Abstract

Objective: According to the principles of drug design, the structures of picotamide and betrixaban were combined to design novel series of 2-methoxy-5-aminobenzamides. A total of twenty new compounds 1a-1t have been synthesized and evaluated for their antiplatelet aggregation activities in vitro.

Methods: In the structural design of target compounds 1a-1t, the betrixaban was retained group characteristics and the picotamide was retained its 1, 3, 4-substitution position. With 2-methoxybenzoic acid as starting material, compounds 1a-1t were synthesized after 5 steps of nitration, acylation, ammoniation, reduction and secondary ammoniation. And their antiplatelet aggregation activities in vitro were assessed by the Born test with ADP, arachidonic acid and collagen as inducing agents, respectively, and with aspirin and picotamide as two reference drugs.

Results: The compound 1f (46.14%±0.07) had the highest activity for ADP and its IC50 value was 0.17 µM, far better than the two control drugs aspirin (0.44 µM) and picotamide (0.47 µM). The IC50 value of four compounds 1i (0.24 µM), 1j (0.22 µM), 1r (0.25 µM) and 1t (0.24 µM), displayed higher antiplatelet activities in vitro for AA than aspirin (0.43 µM) and picotamide (0.34 µM). Evaluation of cytotoxicity activity of the compounds against L929 cells line revealed that at lower concentration of 10 µmol·L-1, compound 1p had lower effect on L929 cells, and its cell survival rate (88.24%±4.16) was higher than that (82.35%±4.16) of picotamide.

Conclusion: Novel series of 2-methoxy-5-aminobenzamides has shown higher in vitro antiplatelet activities and lower effect on L929 cells at lower concentration.

Keywords: Drug design, 2-methoxy-5-aminobenzamides, picotamide, betrixaban, structural modification, antiplatelet aggregation activities.