Lapachol and synthetic derivatives: in vitro and in vivo activities against Bothrops snake venoms

Abstract

BackgroundIt is known that local tissue injuries incurred by snakebites are quickly instilled causing extensive, irreversible, tissue destruction that may include loss of limb function or even amputation. Such injuries are not completely neutralized by the available antivenins, which in general are focused on halting systemic effects. Therefore it is prudent to investigate the potential antiophidic effects of natural and synthetic compounds, perhaps combining them with serum therapy, to potentially attenuate or eliminate the adverse local and systemic effects of snake venom. This study assessed a group of quinones that are widely distributed in nature and constitute an important class of natural products that exhibit a range of biological activities. Of these quinones, lapachol is one of the most important compounds, having been first isolated in 1882 from the bark of Tabebuia avellanedae.Methodology/Principal findingsIt was investigated the ability of lapachol and some new potential active analogues based on the 2-hydroxi-naphthoquinone scaffold to antagonize important activities of Bothrops venoms (Bothrops atrox and Bothrops jararaca) under different experimental protocols in vitro and in vivo. The bioassays used to test the compounds were: procoagulant, phospholipase A2, collagenase and proteolytic activities in vitro, venom-induced hemorrhage, edematogenic, and myotoxic effects in mice. Proteolytic and collagenase activities of Bothrops atrox venom were shown to be inhibited by lapachol and its analogues 3a, 3b, 3c, 3e. The inhibition of these enzymatic activities might help to explain the effects of the analogue 3a in vivo, which decreased skin hemorrhage induced by Bothrops venom. Lapachol and the synthetic analogues 3a and 3b did not inhibit the myotoxic activity induced by Bothrops atrox venom. The negative protective effect of these compounds against the myotoxicity can be partially explained by their lack of ability to effectively inhibit phospholipase A2 venom activity. Bothrops atrox venom also induced edema, which was significantly reduced by the analogue 3a.ConclusionsThis research using a natural quinone and some related synthetic quinone compounds has shown that they exhibit antivenom activity; especially the compound 3a. The data from 3a showed a decrease in inflammatory venom effects, presumably those that are metalloproteinase-derived. Its ability to counteract such snake venom activities contributes to the search for improving the management of venomous snakebites.

Synthesis, characterization and utilization of a new series of 1,2,3-triazole derivatives to neutralize some toxic activities of Bothrops jararaca snake venom

“…Injection of each derivative or solvents did not cause edema (data not shown). Strauch et al, (2019) showed evidence that lapachol, a naphthoquinone isolated from a variety of plants inhibited proteolytic, hemorrhagic, and edematogenic activities of B. atrox venom and the hemorrhagic activity induced by B. jararaca venom, but failed to inhibit the phospholipase A 2 , myotoxic, and coagulant activities of B. atrox venom. The authors postulated that laphacol and its derivatives may be inhibitors of SVMPs from these venoms.…”

Plant-Derived Toxin Inhibitors as Potential Candidates to Complement Antivenom Treatment in Snakebite Envenomations

“…The natural naphthoquinone, lapachol ( 69 ), was isolated from the species Tabebuia impetiginosa (Bignoniaceae) from Brazil (state of Rio de Janeiro), and has been used as a starting point for obtaining new bioactive quinones ( 180 ). In this same work, an analogue of this natural compound ( 69a ) showed the ability to antagonize the proteolytic activity (3-100 µM) and collagenase activity (10-100 µM) of B. atrox venom.…”

“…In addition, in vivo pre-incubation of the venom with compound 69a at concentrations of 1 mg/kg and 3 mg/kg eliminated the hemorrhage induced by the venom of B. atrox and, in relation to the venom of B. jararaca , the inhibition was greater than 70% with 10 mg/kg of the compound. The authors attributed the protective effect of the analogue of 69a in the skin to the inhibition of proteolytic activities and collagenase, i.e., this compound may be interesting for preventing degradation of the vessels ( 180 ).…”

Ethnobotanical survey and phytochemical screening of anti-snakebite plants used in Bissok District of Gabon

“…was successfully tested against South American rattlesnake venom (Félix-Silva et al 2017). Furthermore, antimyotoxic, antihemorragic, antiproteolytic and anti-phospholipase properties of those plant extracts were revealed (Hasan et al 2016;Strauch et al 2019). Aqueous stem bark extracts of M. indica have been shown to inhibit the toxic and lethal effect of the Indian Russell's viper venom (Dhananjaya et al 2011).…”