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

Isabel Henao Castañeda,Lina María Preciado,Jorge Jios,Jaime Andrés Pereañez

doi:10.3390/molecules25061373

Isabel Henao Castañeda, Lina María Preciado + Show 2 more

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https://doi.org/10.3390/molecules25061373

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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 Crotalus durissus cumanensis 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.

Highlights

Based on our previous results, we decided to compare the biological activity of a thioester with the corresponding carbodithioate exchanging oxygen by sulfur
4-nitrobenzenecarbodithioate (I) to inhibit a myotoxic Asp-49 phospholipases A2 (PLA2 ) from Crotalus durissus cumanensis venom, as we are interested in the search for inhibitors of snake venom enzymes that complement antivenom therapy
We found that substituted thiobenzoic acid S-benzyl esters and thioesters derived from 2-sulfenyl ethylacetate are inhibitors of an Asp49-PLA2 enzyme isolated from the venom of the Colombian Crotalus durissus cumanensis rattlesnake in micromolar concentrations [12,19]

Summary

Introduction

Based on our previous results, we decided to compare the biological activity of a thioester with the corresponding carbodithioate exchanging oxygen by sulfur. 4-nitrobenzenecarbodithioate (I) to inhibit a myotoxic Asp-49 phospholipases A2 (PLA2 ) from Crotalus durissus cumanensis venom, as we are interested in the search for inhibitors of snake venom enzymes that complement antivenom therapy. We show, for the first time, the capacity of a carbodithioate to inhibit snake venom toxins. The World Health Organization (WHO) recognizes snakebite as a Neglected Tropical Disease [1]. Each year between 4.5 and 5.4 million people are bitten by snakes [2], mainly poorer people living. Molecules 2020, 25, 1373 in rural areas of tropical countries; this disease has significant medical importance since it is associated with high morbidity and mortality. There are between 81,410 and 137,880 deaths per year, and approximately three times this number of people are left with permanent disabilities [3].

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