Abstract
Snake envenomation is a public health problem, and while serum therapy prevents death, the local effects of venoms can lead to amputations or morbidities. Thus, alternative treatments deserve attention. In this study, we tested eight derivatives of 1,2,3-triazole against some toxic activities of Bothrops jararaca venom. The derivatives were synthesized, and their structures analyzed by infrared and nuclear magnetic resonance. After that, the ability of compounds to inhibit hemolysis, coagulation, proteolysis, hemorrhaging, edema, and lethal activities of B. jararaca venom was investigated. The derivatives were incubated with B. jararaca venom (incubation protocol), administered before (prevention protocol) or after (treatment protocol) injecting venom into the mice. Then, hemorrhaging assay occurred. As a result, most of the derivatives inhibited the activities, even if they were incubated, injected before or after B. jararaca venom. However, the derivatives TRI 07 and TRI 18 seemed to be the most efficient in impairing hemorrhaging. The derivatives showed a low drug score of toxicity based on an in silico technique. Therefore, the derivatives fulfilled physicochemical and biological requirements to become drugs, and they may be a brand new initiative for designing antivenom molecules to complement antivenom therapy to efficiently block tissue necrosis or any other local effects.
Keywords:
1,2,3-triazole derivatives. Organic synthesis. Bothrops jararaca. Snake venom. Neutralization. Antivenom
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
B. jararaca venom (100 µg/mL) was incubated with saline, DMSO or with 150 µg/mL of derivative (TRI 03, TRI 04, TRI 07, TRI 08, TRI 09, TRI 16, TRI 17, and TRI 18) for 30 min at 25 ºC, and then the mixture was injected s.c. into mice (Panel A, incubation protocol). The derivatives (TRI 04, TRI 07, TRI 09, and TRI 18) were injected s.c. into mice 30 min after (Panel B, treatment protocol) or before (Panel C, prevention protocol) injecting s.c. B. jararaca venom. After the injections, the hemorrhagic halo was measured, and expressed as % of hemorrhage activity. Results are expressed as means ± SD of two individual experiments (n = 3). *, significance level (p < 0.05) when compared to the positive control groups (B. jararaca venom + saline or B. jararaca venom + DMSO).
B. jararaca venom (50 µg/mL) was incubated with saline, DMSO (0.9 %, final concentration) or with 150 µg/mL of each derivative (TRI 03, TRI 04, TRI 07, TRI 08, TRI 09, TRI 16, TRI 17, and TRI 18) for 30 min at 25 ºC, and then the edematogenic activity was evaluated. Results are expressed as means ± SD of two individual experiments (n = 3). *, significance level (p < 0.05) when compared to the positive control groups, B. jararaca venom + saline or B. jararaca venom + DMSO.
The derivatives (TRI 03, TRI 04, TRI 07, TRI 08, TRI 09, TRI 16, TRI 17, and TRI 18) were evaluated on their theoretical risk of toxicity, negative reproductive effect, tumorigenic, mutagenic, and irritant aspects using the software Osiris Property Explorer®. Toxicity risk scores are: 1 = low toxicity, 2 = moderate toxicity, 3 = high toxicity.