Phenylpropanoids in species of plants of the Duguetia genus: A review Fenilpropanoides em espécies de plantas do gênero Duguetia: Uma revisão Fenilpropanoides en espécies vegetales del género Duguetia: Una revisión

The genus Duguetia encompasses 93 species, 63 of which are distributed in Brazil. However, only ten species had their chemical and biological profiles investigated so far. Although the alkaloids are the class of phytocompounds most studied, the interest in the phenylpropanoids is growing since distinct biological activities have been attributed to these derivatives lately. This review gathered studies describing the phytochemical distribution, methods of extraction, and biological activities of the phenylpropanoid from Duguetia species. It was evidenced that nonpolar solvents were able to provide the highest yield of 2,4,5-trimethoxystyrene, γ-asarone, and asaraldehyde which were mainly located at the ground stem barks. On the other hand, the α-asarone, elimicin, and (E)-methyl-isoeugenol were isolated from the polar extracts or the essential oils from the barks and leaves. The 2,4,5-trimethoxystyrene and asarone derivates were effective as crop protectors. The αand γ-asarone, 2,4,5-trimethoxycinnamic acid, asaraldehyde, elemicin, and (E)-methyl-isoeugenol demonstrated anti-inflammatory, antidyslipidemic, antinociceptive, antibacterial, antidepressant, anxiolytic, insecticide, and larvicide activities. The Duguetia species can be a potential source of phenylpropanoids, therefore, future studies involving their extraction, identification, and application are still necessary and may culminate in the discovery of new drug candidates or natural agricultural defensives.


Introduction
The Annonaceae are a family of dicotyledonous flowering plants from Magnoliales order. It is considered the Family with the largest taxon with 235 genera and 2,500 species (Chatrou et al., 2004;Simpson, 2010).
The genus Duguetia is the third largest genus of Annonaceae in the Neotropics, encompassing 93 species, 63 of which are distributed in Brazil, and 29 are endemic (Maas et al., 2003). These species are geographically distributed in North, Center-West, Southeast, and South of Brazil within the Amazon, Cerrado, Pantanal, Caatinga, and Atlantic Forest ecosystems. The individuals are further dispersed across Paraguay, Colombia, Suriname, Guianas, Bolivia, and Peru, although 4 species are exclusive from the West Coast of Africa (Almeida et al., 2010;Maas et al., 2003;Perez & Cassels, 2010).
Regarding the morphology, most of the Duguetia species consists of trees or shrubs recognized by the presence of star-like or peltate trichomes which differ from those of another genus of Annonaceae. The leaves are simple, entire, petiolate, and exstipulate presenting a distichous phyllotaxis. The inflorescences are bibracteated flourishing in the terminal ending of the bracts which are displayed in opposite sides of the stalk with the articulation of the upper bract located above the lower axis. In general, the inflorescences and leaves growth together and the former remain perennial even after the leaf's abscission. Yet, the flowers are actinomorphic, cyclic, trimerous, and bisexual while the fruits present varied diameters (1-15 cm) containing a basal ring-shaped structure composed of connate carpels known as collar (Maas et al., 2003;Mello-Silva et al., 2012;van Zuilen et al., 1995).
Although, the majority of the biological activities initially investigated were attributed mainly to the alkaloids, additional attention has been devoted to the phenylpropanoid derivatives (Perez & Cassels, 2010). In an attempt to contribute with those dedicated to further investigate the phytochemical composition, the therapeutical, and the biological potential of these secondary metabolites from Duguetia genus, this review aimed for the first time to integrate the scientific data about the phenylpropanoids present in these species focusing on their extraction, identification, and biological activities. Research, Society andDevelopment, v. 11, n. 4, e18511427266, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i4.27266 4

Methodology
This review was conducted using the following databases: Google Scholar ® , PubMed ® , Scifinder ® , Web of Science ® , Science Direct ® , ACS ® , Springer ® , Taylor-Francis ® , and J-Stage ® . We did not include temporal and language restrictions on the ethnopharmacological use, obtention of the extracts, isolation of the pure compound, and their biological activities. The search terms "Duguetia," or "Duguetia extract," or "Duguetia essential oil" or "Duguetia phenylpropanoids" or "Duguetia ethnopharmacology" or "Phenylpropanoids" were applied in order to refine the search. Potential full-texts of the eligible papers were identified and included according the title and abstract. Duplicate studies were excluded. The full texts of the selected papers from the year 1976 to 2021 were assessed and their relevant references were also checked for additional inclusion as presented in Figure 2. This search methodology was also conducted by others (Arora et al., 2013;Chellian et al., 2017;Geethangili & Ding, 2018). The papers selected for this review are presented in Table 1.
Chemically, the basic skeleton of the phenylpropanoids consists of an aromatic ring with a 3-carbons side chain as presented in table 1. The nature and position of the moieties linked to the benzene ring as well as the position of the double bond in the propyl side chain results in distinct biological activities (Deng & Shanfa, 2017).
The phenylpropanoid pathway was precisely reviewed and discussed by others and it is beyond the scope of this study (Deng & Shanfa, 2017;Ibrahim & Barron, 1989;Singh et al., 2021;Vogt, 2010). Briefly, the initial biosynthesis reaction involves an enzymatic action of the phenylalanine ammonia-lyase or tyrosine ammonia-lyase on the amino acids Lphenylalanine or L-tyrosine, respectively (Ibrahim & Barron, 1989). These precursors are obtained through the shikimate pathway (Jensen, 1986). The biosynthesis of p-cumaroil-CoA is an important branching point that leads to the generation of several phenylpropanoid compounds ( Figure 2). The p-cumaroil-CoA may also suffer other specific ramifications to give rise flavonoids, stilbenes, monolignols, phenolic acids, and coumarins (Deng & Shanfa, 2017;Singh et al., 2021;Vogt, 2010)
This compound was also identified in the organic phase after the stem barks of D. gabriuscula had been subjected to maceration with ethanol 95% (40 o C), followed by partition with methanol:water (9:1, v/v -1 ) and chloroform, however, the authors did not report the yield (Siqueira et al., 2001).
The α-asarone was found in both essential oil and organic soluble fraction derived of polar extracts from the stem barks. After a CG/MS analysis of the essential oil from D. furfuracea, it was observed that this phenylpropanoid comprised 21.9% of total compounds (Saldanha et al., 2019). Further studies demonstrated that it was possible to isolate 160.2 mg of αasarone corresponding to 4.45% (w.w-1) of the oil (da Silva et al., 2007). On the other hand, this compound represented only 1.9% of the composition of the essential oil from D. lanceolata. When a dichloromethane soluble fraction of a methanolic extract derived from the dried stem barks of D. lanceolata was investigated, two major peaks were observed after CG/MS analysis, which were referred as 2,4,5-trimethoxystyrene and α-asarone, respectively, but the authors were not able to quantify both compounds (Alves et al., 2015). The same group, however conducted additional purification studies of the extract and was able to obtain 452.2 mg of α-asarone from 1,059 g of dried stem barks of D. lanceolata (0.04%, w.w-1) (Alves et al., 2020).
Other phenylpropanoids derivatives were found in minor amount on distinct species of Duguetia. In this sense, 13 mg (0.001%, w.w-1) of 1,2,4-trimethoxy-5-(1-methoxy-ethyl)-benzene were obtained after the dried barks (968 g) of D. confinis had been successively extracted with dichloromethane (4 x 3L) and the resultant extract (17.14 g) chromatographed on silica gel column (Mathouet et al., 2007). Among the compounds identified in the essential oil of the dried leaves of D. gardneriana the phenylpropanoid, elimicin comprised 8% of the total isolated compounds (A. C. B. C. Rodrigues et al., 2015). Whereas, 17.2 mg of (E)-methyl-isoeugenol, representing 0.48% of the eluted compounds were obtained from the essential oil of the underground stem barks of D. furfuracea (da Silva et al., 2007).
Although the compounds 3-methoxy-4-ethoxy benzoic acid and methyl 3,5-dihydroxy-4-ethoxycinnamate had been isolated from the ethanolic extracts derived from the dried fruits of D. Duguetia chrysocarpa (Almeida et al., 2012) and from the stem barks of D. gardneriana (Almeida et al., 2007), respectively, the authors were not able to inform the yield. Therefore, according to the studies available so far it was possible to observe that the highest amounts of 2,4,5trimethoxystyrene, γ-asarone, and asaraldehyde could be obtained from the ground stem barks when using organic solvents during the initial step of the extraction. On the other hand, the α-asarone, elimicin, and (E)-methyl-isoeugenol were isolated from the polar extracts or the essential oils.

Biological activities
Despite the biological activities of the phenylpropanoids had been systematically reviewed elsewhere (Ilijeva & Buchbauer, 2016;L. Korkina et al., 2011;Silveira e Sá et al., 2014), this current work was focused specifically in those derivatives obtained from the Duguetia species. In fact, the studies are complementary and reinforce the importance of this class of secondary metabolites as potential source of new drug candidates or prototypes for further chemical modifications

Insecticide and herbicide activities
The activities of a diet supplemented with dichloromethane soluble fractions derived from methanolic crude extracts of distinct parts of D. lanceolata against the caterpillars of the crop pest Spodoptera frugiperda were investigated . Only the fraction from the bark showed insecticidal activity with median values of lethal time and lethal concentration to 50% of the larvae equals to 61.4 h (LT50) and 946.5 g.mL-1 of diet (LC50). The same group demonstrated that a dichloromethane soluble subfraction rich in 2,4,5-trimethoxystyrene (45.5%, w.w-1) and α-asarone (42.9%, w.w-1), produced a more pronounced killing effect with LC50 and LT50 values of 124 g.mL-1 of diet and 38.5 h, respectively. Moreover, 100% of mortality was observed 96 h after the treatment (Alves et al., 2020). The discrepancy between the LC50 and LT50 values observed in both studies can be attributed to the fact that in the latter a more concentrated subfraction was used suggesting that the observed effect could be attributed to those phenylpropranoids. Moreover, when the pure compounds were investigated under the conditions previously described, the 2,4,5-trymethoxystyrene was more active than the α-asarone but no synergistic effect was verified (Alves et al., 2020).
Callosobruchus maculatus, Sitophilus zeamais, and Acanthoscelides obtectus are common pests responsible for serious damage in stored grains and cereals. When these insects were introduced in Petri dishes containing cowpea and maize grains pre-treated with 2,4,5-trimethoxystyrene extracted from D. staudtii at concentrations of 0.02, 0.04, 0.08, and 0.16% (w.w-1), it was observed 100% of mortality at all concentration levels. Such effect was time-dependent and occurred between 72 h and 168 h after the feeding (Koona & Bouda, 2004;Koona & Bouda, 2006). Additionally, an inhibition on the oviposition was verified even at the lowest dose. Similar result was observed against Zabrotes subfasciatus, a pest of stored beans and legume seeds (Gonçalves et al., 2017). In this case, when a hexanic partition rich in 2,4,5-trimethoxystyrene (101.1 mg per 11.2 g of the dried fraction; 0.9%, w.w-1), obtained from an ethanolic crude extract of the D. lanceolata leaves, was sprayed over the grains (1.5 g.kg-1), 98% of adult's mortality and a complete eradication of eggs were observed. These results were comparable to those obtained with a commercial insecticide based on deltamethrin (2 g.kg-1). A less pronounced effect against S. zeamais was verified by Ribeiro and co-workers who demonstrated that a treatment of corn grains with an ethanolic crude extract prepared from the leaves of D. lanceolata (3 g.kg-1) produced only 37.5% of mortality after 10 days (Ribeiro et al., 2016). Th toxic effect of two essential oils obtained from the stem barks and the aerial parts of D. furfuracea against Artemia saline, revealed that only the oil derived from the barks was active (LC50= 715.2 mg.mL -1 ) (Vidotto et al., 2013). A fresh volatile oil and petroleum ether extract from the stem barks D. furfuraceae were even more active (LC50 = 2.6 and 6.1 g.mL -1 , respectively) (da . According to the authors, among the oil constituents were found 2,4,5-trimethoxystyrene (3.25%), α-asarone (4.45%), and (E)-methyl-isoeugenol (0.48%), whereas the asaraldehylde was found in the organic extract (0.25%). In fact, the compounds 2,4,5-trimethoxy-acetophenone and asaraldehyde isolated from D. staudtii stem barks were reported to be active against the shrimp, presenting LC50 values of 80.5 g.mL -1 and 32.6 g.mL -1 , respectively (Nahar & Sarker, 2006). A former study also demonstrated that the 2,4,5-trimethoxystyrene isolated from the barks of D. panamensis was active against the shrimp (LC50= 8 g.mL -1 ) (Z. W. Wang et al., 1988). Conversely, no toxicity towards Brine shrimps was observed for the asaraldehyde isolated from D. gabriuscula (Siqueira et al., 2001). The reasons for such divergence are inconclusive but could be related to an erroneous identification of the isolated compound or due the test protocol used by the groups.
Based on the evidences already presented, the compounds responsible for the insecticidal effect are naturally lipophilic and are concentrated in the stem barks of the Duguetia species, therefore one can expect that fractions obtained using polar solvents and originated from the aerial parts of these plants will be less effective.
Although the phenylpropanoids seems to be promising for the development of new insecticides, further studies regarding their mechanism of action are still necessary. The effect seems to be species-dependent (Bhardwaj et al., 2010) and to be related to the inhibition of α-amylase (Huang et al., 1999), acetylcholinesterase, gluthathione-S-transferase, and carboxyesterase due the reaction with the enzymatic thiol moieties (Popławski et al., 2000). Moreover, the α-asarone and the 2,4,5-trymetoxystyrene were reported to present a strong antifeedant activity against larvae and adult forms of distinct insects (Alves et al., 2020;Łozowicka & Kaczynski, 2013;Popławski et al., 2000).
Regarding the phytotoxic activity of the phenylpropanoids, the 2,4,5-trimethoxybenzaldehyde and its chemically modified analogues were reported to inhibit the Auxin-binding protein (ABP-1), a molecular target growth regulators and commercial herbicides (R. P. Rodrigues et al., 2020).

Acaricide activity
The acaricidal activities of dichloromethane soluble fractions (10 mg.mL-1) derived from methanolic extracts of the leaves, berry fruits, and stem barks of D. lanceolata against adult's females of Tetranychus tumidus and T. urticae were compared (Alves et al., 2015). Again, only the stem bark fraction promoted a significant killing effect, which was 13-fold higher against T. urticae than T. tumidus after 72 h of contact (survival %: 4.5 ± 4.3 versus 59.0 ±7.4, respectively) (Alves et al., 2015). Moreover, the most abundant compounds found in the active fractions were the 2,4,5-trimethoxystyrene and αasarone.
Therefore, for those investigating the potential biological activities of the phenylpropanoids from Duguetia species, studies involving the acaricidal effect of non-polar crude extracts from stem barks of Duguetia seem to be a promising topic.
Other constituents present in the Duguetia species may also contribute for the overall effect of the extract. Santana and co-workers demonstrated the larvicidal properties of the essential oils extracted from the leaves of three species of the genus Piper (Santana et al., 2015). The phenylpropanoids comprised 75% of the oils tested and among them, the (E)-methylisoeugenol was found in the highest amount (27.08%) and the elemicin at 7.82%. Both compounds are also present in plants of the Duguetia genus (da Silva et al., 2007;Rodrigues et al., 2015). In fact, a structure-activity relationship (SAR) study revealed that distinct natural phenylpropanoids and their semisynthetic derivatives were active against the larvae of the tobacco armyworm Spodoptera litura (Bhardwaj et al., 2010).

Anti-inflammatory and anti-nociceptive activities
The evidences that phenylpropanoids can reduce the inflammatory responses by acting in distinct inflammatory pathways were assembled in two previous reviews (L. Korkina et al., 2011;Silveira e Sá et al., 2014). In this sense, the therapeutic use of plants of the genus Duguetia for the treatment of inflammation would be of great value, specially for those individuals living the remote areas of the Amazon Forest and Africa where the access to conventional medicines is restricted.
A pre-clinical study investigated the anti-inflammatory and antinociceptive effects following the oral administration of the essential oil obtained from the bark of the underground stem of D. furfuracea to mice (Saldanha et al., 2019). According to the authors, besides the sesquiterpenes, the essential oil contained 38% of phenylpropanoid derivatives and the main compounds were α-asarone (21.9%), bicyclogermacrene (16.7%), 2,4,5-trimethoxystyrene (16.1%), α-gurjinene (15%), cyperene (7.8%), and (E)-caryophyllene (4.6%). The oil (1, 3, and 10 mg.kg-1) inhibited the paw oedema induced by lipopolysaccharide (LPS) in a dose-dependent manner for 6 h. The dose of 10 mg.kg-1 inhibited the production of tumor necrosis factor alpha (TNF-α), the recruitment of polymorphonuclear leukocytes, and the inducible nitric oxide synthase (iNOS) expression in the paw tissue. Significant analgesia was also observed during the formalin and hot-plate tests for the doses of 10 and 30 mg.kg-1. In part, these effects could be attributed to the presence of the α-asarone, since in a complementary study, its oral administration to mice (3 and 10 mg.kg-1) promoted similar results. In addition, the adenosinergic and opioidergic systems was suggested to be involved in the central and peripheral anti-nociceptive effects of αasarone (Saldanha et al., 2020). A more recent but similar study from the same group employed a phenylpropanoid-enriched fraction of the essential oil from the D. furfuracea containing 36.4% of α-asarone and 27.8% of 2,4,5-trimethoxystyrene in addition to bicyclogermacrene (11.1%), α-gurjunene (10.5%), cyperene (5.8%), and (E)-caryophyllene (3.3%) (Saldanha et al., 2021). When comparing the results after the administration of 3 mg.kg-1 of the enriched-phenylpropanoid fraction and the ordinary oil, no difference was observed on their anti-nociceptive effects. On the other hand, the former resulted in a more pronounced reduction of the paw oedema after 2 h and 4 h of intake than the latter (2 h: 90.9% versus 41.7% of inhibition; 4 h: 77.8% versus 63.6%. respectively) (Saldanha et al., 2019;Saldanha et al., 2021). Although these results suggest the phenylpropanoids (α-asarone and 2,4,5-trimethoxystyrene) may have contributed to the anti-inflammatory effects of essential oil, the involvement of the additional phytocompounds cannot be excluded. In fact, a methanolic extract of D. furfuracea leaves, its fractions, and the isolated alkaloid dicentrinone, were able reduce significantly the paw oedema and leukocyte migration induced by carrageenan in mice (dos Santos et al., 2018).
Another species which the anti-inflammatory and anti-nociceptive activities were investigated was the D. lanceolata.
The essential oil from the stem barks was given intraperitonially (i.p.) to mice at distinct doses and the inhibitory effects on the carrageenan-induced paw oedema, on the number of acetic acid-induced writhing, and the time of paw licking promoted by formalin were evaluated (Sousa et al., 2004). The essential oil reduced significantly the paw oedema in a dose dependent way after 4 h of its administration (50 mg.kg-1: 20.8%, 100 mg.kg-1: 36.5%, and 200 mg.kg-1: 49.0% of inhibition) when compared to the control group. The effective doses able to reduce in 50% the number of writhing and the time of licking on the first and second phases were 21.8 mg.kg-1 (95% CI: 16.7 -28.0), 5.3 mg.kg-1 (95% CI: 3.6 -7.7), and 1.4 mg.kg-1 (95% CI: 0.9 -2.3), respectively. Similar study was conducted following the oral administration of an ethanolic extract obtained from the leaves of D. lanceolata (Sousa et al., 2008). The extract reduced significantly the paw oedema (50 mg.kg-1: 22.6%, 100 mg.kg-1: 32.3%, and 200 mg.kg-1: 40.3% of inhibition) when compared to the control group. This result is comparable to that observed after the i.p. administration of the essential oil, suggesting that the oral pathway may be a promising route of administration, however, further studies using the same type of preparation are still necessary to evaluate the bioavailability and efficacy. In fact, despite the extract had reduced the number of abdominal contortions significantly when compared with control group, this effect was less effective of that using the essential oil (10 mg.kg-1= 11.4% versus 25%, 50 mg.kg-1= 17.5% versus 50%, 100 mg.kg-1= 37.5% versus 87%, 200 mg.kg-1= 48% versus 100% of inhibition, respectively) (Sousa et al., 2008;Sousa et al., 2004). Doses of the extract from 50 to 200 mg.kg-1 were able to reduce approximately 11% to 83% the time that the animals spent licking the paw and to increment the time that they support the hot plate test from 37% to 102% when compared to the control groups (Sousa et al., 2008). Although these results suggest that D. lanceolata is a potential source of substances with anti-nociceptive and anti-inflammatory properties, the authors did not evaluate the phytochemical composition of the extract. Further studies, suggested that besides the phenylpropanoids, the sesquiterpene (E)-caryophyllene found as a major component in the essential oil of D. lanceolata branches and the alkaloid discretamine, present in the methanolic extract of D. moricandiana fruits can also exert anti-inflammatory and anti-nociceptive activities (Almeida, De Lima, et al., 2011;Sousa et al., 2016).
The investigations regarding the anti-inflammatory and anti-nociceptive activities of Duguetia species were restricted to animals but the results were promising, highlighting the need of further studies not only to discriminate the phytocompounds responsible for the therapeutical effects but also to evaluate their efficacy and safety.
An in vitro cytotoxicity study revealed that an acetogenin-rich extract from Duguetia sp. leaves was active against Ehrlich tumor cells (Castoldi et al., 2020). The percentage of cell viability was reduced by 16% and the number of dead cells increased two-fold independently of the concentration of extract (0.34 mg.mL-1; 0.67 mg.mL-1, and 1.35 mg.mL-1).
Unfortunately, the authors did not perform the chemical characterization of the extract. Although the alkaloids have been suggested as the major phytocompounds responsible for the antitumoral activity of the extract from Duguetia species (da Silva et al., 2009;Muhammad et al., 2001;Perez & Cassels, 2010), other components such as β-sitosterol isolated from D.
Despite the studies so far available did not correlated the antimicrobial and antifungal activities to the presence of the phenylpropanoids, it is currently known that the phytocompounds such as α-and β-asarone, asaraldehyde, (E)-methylisoeugenol, and elemicin, already found in the Duguetia species, are effective against distinct strains of bacteria and fungi (Ilijeva & Buchbauer, 2016;Lee et al., 2004;Rossi et al., 2007;Wang et al., 2020).

Other pharmacological activities
Studies involving the evaluation of the effect of α-asarone and 2,4,5-trimethoxycinnamic acid on the activity of the enzyme HMG-CoA reductase in Wistar rats revealed that both were able to inhibit enzymatic activity in 50% at concentrations of 3 mM and 60 mM, respectively (Antunez-Solis et al., 2009). Yet, according to the authors, the higher potency of α-asarone may be associated with its greater hydrophobicity and better interaction with the enzyme. On the other hand, it has been suggested that 2,4,5-trimethoxycinnamic acid is a better choice for the next studies in the search for hypocholesterolemic and cholelitholytic agents, due to the higher toxicity of α-asarone. Finally, it is worth mentioning the action of (E)-methylisoeugenol in the central nervous system. Behavioral studies in male Swiss mice involving pentylenetetrazole-induced seizure test, dark and light box test, elevated cross maze test, wire suspension, exploratory activity, and forced swimming test revealed that, although the anticonvulsant activity had not been demonstrated, the phytocompound promoted a sedative effect when administered at a dose of 500 mg.kg-1, as well as anxiolytic and antidepressant effects at doses between 125 and 500 mg.kg-1 (Fajemiroye et al., 2014). This compound was isolated from extracts of the stem of D. furfuracea (da Silva et al., 2007). Therefore, it is evident the capacity of the phenylpropanoid derivatives to modulate distinct biological activities, evidencing the application of these phytocompounds in the treatment of diseases, as well as, in the control of pests and vectors.
We expect that this work can contribute to those interested in further explore the therapeutic and commercial potential of the distinct species of the Duguetia.

Conclusion
This review brought together several studies involving the extraction, biological, and pharmacological activities of phenylpropanoid derivatives already isolated from plants of the genus Duguetia. It was evidenced that nonpolar solvents were able to provide the highest yield of 2,4,5-trimethoxystyrene, γ-asarone, and asaraldehyde which were mainly located at the ground stem barks of the plants investigated so far. On the other hand, the α-asarone, elimicin, and (E)-methyl-isoeugenol were isolated from the polar extracts or the essential oils. Such compounds were reported to have distinct biological activities, therefore, future studies investigating additional species of Duguetia and the activities of the phenylpropanoids is a promising topic and may result in prototypes for the development of new compounds with potential applications in both human health and agriculture.
In fact, our research group is current investigating the pharmacokinetic and biopharmaceutic characteristics of the asaraldehyde and α-asarone extracted from Duguetia species as part of the efforts to explore the therapeutic applicability of these compounds.Conflicts of interest statement The authors declare there are no conflict of interests.