A new class of anti-thrombosis hexahydropyrazino-[1',2':1,6]pyrido-[3,4-b]-indole-1,4-dions: design, synthesis, logK determination, and QSAR analysis.

ABSTRACT

Based on the fact that the cyclization of N-[(3S)]-1,2,3,4-tetrahydro-beta-carboline-3-carboxyl]-l-lysine in both of acetic acid aqueous (5%) and rat plasma gave the same product and the hypothesis that the cyclization product is antithrombotic active, we report the synthesis, in vitro anti-aggregation, and in vivo anti-thrombosis activity of 20 hexahydropyrazino[1',2'1,6]pyrido[3,4-b]indole-1,4-dions (5a-t) as potential anti-thrombosis agents in this study. Two intermediates (tetrahydro-beta-carboline-3-carboxy-l-amino acid benzylesters, 2-aminoacyltetrahydro-beta-carboline-3-carboxylic acid benzylesters) were prepared and used for the cyclization to form 5a-t. Coupling hydrochloric acid salt of tetrahydro-beta-carboline-3-carboxylic acid esters and Boc-amino acids in the reported literature usually generates very low yield products accompanied by racemization. However, in our case, the free base of tetrahydro-beta-carboline-3-carboxylic acid benzylester produced the desired products in high yields and without racemization. The anti-thrombosis results from both in vitro and in vivo studies revealed that 5a-t may be a new class of anti-thrombosis agents with potent effective concentration at 0.5mumol/kg with oral administration. Moreover, a QSAR analysis was performed on these 20 compounds by using molecular descriptors generated by e-dragon server. Although the activities of these compounds are weakly correlated with the logP values, the current QSAR analysis revealed that the anti-thrombotic activity of these compounds can be explained by their steric and electrostatic effects.