1. Introduction

A growing world-wide interest in the use of phytopharmaceuticals as complementary or alternative medicine, either to prevent or to ameliorate many diseases, has been noted in recent years. Furthermore, a great portion of the world’s population uses plants as their primary source of medicinal agents ^[1]. Nowadays, medicinal plant’s importance relies not only on their cultural richness but also on the scientific knowledge generated from ecological, geographical, cultural, pharmacological, and chemical analysis, which constitutes the current research context of traditional medicine.

Plants of the genus Porophyllum (family Asteraceae) are native to the western hemisphere, growing in tropical and subtropical areas from North and South America ^{[2][3][4][5][6][7]}. It consists of 25 species ^[8], 17 of which are found in Mexico, with Guerrero, Morelos, Puebla, and Hidalgo, the main states of large-scale production ^[2].

These are annual or perennial plants that possess developed green leaves with aromatic glands and a strong flavour. Some of these species are grown in family gardens and are sometimes associated with tropical deciduous, sub-deciduous, sub-evergreen, evergreen, thorn, mesophyll mountain, oak, and pine forests ^[9][10][11].

Due to the strong flavour of its leaves, they are consumed in a fresh state or to spice some dishes, as well as being used as pesticides ^[1][12]. Mexican species, Porophyllum linaria (Cav.) DC. and Porophyllum ruderale (Jacq.) Cass. var. macrocephalum (DC.) R.R. Johnson. Known as ‘papalos’ or ‘papaloquelites’, particularly in central Mexico. Moreover, the infusions of some species of Porophyllum are used in traditional medicine because of activity against cramps and venereal diseases, as well as their antispasmodic, antibacterial, anti-inflammatory, antifungal, and insecticide properties, especially Porophyllum gracile Bent, P. linaria, Porophyllum obscurum (Spreng.) D.C., P. ruderale, Porophyllum tagetoides, Porophyllum scoparia A. Gray, and Porophyllum riedelli Baker ^[2][12].

2. Porophyllum Genus Compounds and Pharmacological Activities

Although current ethnopharmacological investigations of traditional medicines have achieved important contributions to plant-derived medicines, as well as the advancement of pharmacology, drug discovery from medicinal flora is more complex than is generally recognized because plants are applied for different therapeutic indications within and between cultures ^{[13][14][15][16][17][18][19][20][21]}.

Many plants of the genus Porophyllum have been used in folk medicine as remedies to treat a wide variety of human pathologies, particularly those related to digestive disorders. Of all the known species of this genus, the specie P. ruderale is the most investigated, however, there are few studies focused on the pharmacological activity of its compounds.

In vitro and in vivo studies performed with the purified extracts and compounds of these plants support most of their reported uses in folk medicine for the treatment of a wide variety of pathological conditions, including its use as an antifungal agent and insecticide ^{[4][22][23][24][25][26]}. In addition, some studies in animals have shown antinociceptive properties for some of the pure constituents of these plants ^[4]. It is important to mention that there are very few studies on its toxicity, which indicates that plants of this genus are well tolerated for human consumption.

The compounds of the Porophyllum genus have been of great interest due to the large number of biological activities they present ^[27]. In plants, these compounds fulfil chemical defence functions against environmental stress, as well as wound and injury repair mechanisms. The compounds present in the genus have been evaluated for their antibacterial and insecticidal activities ^{[22][28][24][25][26][29][30][31][32]}. This effects could be mediated by the activation of the Mucosal-associated invariant T (MAIT) cells in charge of recognizing the antigens sent by non-polymorphic MR1, MAIT cells are activated by a metabolic precursor of riboflavin (present in the genus Porophyllum) synthesis presented by MR1 and, therefore, respond to many bacteria and some fungi. Despite their broad antibacterial properties, their functional role in persistent viral infections is poorly understood, and several studies have reported that MAIT cells recognize only bacterial- and yeast-derived antigens presented via MR1 and that they do not have antiviral specificity ^[2][33][34]. There is accumulating evidence suggesting that terpene compounds like myrcene, limonene, linalool and caryophyllene are a promising target for use as real alternatives that can be applied in vector-borne disease control programs, for their considerable potential as repellents and larvicides, their low level of toxicity to mammals, and their limited environmental impact ^[26]. In the study carried out by Fontes-Jr et al. ^[24], it was found that the larvae of A. aegypti were susceptible to the composition of essential oil from the flowers and leaves of P. ruderale; the main compounds identified in the oil were (E)-β-ocimeno (93.95%), myrcene (3.37%), (Z)-β-ocimeno (1.38%), and β-pinene (0.27%). The responsibility of this biological activity has been studied, showing that the lipophilicity of monoterpene compounds is related to the production of neurotoxic intoxication, in addition to the fact that components of essential oils act to block octopamine receptors, producing serious neurological alterations with harmful effects on insects ^[31] octopamine and tyramine are distinguished by the presence or absence of a hydroxyl group at the β position ^[32]. These structurally closely-related amines regulate intracellular cAMP levels in opposite directions, i.e., up and down regulation, by acting on different G protein-coupled receptors. Based on the evaluation of compounds for endocrine disruptor activity using a reporter gene assay, three-dimensional quantitative structure activity relationships were analysed to elicit responses through androgen receptors ^[35]. Therefore, findings regarding the structures of the binding sites of natural biomolecules, such as terpene compounds found in the Porophyllum genus, would be useful to design new insecticidal molecules with a novel mode of action in addition to lower production cost and effective insecticidal activity.

Other monoterpenic compound of pharmacological importance is α-terpineol, whose antihypertensive activity has been studied, mainly mediated by the release of Nitric Oxide (NO) and the subsequent activation of the NO-cGMP pathway (cyclic guanosine 3′,5′-monophosphate). This activity is linked to a reduction in calcium influx that occurs through voltage sensitive CavL channels, resulting in a decrease in vascular resistance attributed to α-terpineol that leads to the induction of hypotension ^[36].

Regarding antinociceptive activity, monoterpenic compounds have been identified to produce significant analgesic effects in formalin and writhing tests, which are related to the inhibition of PGE2 and PGF2α levels in the peritoneal fluid and to the inhibition of the release of substance P and other inflammatory molecules. However, the activity of these compounds has also been linked to a selective inhibition of COX-2 (0.69 mM), so this type of compound could potentially be used in the development of new drugs for the treatment of diseases painful and/or inflammatory ^[37]. Thiophenes are a class of heterocyclic compounds that contain sulphur and are found in both natural and synthetic products, displaying several different pharmacological properties, including anti-inflammatory, antiulcer ^[38], antimicrobial ^[39], antifungal ^[40], and anticancer ^[41] effects. Natural thiophenes are characteristic secondary metabolites of plants belonging to the Asteraceae family, among which Porophyllum is a genus ^[42]. The interest in the bioactivity of these compounds is due to their properties that can be developed synthetically or used naturally for the design of new drugs, using thiophenes as raw material.

These compounds have not yet been thoroughly studied, specifically the mechanisms of action of the pharmacological activities attributed to them, however, some authors such as Takahashi et al. ^[28][43] have shown that the extract in dichloromethane from aerial parts of P. ruderale exhibit strong activity against L. amazonensis, making it a potent antileishmanial compound. Those responsible for these pharmacological activities were bithiophenes and terthiophenes, whose biocidal activities were attributed primarily to the decrease in mitochondrial membrane potential in promastigotes ^[44].

Conversely, it was observed that treatment with a hexane extract of the aerial parts of P. obscurum (PoHex) showed photosensitive activity against a panel of twenty-five Candida strains isolated from patients with head and neck cancer undergoing radiotherapy with MFC values between 0.98 and 1.95 µg/mL, which were resistant to multiple drugs ^[11]. The mechanism of the antifungal activity of the thiophenes contained in PoHex can be classified as photodynamic, considering that thiophenes are excellent producers of singlet oxygen but are not precursors in electron transfer reactions, understanding that oxygen singlets have high chemical reactivity, which leads to rapid death in microorganisms and in lower concentrations than other biocides, in addition to not affecting nearby cells or organs ^[45].

Terthiophenes present in this genus have also been associated with HIV-1 protease inhibitory activities with an IC₅₀ value of 58 µM, but did not show any activity towards HIV-1 integrase ^[46].

Among these effects, its anticancer activity has been highlighted, which has been linked to the induction of cell death by apoptosis, through an increase in the activity of caspase 3 and in the expression levels of the apoptotic proteins Bak and Bim, as well as a decrease in the antiapoptotic proteins Bcl-2 and Bcl-xL. On the other hand, it has been seen that these compounds cause a blockage of the cell cycle in the G2/M phase, decreasing the expression of the regulatory proteins of this phase, cyclins A and b1 and the kinase Cdk1 ^[47].

3. Conclusions

The genus Porophyllum represents one of the most widely used pre-Hispanic species in traditional medicine for the treatment of various diseases. The data presented here show the great potential represented by the compounds contained in their different species. Important pharmacological activities of isolated Porophyllum compounds has been found. Those compounds can be used in the synthesis of some phytopharmaceuticals, including terpenic and azufraid compounds, such as thiophenes, which may even develop synergism among the compounds containing these plants and increase their pharmacological potency. However, a great deal of information remains to be discovered about the mechanisms of action of these molecules, as well as preclinical studies that check these gender and its compounds could be safely used as treatments for different pathologies.