Differential inhibitory effect of newly synthesized pyridine-2-one derivatives on the cercarial serine protease activity of the parasite Schistosoma mansoni.

Herein, we report on the synthesis of 4 novel pyridine derivatives (P1, 2, 3 and 4) with differential serine protease inhibitory effects utilizing pyridine-2 (1H)-ones as starting materials. When these 4 compounds were tried to inhibit cercarial serine protease, the major penetration enzyme of the parasite Schistosoma mansoni, P1 and P3 exerted the most potent inhibitory effects as demonstrated by abolishing 90% and 97%, respectively, of the enzyme activity, whereas, P4 showed moderate inhibitory effect (abolished 60% of the enzyme activity) and P2 exerted the lowest inhibitory effect (only 10%). The biochemical characteristics of this parasite enzyme were previously reported by using specific substrate and inhibitors for such class of enzymes (13). Kinetics of the cercarial serine protease inhibition by the pyridine derivatives that exerted the most potent inhibition, P1 and P3, was further studied with respect to Michaelis-Menten constants (K(m)), maximum velocity (Vmax) and inhibitory coefficients (K(i)). The results showed that serial dilutions of both P1 and P3 abolished the enzyme activity at different concentrations of the substrate Boc-Val-Leu-Gly-Arg-PNA as demonstrated by drop in Vmax. The K(i) values for P1 and P3 were calculated 0.17 and 0.12 mM, respectively.