Synthesis and Biological Evaluation of Novel 1,3-Benzoxathiol-2-one Sulfonamides against Toxic Activities of the Venom of Bothrops jararaca and Bothrops jararacussu Snakes

This work describes the synthesis of new 1,3-benzoxathiol-2-one sulfonamides and evaluation of their ability to inhibit some in vitro (coagulant, proteolytic and hemolytic) and in vivo (hemorrhagic, edematogenic and lethality) toxic activities of Bothrops jararaca and Bothrops jararacussu venoms. Compounds have been synthesized from the coupling of intermediate 5-amino-6 methoxybenzo[d][1,3]oxathiol-2-one 4 with benzenesulfonyl chlorides. Characterization of the products was achieved by nuclear magnetic resonance (NMR) and electrospray ionization mass spectra (ESI-MS) techniques. Biological assay results have shown that most of compounds inhibited the main toxic activities of the venom of the two snake species. Compound 5b (N-(6 methoxy-2 oxobenzo[d][1,3]oxathiol-5-yl)-4-nitrobenzenesulfonamide) was the most efficient in inhibiting hemolysis of B. jararaca, and coagulation and proteolysis induced by both venoms. For in vivo activities, all compounds inhibited the edema, from 35 to 72%, and most of them exhibited antihemorrhagic and antilethality activities. Thus, the results pointed to the biological potential of these compounds, being promising molecules to treat envenomation by these snakes as well as to aid the current antivenom serum therapy.

Keywords:
1,3-benzoxathiol-2-ones; sulfonamides; snake venom; Bothrops jararaca ; Bothrops jararacussu ; antivenom