variables.