Bufotenine, a tryptophan-derived alkaloid, suppresses the symptoms and increases the survival rate of rabies-infected mice: the development of a pharmacological approach for rabies treatment

Abstract

Background: Between 40,000-70,000 people die yearly of rabies, an incurable disease. Besides post-bite vaccination, no treatment is available for it. Methods: First, virus dilution for antiviral effects in mice was determined. Then, animals were treated as follows: control (NaCl 250 µL/animal/day); bufotenine (0.63, 1.05 and 2.1 mg in 250 µL of NaCl/animal/day); rabies (10-6,82 CVS dilution); and test (10-6,82 CVS dilution and bufotenine, in the above-mentioned doses). Animals were observed daily for 21 days or until the 3 rd stage of rabies infection. Twitch-tension and liposome studies were applied to understand the possible interaction of bufotenine with receptors, particularly acetylcholine. Results: Bufotenine was able to increase the survival rate of intracerebrally virus-infected mice from 15 to 40%. Bufotenine did not seem to interfere with the acetylcholine response in the skeletal muscle, indicating that its mechanism of action is not blocking the virus entrance due to nAChR antagonism. By analyzing liposomes, we could observe that bufotenine did not passively penetrates cell membranes, indicating the necessity of complementary structures to cell penetration. Conclusions: Bufotenine is a promising candidate for drug development. After further chemical modification, it might be possible to dissociate minor side effects, increase efficiency, efficacy and pharmacokinetics, yielding a true anti-rabies drug.

5-Hydroxyindole-Based EZH2 Inhibitors Assembled via TCCA-Catalyzed Condensation and Nenitzescu Reactions

“…A more sterically encumbered phenyl group at the β-position of the β-ketoesters, and bulky amine substrate also reacted without incident (entries 8, 16). Since the aromatic amines have weaker nucleophilic activity, a long reaction time was also required (entries 3,7,8,[12][13][14][15]. Moreover, electron-withdrawing groups on the benzene ring were not beneficial to the reaction (entry 15); for example, nitro groups, resulted in longer reaction times and lower conversion rates.…”

“…The 5-hydroxyindole scaffold, ubiquitously present in natural products and pharmaceuticals, with demonstrated diverse biological activities [1,2], such as the selective secretory phospholipase A2 inhibitor LY31172 [3], the antibiotic agent violacein [4], the anti-influenza virus drug arbidol [5], the neurotransmitter serotonin [6], the anti-virus agent bufotenine [7], and the anti-inflammatory drug indomethacin [8] (Figure 1). To date, various protocols have been developed for its preparation [9][10][11][12][13], among which the Nenitzescu indole synthesis where 1,4-benzoquinone is condensed with enamines to afford N-substituted 5-hydroxyindoles has been proven to be the simplest strategy [14].…”

In vitro effects of bufotenine against RNA and DNA viruses

“…Some of these receptors may be nicotinic acetylcholine receptor (nAChR), neuronal cell adhesion molecule (NCAM) and p75 neurotrophin receptor (p75NTR) [ 21 ]. On the other hand, Vigerelli et al (2020) [ 13 ] demonstrated that nAChR does not seem to interact with alkaloids. New investigations are necessary to clarify the relationship between alkaloids and cells.…”

Dehydrobufotenin extracted from the Amazonian toad Rhinella marina (Anura: Bufonidae) as a prototype molecule for the development of antiplasmodial drugs

“…The toads of Bufonidae family have been widely studied due to the bioactive properties found in the Rhinella marina venom, which have already shown antitumor [ 13 , 14 , 15 ], antiviral [ 16 , 17 ], and antiparasitic activities [ 18 ]. The cholesterol-derived steroid structures called bufadienolides are major active compounds in the venom of Bufonidae family and are considered a promising source of bioproducts [ 19 , 20 ]. Furthermore, the alkaloids dehydrobufotenin and bufotenine also identified in R. marina venom have demonstrated to possess antiproliferative and antiviral activity, respectively [ 20 , 21 , 22 , 23 ].…”

“…The cholesterol-derived steroid structures called bufadienolides are major active compounds in the venom of Bufonidae family and are considered a promising source of bioproducts [ 19 , 20 ]. Furthermore, the alkaloids dehydrobufotenin and bufotenine also identified in R. marina venom have demonstrated to possess antiproliferative and antiviral activity, respectively [ 20 , 21 , 22 , 23 ].…”