Preliminary Study On Pharmacologi-cal Activity And Structure Activity Relationships Of 4-methoxybenzene-1,3-Disulfonamides

The pathogenesis of thrombus was described in this thesis. And the structure activity relationship of anti-platelet aggregation drugs was discussed.In order to find efficient, low toxicity, and a variety of broad-spectrum anti-platelet aggregation inhibitors, according to corresponding literature and previous works of our laboratory, Picotamide, which can simultaneously inhibit TXA2 synthetase and antagonise TXA2/PGH2, and Linotroban were chosen as leading comp-ound. Based on the result of Co MFA, fifteen 4-methoxybenzene-1,3-disulfonamides were designed and synthesized on the Basic Principles of Drug Design. The structures of each target compounds were confirmed by Melting point, IR,1H NMR and ESI-MS.All the desired compounds were tested platelet aggregation activity using ADP as an inducer by Born test. Among these compounds, five had higher activity than Picotamide, and especicially, PN555 had the minimum IC50 value and the highest activity. In addition, ten had equivalent or lower activity. compound PN552, PN553,PN555, PN560 and PN562 which had smaller IC50 values were selected to measure aggregation activities induced by collagen and arachidonic acid. Experimental results showed that only PN562 had higher aggregation activity than Aspirin and Picotamide induced by collagen; anti-platelet aggregation activity of each compound was weaker than Picotamide induced by arachidonic. Screening four target compounds(PN553,PN555, PN560, PN562) which higher activities further study on their toxicity, taking Picotamide and aspirin as positive control drugs. The results showed that PN553,PN560 and PN562 have low toxicity equal to Picotamide at three concentrations considerably, much lower to Aspirin. Cytotoxicity test of compounds PN553, PN560 and PN562 on L-929 cells showed that three tested compounds in high and general doses have low toxicities on cells, similar to reference drug Picotamide.The outstanding perfoamance of compound PN562 in anti-platelet aggregation test, acute toxicity test in mice, L-929 cytotoxicity tests, was worthy of further research and development of value. The preliminary structure-activity relationship of the synthesized compounds was summarized and conjectured.