Sulfur Compounds as Inhibitors of Enzymatic Activity of a Snake Venom Phospholipase A₂: Benzyl 4-nitrobenzenecarbodithioate as a Case of Study

Abstract

Snakebite is a neglected disease with a high impact in tropical and subtropical countries. Therapy based on antivenom has limited efficacy in local tissue damage caused by venoms. Phospholipases A₂ (PLA₂) are enzymes that abundantly occur in snake venoms and induce several systemic and local effects. Furthermore, sulfur compounds such as thioesters have an inhibitory capacity against a snake venom PLA₂. Hence, the objective of this work was to obtain a carbodithioate from a thioester with known activity against PLA₂ and test its ability to inhibit the same enzyme. Benzyl 4-nitrobenzenecarbodithioate (I) was synthesized, purified, and characterized using as precursor 4-nitrothiobenzoic acid S-benzyl ester (II). Compound I showed inhibition of the enzymatic activity a PLA₂ isolated from the venom of the Colombian rattlesnake <i>Crotalus durissus cumanensis</i> with an IC₅₀ of 55.58 µM. This result is comparable with the reported inhibition obtained for II. Computational calculations were performed to support the study, and molecular docking results suggested that compounds I and II interact with the active site residues of the enzyme, impeding the normal catalysis cycle and attachment of the substrate to the active site of the PLA₂.