Bioactive alkaloids from the venom of Dendrobatoidea Cope, 1865: a scoping review

ABSTRACT Bioactive compounds derived from secondary metabolism in animals have refined selectivity and potency for certain biological targets. The superfamily Dendrobatoidea is adapted to the dietary sequestration and secretion of toxic alkaloids, which play a role in several biological activities, and thus serve as a potential source for pharmacological and biotechnological applications. This article constitutes a scoping review to understand the trends in experimental research involving bioactive alkaloids derived from Dendrobatoidea based upon scientometric approaches. Forty-eight (48) publications were found in 30 journals in the period of 60 years, between 1962 and 2022. More than 23 structural classes of alkaloids were cited, with 27.63% for batrachotoxins, 13.64% for pyridinics, with an emphasis on epibatidine, 16.36% for pumiliotoxins, and 11.82% for histrionicotoxins. These tests included in vivo (54.9%), in vitro (39.4%), and in silico simulations (5.6%). Most compounds (54.8%) were isolated from skin extracts, whereas the remainder were obtained through molecular synthesis. Thirteen main biological activities were identified, including acetylcholinesterase inhibitors (27.59%), sodium channel inhibitors (12.07%), cardiac (12.07%), analgesic (8.62%), and neuromuscular effects (8.62%). The substances were cited as being of natural origin in the “Dendrobatidae” family, genus “Phyllobates,” “Dendrobates,” and seven species: Epipedobates tricolor, Phyllobates aurotaenia, Oophaga histrionica, Oophaga pumilio, Phyllobates terribilis, Epipedobates anthonyi, and Ameerega flavopicta. To date, only a few biological activities have been experimentally tested; hence, further studies on the bioprospecting of animal compounds and ecological approaches are needed.


Introduction
Natural products are sources of bioactive compounds with a significant potential for pharmacological and biotechnological applications (Atanasov et al. 2021;Bauer and Bronstrup 2014;Furtado et al. 2022;Wainwright et al. 2022;Wu et al. 2020).The diversity of bioactive molecules found in animals is high; however, few compounds have been explored or recognized (Bordon et al. 2020;Chen et al. 2018;Izzati et al. 2021).
A significant gap exists in scientific knowledge regarding animal toxins, although these compounds exhibit refined biological actions in terms of selectivity and potency (Acunha et al. 2023;Sakamoto and Ishikawa 2022;Santos et al. 2021;Slagboom et al. 2022;Souza et al. 2018;Tan 2022;Zhang 2015).Compounds derived from animals are important tools for developing drugs for the treatment of various diseases (Barros et al. 2022;Bordon et al. 2020;Caty et al. 2019;Ferreira, Arcanjo, and Peron 2023;Fox and Serrano 2007;Gutiérrez, Morales, and Pino 2018;Newman and Cragg 2020;Souza et al. 2018).
In Amphibia Gray, 1825, few bioprospecting studies of compounds and tests of biological activities were undertaken and the findings of these studies demonstrate the diversity of poisons in this group.The integument of anurans is a source of bioactive compounds that are secreted to protect against predators, parasites, and pathogens (Mans et al. 2021;Spinelli et al. 2019).The superfamily Dendrobatoidea (Cope, 1865) in the Order Anura (Fischer von Waldheim, 1813) is a monophyletic clade that is endemic to mountainous areas in the neotropics, with over 100 species known for the sequestration of alkaloids and physiological adaptation to chemical defenses through skin secretion (Grant and Frost 2016).Numerous alkaloids were identified in Dendrobatidae, totaling over 500 types, some of these species possessing the remarkable ability to modify the alkaloid structures acquired from their diet, resulting in even more potent and toxic variants (Saporito et al. 2012).
A literature review of the bioactive compounds in Dendrobatidae conducted by Daly et al. (1982) indicated the promise of at least 5 classes of alkaloids for pharmacological studies.The study and utilization of natural resources, especially pharmacological sources, may play an important role in the emergence of commercial bioproducts, such as (1) detection and identification of prototypes, (2) presence of chemical precursors, and (3) discovery of compounds for further synthesis, which eventually contribute to scientific and technological development (Barreiro andBolzani 2009, Newman et al. 2020;Sakamoto and Ishikawa 2022;Scherlach and Hertweck 2021).
According to Ferreira et al. (2023), the use of natural products from animal sources needs to be considered fundamental from a social and economic perspective for the scientific and commercial progress of tropical countries.Recognizing biodiversity and its natural products as a pharmaceutical library enables the establishment of sustainable guarantees for the bioeconomic chain.Biotechnological production generates goods that not only enhance the quality of life in societies, but also add value and provide tangible justifications for the protection of natural resources (Astolfi-Filho, Silva, and Bigi 2014;Scherlach and Hertweck 2021).
Thus, this study conducted a scoping review of the literature focusing on scientometric analysis to examine the state-of-the-art research over the last 60 years.The primary objective was to understand the research trends related to bioassays with alkaloids present in the Dendrobatoidea group, and to explore their potential for bioprospective analyses in the field of pharmaceuticals.Secondly, this investigation sought to answer the following questions: How much research has been conducted in this field of analysis and in what areas?Which chemical compounds were generally used in the experiments, and how were these compounds obtained?Which biological activities were mainly tested in these bioassays?Which taxonomic groups are referenced in the studies?Addressing these questions may aid in identifying gaps in the knowledge within the field of natural products of animal origin and guide further research development in this promising area.

Search strategy
This research adopted a descriptive basis with a quantitative approach, aiming to evaluate the current state of the art in the field of anuran alkaloids from the Superfamily Dendrobatoidea, with a scientometric bias.The literature reviewed spanned up to August 2022.To gather relevant information, documents were retrieved from reputable academic databases, including Google Scholar, PubMed, Web of Science, and Scopus.
The organization of the research was carried out through the structuring defined by PRISMA for Scoping (Prima-Scr) according to Tricco et al. (2018), considering its conceptual definitions for structuring the research, justifications, protocol, PICO objective, research, organization of results, critical analysis of information, and conclusions.
The systematic organization of data following these methodologies ensured a structured approach to data collection and analysis, thus facilitating a comprehensive understanding of research trends and advances in the study of the bioactive products of anuran alkaloids within the Dendrobatoidea Superfamily.This study is an update on Daly's (1982) study.

Eligibility
The search stages followed the systematization presented in Figure 1.Studies selected were published in English.During data refinement, duplicate files of the same size, name, and content were excluded.Review articles, synthesis of molecules, differentiated taxonomic groups, tests of ecological biological activities, and incomplete investigations were excluded.Unpublished academic works such as theses or dissertations were not considered.However, studies on tests of artificially synthesized molecules in which Dendrobatoidea species were referenced were considered for the review.

Data screening
The screening process involved a comprehensive examination of the titles, abstracts, results, and conclusions of the selected documents, adhering to the predefined criteria for inclusion.After meticulous analysis, relevant findings were integrated into the results section.The technique used for this quantitative description ensured a systematic and comprehensive presentation of data obtained from the reviewed literature.

Data extraction and analysis
The process of searching and screening data was conducted independently by two members of the team.The inconsistencies and weightings were discussed in data evaluation meetings, in which results were calibrated to evaluate duplicates.In addition, studies that were inconsistent with the objectives of the proposal, incomplete, gray literature, did not mention the groups studied, or discussed related topics, such as the chemical synthesis of the compounds studied, were also screened.
The variables used for the measurements were tabulated using Excel software: (i) title, (ii) author, (iii) date of publication, species where the compound or its congener was found, (iv) alkaloid class, (v) biological activity of alkaloids, (vi) type of bioassay, and (vii) form of the compounds.The descriptive characteristics and results of each investigation were extracted from the tables.
The selected biological activities followed a pattern similar to the definitions of biological activity demonstrated by amphibian-secreted substances as described by Daly and Myers (1967), with the addition of others.The alkaloid class was based upon the methods described by Daly et al. (1993) and Saporito et al. (2012).The drawings of spatial structures in the program Chem Basic were performed based upon investigation found in the research results or from basic studies on alkaloids, such as Daly et al. (1993Daly et al. ( , 2005)), compared to PubChem (https://pubchem.ncbi.nlm.nih.gov/).The observations were structured in tables and graphic figures, and word clouds were elaborated using Infogram software (https://infogram.com/app).

Scientific studies
After screening the titles, 48 publications that conducted experiments with bioactive alkaloids present in Dendrobatoidea anurans met the inclusion criteria.These investigations date back 60 years, covering the period between 1962 and 2022 and are distributed with a maximum of three (3) publications each year.The selected publications were published in 30 journals, with only "Proceedings of the National Academy of Sciences" (12.7%), "Toxicon" (10.6%), "Journal of Natural Products" (6.3%), and "European Journal of Pharmacology" (6.3%) publishing three or more articles related to this topic.
In amphibians, the venom is composed of a complex mixture of secondary metabolites developed over thousands of years in response to biological and ecological stressors, such as arm race defenses in trophic networks (Barros et al. 2022;Mans et al. 2021;Rodríguez-Saona 2012;Scherlach and Hertweck 2021).Dendrobatoidea skin alkaloids were studied for at least 60 years; however, the largest number of investigations, including the most current ones, are directed toward the origin and identification of compounds and other aspects of chemical ecology, such as seasonal variation of the alkaloid profile in different populations, as well as physiological aspects related to absorption, tolerance, and maintenance of compounds in the body.Nevertheless, assessment of biological (Basham et al. 2021;Caty et al. 2019;Gonzalez et al. 2021;Jeckel et al. 2019Jeckel et al. , 2022;;Protti-Sánchez et al. 2019) and pharmacological activities were considered in relatively few studies.
Although bioprospecting advances in bioactive compounds secreted by Dendrobatidae anurans are well-established, the number of scientific publications involving biological activity experiments still proved to be low with a deficit in the number of alkaloids already discovered in the group, especially when compared with the analysis conducted by Daly et al. (1982).However, it should be noted that there has been a marginal increase in the number of publications in this field.
Alkaloids are a rich class of secondary metabolites that are known for their effective biological activity and diverse applications and were found to be crucial components for the future production of medicines, making them an essential focus of research in pharmaceutical development (Abookleesh, Al-Anzi, and Ullah 2022;Ajebli, Khan, and Eddouks 2021;Scherlach and Hertweck 2021;Seteyen et al. 2022;Wainwright et al. 2022).
Drugs based upon animal toxins may generate millions of dollars, leading to the development of agents with multiple or promising targets for various groups of diseases (Atanasov et al. 2021;Bauer and Bronstrup 2014;Caty et al. 2019;Ferreira, Arcanjo, and Peron 2023;Scherlach and Hertweck 2021;Spinelli et al. 2019;Wu et al. 2020).These compounds are bioactive with wide structural diversity, specific effects, and multi-target actions and exhibit significant potential for development of new bioprospective targets for therapeutic purposes (Sakamoto and Ishikawa 2022;Souza et al. 2018).

Biological activity tests
Biological activity tests were performed on at least 23 structural classes of alkaloids.Among these, there was a notable citation frequency of 21.82% for batrachotoxins, 16.36% for pumiliotoxins, 13.64% for pyridinic alkaloids, with a specific emphasis on epibatidine, and 11.82% for histrionicotoxins (Figure 2).
The remaining alkaloids, including pyrrolidine, piperidine, indolizidine, decahydroquinoline, and gephyrotoxins, were distributed in groups with comparatively lower citation frequencies.These findings emphasize the diversity of alkaloids tested for their biological activities and the significance of specific structural classes illustrated in Figure 3.
Within Dendrobatidae, more than 500 types of alkaloids have been described in at least 25 structural classes, with compounds acquired by (1) feeding on arthropods, (2) compounds that are fully sequestered, or (3) undergoing slight modifications.Those compounds include alkaloids, histrionicotoxins, pumiliotoxins, decahydroquinoline, quinolines, indolizidines, quinolizidenes, pyrrolizidenes, and pyrrolidines (Saporito et al. 2012).Daly et al. (1982) reported the presence of at least 5 classes of alkaloids with pharmacological properties.Thus, several classes of alkaloids were examined in bioassays for biological activities, despite the limited number of publications.
The tests used in the studies comprised the following methods: in vivo (54.9%), in vitro (39.4%), and in silico (5.6%).Compounds isolated from skin extracts accounted for 54.8% of cases, whereas the remaining compounds were obtained through molecular synthesis.In some tests, a mixture of toxic compounds was used to conduct bioassays.Although in vivo experimentation initiated moral debates regarding animal use, it is important to explore suitable alternatives, such as conducting more in silico tests to examine the activity of compounds.Emphasising the use of in silico methods may provide valuable insights into potential ethical concerns (Atanasov et al. 2021;Bordon et al. 2020;Tan 2022).
Studies on the bioactive molecules of anuran alkaloids related to biotechnological innovation might contribute to science in different ways, either as a basis for testing diagnostic tools or as experimental molecules for the validation of postulated therapeutic targets, drug libraries, prototypes for drug planning, and therapeutic agents (Barreiro and Bolzani 2009;Bauer and Bronstrup 2014;Chen et al. 2018;Ferreira, Arcanjo, and Peron 2023;Fox and Serrano 2007;Gotti et al. 2000;Gutiérrez, Morales, and Pino 2018;Newman and Cragg 2020;Slagboom et al. 2022;Souza et al. 2018).
Animal toxins perform important biological activities (Souza et al. 2018).Batrachotoxin, a natural compound with the chemical formula (3α,5β,6α,14α,15β,16β)-20-(3-amino-3-carboxypropyl)-14,15-epoxy-5,6-dihydro-3-hydroxy-16-(methylamino) stigmastane-3,14-diol), was noted to be bioactive for 12 of the 13 reported activities.Batrachotoxin is a steroidal alkaloid consisting of intricate steroid rings with a highly reactive guanidine-containing side chain.The three-dimensional structure of batrachotoxin is crucial for its potent and toxic biological activity (Tokuyama, Daly, and Witkop 1969).According to Bosmans et al. (2004), batrachotoxin and its metabolites, detected in Phyllobates, have emerged as important compounds of technological applicability as these compounds specifically act on the Na + voltage channels by (1) increasing the rate of uptake of this ion, and (2) acting in the regulation or prevention of inactivation of nerve and muscle cells.Consequently, these actions exhibit potential for analgesic use, regardless of the restrictions attributed to severe   In Epipedobates, the main alkaloid cited was epibatidine ((−)-7-(3,4-dimethoxyphenyl)-1-methyl-6,7,8,9-tetrahydro-5 H-benzocyclohepten-5-ol), which has been widely studied and acts specifically on sodium channels with associated analgesic activity (Qian et al. 1993).Thus, Epipedobates-derived alkaloids also act as anticholinesterases (Qian et al. 1993), produce cardiorespiratory disturbances such as bradycardia and reduced respiratory rate (Fisher et al. 1994), impair muscular function (Green et al. 2018), and decrease fetal movement (Green et al. 2016(Green et al. , 2018) ) activities.This compound was evaluated for development of (1) non-opioid analgesics, (2) nicotinic receptors, and (3) cardiac-lowering activity.In addition, epibatidine is a promising substance for medicinal bioprospecting (Dolci et al. 1999;Fox and Serrano 2007;Gotti et al. 2000;Houghtling, Dávila-García, and Kellar 1995;Khan, Yaksh, and Taylor 1997).Fitch et al. (2018) evaluated the activities of phantasmidine derived from Epipedobates anthonyi (Noble, 1921), which was tested for its potential for pharmaceutical use, and noted that the substance is a highly potent nicotinic receptor agonist.It is noteworthy that although it is found only in small amounts naturally, phantasmidine may be synthesized and exhibits actions similar to those of epibatidine, a widely studied alkaloid (Qian et al. 1993).Phantasmidine is extremely toxic and might result in respiratory failure.Consequently, this compound has a limited potential for pharmaceutical development, emphasizing the importance of handling this substance with caution during scientific investigations.Mortari et al. (2004) identified pumiliotoxins in Ameerega flavopicta (Lutz, 1925) from samples obtained from the Brazilian cerrado.Pumiliotoxins comprise a class of alkaloids with pyrrolizidine or indolizidine rings, and histrionicotoxins, a class of alkaloids with a quinoline ring and an ethylamine side chain.In addition, decahydroquinoline was also detected.Bioassays of neurotoxic and myotoxic activities demonstrated significant biological activity.These effects were shown to be reversible upon withdrawal of contact with these alkaloids.These findings indicate complex and potent actions of these alkaloids on the nervous and muscular systems and suggest their potential therapeutic implications.
The importance of handling these compounds with caution should be emphasized because of their toxicity.For substances derived from Oophaga pumilio (Schmidt, 1857), Sheridan et al. (1991) showed that pumiliotoxins injected into the nerve cells of pigs, induced enhanced electrical activity in Na + channels.The action triggered spontaneous  and synchronous activity, with convulsions at regular frequencies without leading to dependence, due to the reduction of the minimum voltage for performance of the channel, without blocking inactivation, thus enhancing the performance in the channel closure stage by inversion (Sheridan et al. 1991).Thus, despite changing the action potentials to avoid depolarizing cells at rest, such as with batrachotoxin, spontaneous activity in neurones occurred.Hovey et al. (2018) and Mina et al. (2015) indicated that variations in alkaloid profiles, for ecological reasons, directly reflect their biological performance as antimicrobial agents, which was experimentally observed in both studies.
Frogs of the family Dendrobatidae contain a variety of highly potent and toxic alkaloids on their skin.The most prominent compounds are batrachotoxin, epibatidine, pumiliotoxins, histrionicotoxin, and decahydroquinoline.Batrachotoxin is known for its action as a sodium channel activator, initiating hyperexcitation of the nervous and muscular systems, leading to paralysis and subsequent death.In contrast, epibatidine acts as an agonist of the nicotinic acetylcholine receptors and exhibits extremely potent analgesic properties.Pumiliotoxins are complex alkaloids with pyrrolizidine or indolizidine rings, while histrionicotoxins comprise a class of alkaloids that contain a quinoline ring and an ethylamine side chain.Both compounds exhibit diverse biological activities, including ion channel inhibition.Further, decahydroquinoline has also been identified in frogs, indicating the richness and complexity of the alkaloids detected in these species.Understanding these compounds and their biological effects is of great interest in pharmacological research, but extreme caution is required in their handling and exposure owing to their significant toxicity (Daly et al. 2000(Daly et al. , 2005)).
According to Grant and Frost (2016), there are at least 100 species of Dendrobatoidea that secrete toxic alkaloids; nevertheless, only the nomenclatures "Dendrobatidae," genus "Phyllobates," "Dendrobates" and seven species (E.tricolor, P. aurotaenia, O. histrionica, O. pumilio, P. terribilis, E. anthonyi, and A. flavopicta, which despite being inserted in the definitions, include groups with distinct genetic patterns for alkaloid tolerance.The designations of Dendrobatidae always refer to compounds present in the group (more broadly, as a family), but in this group, the type of secreted compound is not uniform and the profile of alkaloids differs between genera and populations of the same species.
The genus Dendrobates, despite being considered in older investigations, is synonymous with other genera.Few studies on Dendrobates with a single citation are available regarding the biological activity of their chemical compounds.The other reference genus, Phyllobates, is a physiological clade adapted for the secretion of highly toxic alkaloids such as batrachotoxin, one of the most lethal animal secretions, and has a low diversity of less toxic types, even when exposed to similar food patterns as that of sympatric species such as O. pumilio, Dendrobates auratus (Girard, 1855), and Oophaga granulifera (Taylor, 1958) (Castano et al. 2009;Mebs et al. 2014).
An essential aspect to consider is that within Dendrobatoidea, variations exist in the compounds secreted by populations from different localities.Bolton et al. (2017) noted that the alkaloids secreted by Dendrobatidae depend upon the palatability pattern of arthropods; that is, these compounds are influenced by the available diet,  Shimizu and Yokotani, (2009) in vivo, in vitro synthesis Rupniak et al., (1994) in vivo synthesis Dolci et al., (1999) in vivo synthesis Alkondon and Albuquerque, (1995) in vivo, in vitro synthesis Houghtling et al., (1995) in vivo, in vitro synthesis Heugebaert et al., (2014) in vivo synthesis Khan et al., (1997) in vivo synthesis Epipedobates tricolor Fisher et al., (1994) epiquinamide (e)  2015)   Green et al., (2018) which varies between specialist or generalist species and environmental conditions.Consequently, it becomes evident that research concerning this group of Dendrobatoidea needs to be broadened in scope to encompass a larger number of species and diverse regions for comprehensive analyses.In the species cited, there are several studies on chemical ecology, for example, Saporito et al. (2007) studied the evaluation of Oophaga pumilio alkaloids in Panama over a period of 30 years.
Dendrobatoidea is a group distributed in Nicaragua to the Pacific slopes of Colombia and Ecuador, east of the Andes to Bolivia, and to Guianas and southeastern Brazil.However, most of the species referenced with bioactive agents are of Andean or Western Amazon distribution, with only Epipedobates flavopictus cited from Brazil, which is related to the Cerrado ecosystem.These aspects indicate the need for expansion of studies on species with greater distribution and endemic distribution in the Eastern Amazon.
According to Ferreira et al. (2023), the use of natural products from animal sources must be considered fundamental from a social and economic perspective for Brazil's scientific and commercial progress, given its rich biodiversity.Recognizing biodiversity and its natural products as a pharmaceutical library makes it possible to scale sustainable guarantees for the bioeconomic chain, in which biotechnological production generates goods that improve the quality of life of societies in a sustainable manner by adding value to natural capital while protecting natural resources (Astolfi-Filho, Silva, and Bigi 2014).

Data analysis and infographics
The representative word clouds integrated into this study were meticulously designed to generate a visually comprehensible representation that precisely encompassed the key molecules or categories of alkaloids that were isolated and identified in the scientifically reviewed studies of the systematic review.Special attention was directed toward decahydroquinoline, as well as the classes of alkaloids batrachotoxin, pumiliotoxin, and histrionicotoxin, along with their biological activities that interact with the enzyme acetylcholinesterase and their effects within the neuromuscular and analgesic domains (Wang et al. 2020).
It is of critical importance to emphasize that the preference for in vitro methods, notably assays involving the inhibition of acetylcholinesterase activity, has led to an increased emphasis on these tests owing to their economic feasibility and viability of their implementation in spectrophotometry systems.These tests offer easy reproducibility and repeatability even when performed by less experienced analysts.It is important to emphasize not undermining the legitimacy of the responses generated through these in vitro methods, but rather to indicate the need for a comprehensive evaluation of manifestations related to neuromuscular activities in in vivo systems.Notably, absent from the studies reviewed were in silico methods; however, these methods are evidently gaining traction as these assays enable the screening of molecules, pharmacophores, and simulations of biological and toxicological activities (Liu, Xu, and Dong 2021;Marucci et al. 2021).
These alkaloids play critical roles in ecosystems and have been the subject of extensive research owing to their significant biological activities.Through these analyses, it is possible to elucidate connections that transcend the boundaries of individual molecules, offering comprehensive perspectives on their interactions with biological systems.Further, by exploring alkaloids originating from animals, a promising avenue emerges for determining the intricate evolutionary adaptations that led to the synthesis, transformation, or accumulation of these compounds in specific ecological contexts.This understanding not only expands our perception of chemical diversity but also enhances potential paths for biomedical and pharmaceutical applications (Islam and Mubarak 2020;Zhang et al. 2020).

Conclusions
An analysis of the reference scientific literature showed that the biological activities of compounds existing in the venom of Dendrobatoidea anurans are not well understood and research has been published in relatively few articles, despite their potential for bioprospective analysis of drugs.Of the few species referenced in the research, there is a lack of comprehensive studies on animals of the Eastern Amazon; therefore, it is necessary to encourage investigations on other species and in different populations to expand the library of chemical compounds.
Studies on potential biological compounds are centered on established compounds, such as batrachotoxin, epibatine, pumiliotoxin, and histrionicotoxin, although indolizidine, quinolizidine, pyrrolidine, and gephyrotoxin, are significantly less cited as potential pharmacological agents.In vivo tests were used to assess the neuromuscular activity, respiratory muscles, and intestinal musculature.However, despite the numerous benefits and vast chemical libraries of silicon testing, in silico tests are largely lacking.
The biological activities of anuran alkaloids include: 1) inhibition of acetylcholinesterase, cardiac tissue and intestinal musculature (2) as an analgesic, antineoplastic, antimicrobial and insecticide, 3) actions on the central and peripheral nervous system, neuromuscular system, and respiratory muscle, 4) effects on sodium channels, 4) teratogenicity, and 5) general toxicity.Batrachotoxin exhibited most of the activities considered in this study, but its pharmacological use is restricted in its natural form because it is a highly toxic compound.Similarly, phantasmidine exhibits a high degree of toxicity.The alkaloid of the pyridinic class, epibatina, acts as an agonist of nicotinic acetylcholine receptors, exhibiting extremely potent reversible analgesic properties and therefore has vast medicinal potential.
These findings indicate the diverse and potent bioactive properties of the alkaloids present in Dendrobatidae anurans, displaying high potential for bioprospective and pharmacological applications.Thus, the recognition of these bioactive compounds represents a scientific advancement and may act as a marker of environmental importance by defining biodiversity as natural capital and as a reserve for use in the future, which urgently needs to be protected.Similarly, the potential for biotechnological and pharmacological use of genetic heritage, if managed, might generate benefits for humanity, such as the development of medicines to counteract various diseases and for other purposes.

Figure 1 .
Figure 1.Flowchart on the refinement of information obtained in the database for inclusion in the study.

Figure 2 .
Figure 2. Word cloud with the proportion of use of the chemical compounds from Dendrobatoidea in tests of biological activities over the last 60 years.

Figure 4 .
Figure 4. Word cloud with the sizing of the classes of biological activities tested experimentally from compounds of poisonous anurans of the family Dendrobatoidea year over 60 years.

Table 1 .
Biological activity studies of compounds originating from Dendrobatoidea anurans.