Novel halogenated sulfonamide biguanides with anti-coagulation properties

Apart from its hypoglycaemic properties, metformin also offers beneficial effects for the cardiovascular system resulting in significant reduction of diabetes-related death, and all-cause mortality. The aim of this study was to synthesize nine new benzenesulfonamide derivatives of metformin with a halogen substituent, and estimate their influence on selected parameters of plasma and vascular hemostasis. The study describes the synthesis of nine benzenesulfonamide biguanides with o-, m-, and p- chloro-, bromo-, and fluoro substituents. All orto- derivatives (chloro- (1), bromo- (4), and fluoro- (7)) significantly prolong prothrombin time (PT) and partially activated thromboplastin time (APTT). In addition compounds 4 and 7 slow the process of fibrin polymerization, and contribute to increased TT. Multiparametric CL-test revealed that compounds 1, 4, 7 and p-fluorobenzenesulfonamide (9) significantly prolong the onset of clot formation, decrease initial clot formation velocity, and maximum clotting. Analysis of human endothelial cell (HUVECs) and human aortal smooth muscle cell (AoSMCs) viability over the entire tested concentration range (0.001-3.0 μmol/mL) indicated that the examined compounds can undergo further tests up to 1.5 µmol/mL concentration without decreasing cellular viability. Furthermore, none of the synthesized compounds exert an unfavourable effect on erythrocyte integrity, and thus do not interact strongly with the lipid-protein bilayer. In summary, chemical modification of the metformin backbone into benzenesulfonamides containing halogen substituents at the o- position leads to the formation of potential agents with stronger anti-coagulant properties than the parent drug, metformin. Therefore, o-halogenated benzenesulfonamides can be regarded as an initial promising step in the development of novel biguanide-based compounds with anti-coagulant properties.