Synthetic Inhibitors of Snake Venom Enzymes: Thioesters Derived from 2-Sulfenyl Ethylacetate

Snakebite envenomings are a global public health issue. The therapy based on the administration of animal-derived antivenoms has limited efficacy against the venom-induced local tissue damage, which often leads to permanent disability. Therefore, there is a need to find inhibitors against toxins responsible for local damage. This work aimed to synthesize thioesters derived from 2-sulfenyl ethylacetate and to evaluate the inhibitory effects on two snake venom toxins. Ethyl 2-((4-chlorobenzoyl)thio)acetate (I), Ethyl 2-((3-nitrobenzoyl)thio)acetate (II) and Ethyl 2-((4-nitrobenzoyl)thio)acetate (III) were synthesized and spectroscopically characterized. Computational calculations were performed to support the study. The inhibitory capacity of compounds (I–III) was evaluated on a phospholipase A 2 (Cdcum6) isolated from the venom of the Colombian rattlesnake Crotalus durissus cumanensis and the P-I type metalloproteinase Batx-I isolated from Bothrops atrox. I–III inhibited PLA 2 with IC 50 values of 193.2, 305.4 and 132.7 μM, respectively. Otherwise, compounds II and III inhibited the proteolytic activity of Batx-I with IC 50 of 2774 and 1879 μM. Molecular docking studies show that inhibition of PLA 2 may be due to interactions of the studied compounds with amino acids in the catalytic site and the cofactor Ca 2+. Probably, a blockage of the hydrophobic channel and some amino acids of the interfacial binding surface of PLA 2 may occur. View Full-Tex