Abstract
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 A2 (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 PLA2 with IC50 values of 193.2, 305.4 and 132.7 µM, respectively. Otherwise, compounds II and III inhibited the proteolytic activity of Batx-I with IC50 of 2774 and 1879 µM. Molecular docking studies show that inhibition of PLA2 may be due to interactions of the studied compounds with amino acids in the catalytic site and the cofactor Ca2+. Probably, a blockage of the hydrophobic channel and some amino acids of the interfacial binding surface of PLA2 may occur.
Highlights
The World Health Organization (WHO) recognized snakebites as one of the most important Neglected Tropical Diseases in 2017
SWynethrespios ratntdheSpseycntrtohsecsoipsiacanldCchhaararactcetreirziaztaiotinon by GC-MS, IR and NMR of thioesters derived from 2-sulWfeneyrleeptohrytltahceetsaytne.thSepseisctarnadarcehaavraaciltaebrilzeaatisoSnubpypGleCm-eMntSa,rIyRManadteNriaMl.R of thioesters derived from 2-sulfenyl ethylacetate
Synthesized compounds were tested to inhibit the enzymatic activity of a Snake venom metalloproteinases (SVMPs), only II and III showed some ability to inhibit the enzyme with IC50 values about 10 times higher than those found for Phospholipases A2 (PLA2)
Summary
The World Health Organization (WHO) recognized snakebites as one of the most important Neglected Tropical Diseases in 2017. 5.4 million snakebites occur each year, and more than 95% of cases occur in tropical or developing countries, mostly in rural areas [1]. There are between 81,410 and 137,880 deaths per year and around three times as many cases of permanent disabilities including amputations [2]. Pathophysiological effects observed in snakebite envenomations combine the action of several enzymes, proteins and peptides, such as phospholipases A2 (PLA2), hemorrhagic metalloproteinases, and other proteolytic enzymes, coagulant components, neurotoxins, cytotoxins and cardiotoxins, among others [4]. Snake venom metalloproteinases (SVMPs) have been shown to participate in the hemorrhagic process by proteolytic degradation of endothelial cell surface proteins and extracellular matrix components, involved in the maintenance of capillary structure and integrity, leading to capillary network disruption, edema and hemorrhage [5].
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