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

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.

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…In this work, the presence of and several alkenes resulted in the successful scandium-C(sp 3 )-H alkylation of methyl thioethers (Scheme 4B), by which different activated internal thioethers were obtained in good yields (Scheme 4C). The transformation facilitates direct access to several sulfur-containing pharmacological compounds that present valuable biological activities, such as anti-HIV ( 9) [51], inhibition of snake venom enzymes (10) [52], or even anti-estrogenic effects (11) [53] (Scheme 4A).…”

Prospects and Challenges of Developing Plant‐Derived Snake Antivenin Natural Products: A Focus on West Africa

“…Ongoing efforts to develop alternative therapeutics for the treatment of SBE have targeted the inhibition of major toxic components of snake venom. In this regard, inhibitors of sPLA2, [60–62] SVMPs [63–69] and SVSPs [70,71] have shown varying degrees of promise at protecting against the lethal effects of some medically important snake venoms in preclinical studies. Given that some enzymatically active snake venom toxins are dependent on metal ions as cofactors, small‐molecule metal chelators have also been investigated in the search of novel treatment [72–74] .…”

An Appraisal of Antidotes’ Effectiveness: Evidence of the Use of Phyto-Antidotes and Biotechnological Advancements

“…Specifically, snakebite, recently categorized as a Neglected Tropical Disease (NTD), is a serious health issue in tropical and subtropical regions of the world [96]. There have been several reports on the use of herbal antidotes against snake poisons and some initial scientific reports concluded that the majority of these remedies were ineffective [97].…”