JBCS

INTRODUCTION

Natural products are of great importance in the health studies: about 68.8% of all active principles found in drug formulations originate directly or indirectly from a plant-based product.^1,2

Malvaceae sensu lato is a family comprising about 245 genera and 4,465 species distributed mainly in tropical and subtropical regions and, less commonly, in temperate regions.^3,4 In Brazil, it is part of one of the most varied families represented with about 80 genera and 859 native species, of these 7 genera and 457 species are endemic to the country.⁵

Several species belonging to this family are part of the botanical arsenal of traditional medicine in the northeast region of Brazil: Helicteres baruensis Jacq. is used in folk medicine to treat dysmenorrhea, renal failure and as an analgesic; Guazuma ulmifolia Lamarck is used to treat bursitis, arthritis and hemorrhoids; Hibiscus esculentus L. is used in the prevention of hair loss, constipation, and asthma; and Cavanillesia umbellata Ruiz & Pav. is used to treat appendicitis, skin mycoses, as analgesics, to suppress gynecological inflammation and breast tumors.⁶

The family Malvaceae sensu lato comprises a rich source of alkaloids that present significant pharmacological effects and scientifically proven described in the literature, as seen in the species Waltheria douradinha (vanessine), Sida rhombifolia (cryptolepinone), Tilia cordata (trigonelline), Triumfetta grandidens (waltherione A) etc., reporting cytotoxic, antimicrobial, anti-inflammatory, analgesic, antispasmodic, hepatoprotective and antiparasitic activities, thus demonstrating the pharmacological potential that alkaloids have after being isolated from natural products.^7-10

Based on the data presented, the objective of this review was to carry out a bibliographic survey about the alkaloids reported in species of the Malvaceae sensu lato family, to evaluate their chemical and pharmacological potential, encouraging and reinforcing the importance of research on natural products as a source of new drugs.

 

METHODOLOGY

Available information on traditional use, phytochemical studies, and biological activities of alkaloids of Malvaceae sensu lato were collected from scientific databases: Web of Science, Scifinder, Pubmed, ScienceDirect and Google Scholar. Through this methodology, 99 works involving the subject were consulted, which were described in articles, books, dissertations, and thesis from 2010 to May 2022, using the keywords "Alkaloids" and "Malvaceae".

Articles with isolated and identified alkaloids from the Malvaceae sensu lato family, phytochemical studies, pharmacological and/or biological activities of these metabolites were used as inclusion criteria. Repeated articles, papers containing information on protoalkaloids, pseudoalkaloids and other nitrogen compounds, as well as articles with only botanical data or articles not available for access on consulted platforms were excluded.

The present study and data have been extracted by the author (A. L. C. S.) and confirmed by others (J. B. L. A., W. A. M. Q., D. A. F., P. I. V. S., M. F. V. S.). The interest in scientific studies with alkaloids present in the Malvaceae sensu lato has increased over the years due to favorable results of research on its biological activity. Data obtained were arranged in the form of tables and figures and a narrative description was performed to provide a summary of the information.

 

RESULTS AND DISCUSSION

Alkaloids are often classified by some authors by their chemical structure as protoalkaloids, pseudoalkaloids, and true alkaloids. Protoalkaloids and pseudoalkaloids do not follow the same biosynthetic route as alkaloids themselves¹¹ but are considered part of this group by some authors because they are nitrogenous substances. Considering these biosynthetic and biogenetic data, this review lists only the alkaloids themselves isolated from Malvaceae sensu lato, which may have the pyrrolidine, pyridine, piperidine, tropane, pyrrolizidine, quinolizidine, quinoline, indoquinoline, indole, and imidazole types as basic nuclei, among others found in the Malvaceae sensu lato family.^12-13

Alkaloids are secondary metabolites produced mainly by plants, although they can also be found in fungi, bacteria and animals.¹⁴ Therefore, alkaloids are one of the most diverse, efficient and therapeutically significant plant substances and are primarily involved in the defense of plants against herbivores, pathogens and even other plants.¹⁵

Traditional use of alkaloid-rich species

The traditional use of medicinal plants that have alkaloids has been reported over the centuries. Malvaceae sensu lato comprises species rich in these compounds, such the ones in the genera Waltheria, Sida, Hibiscus, Melochia, Helicteres, among others. Several species have great pharmacological importance, since they are widely used in traditional medicine for the treatment of diseases such as asthma, ulcers, parasitic infections, headaches, bacterial infections, inflammatory diseases, respiratory and urinary diseases.^16-21 Regarding Ethnobotany, several studies have been developed by the scientific community in order to investigate which compounds would be responsible for those activities reported by people, highlighting the scientific evidence of the biological and pharmacological activities of alkaloids.^17-19

Some species are commonly present in the field of phytochemical studies. Sida rhombifolia can be listed as an example, being used in folk medicine against hypertension, diabetes and the treatment of gout.^4,12 Waltheria indica is used by traditional medicine to treat malaria and other parasitic diseases.²² Helicteres angustifolia is reported by traditional medicine to have analgesic, antibacterial, anti-inflammatory and anticancer activities.²³

Several cytotoxic assays were performed with alkaloids isolated from Waltheria indica, Microcos paniculata, Sida acuta, Sida cordifolia, Kleinhovia hospita, among others, which were described throughout this review.

Alkaloids from Malvaceae sensu lato

Among plant extracts, we can mention those alkaloids that are identified in the species that belong to the Malvaceae sensu lato family (Table 1 and Figure 1), which are distributed in different genera and are found in different parts of plants.

 

 

 

 

Biological activities of alkaloids

Alkaloids play essential and specific roles on the treatment of various diseases through different mechanisms of action, including anti-inflammatory, analgesic, antifungal, antimicrobial, anticancer, antiparasitic and several other biological activities (Table 2).

 

 

Analgesic and anti-inflammatory activities

Anti-inflammatory activity of alkaloids is directly linked to their chemical structure. As an example of secondary metabolites with proven pharmacological activities we can quote antidesmone (33) isolated from the roots of the species Melochia chamaedrys A. St.-Hil., a tetrahydroquinolone alkaloid that showed an anti-inflammatory effect by suppressing the production of inflammatory cytokines, including tumor necrosis factor-α, interleukin-6 and interleukin-1β in RAW264.7 cells on mouse macrophages induced by lipopolysaccharides (LPS), exerting an apparently anti-inflammatory effect in acute lung injury, regulated by two signaling pathways, being the protein pathway mitogen-activated kinase (MAPK) and nuclear factor kappa β (NF-λβ).²¹

A study with the quinazoline alkaloid 5'-hydroxymethyl-1' (1,2,3,9-tetrahydropyrrolo[2,1-b]-quinazolin-1-yl)-heptan-1-one (28) isolated from aerial parts of Sida cordifolia showed that this secondary metabolite acted in the inflammatory process induced by carrageenan, acting in an inhibitory way on the cyclooxygenase enzyme, leading to the inhibition of prostaglandin synthesis. An acetic acid induced writhing test also demonstrated the peripheral analgesic evaluation of drugs, showing responses mediated through peritoneal mast cells, acid-sensitive ion channels and prostaglandin pathway. The antinociceptive activity was also significant by the evaluation of the same signaling pathway, where the tested compound increased the stress tolerance capacity of the animals involved in the study.²⁴

Furthermore, other studies with the alkaloids vasicine (84) and vasicinol (85) isolated from the species Sida cordifolia L.⁹⁸ also showed anti-inflammatory and analgesic activities.

Cytotoxic and anticancer activities

Cancer is one of the most serious health problems today, being responsible for 7.6% of deaths around the world. About 75-80% of the world population use medicinal herbs to treat cancer.⁹⁹

One of the most responsible factors for tumor promotion and progression is the activation of the NF-λβ transcription. A phytochemical study carried out with the aerial parts and roots of Waltheria indica resulted in the isolation of the quinoline alkaloids waltherione A (88) and waltherione C (90), which showed inhibitory properties of the nuclear factor NF-λβ (56.1 ± 11.9 µmol L^-1 and 55.5 ± 8.4 µmol L^-1, respectively). Those bioactive compounds that have inhibitory activity can act as chemopreventives and chemotherapeutics in tumor suppression.⁴¹

The cryptolepine indoquinoline alkaloid (36), isolated from the species Sida acuta Burm. and S. cordifolia, showed anticancer activity through the activation of the caspases-3/7 cascade inducing apoptosis in gastric adenocarcinoma cells⁸² and the arrest of G₂/M cell cycle in osteosarcoma cells, activating p53-independent p21WAF1/CIP1 promoter genes, making this drug a promising chemotherapeutic candidate.⁴⁵

The quinoline alkaloid waltherione C (90) isolated from Melochia umbellata (Houtt.) Stapf has demonstrated significant cytotoxic activity against murine leukemic cell lines. The alkaloid waltherione C isolated from Melochia odorata L.f. has demonstrated an LC₅₀ activity of 0.29 mg mL^-1 in the salt brine shrimp assay and toxicity against CEM-TART cells showing an LC₅₀ of 3.8 mg mL^-1.⁷²

A study by Zhang et al.⁶⁰ showed that microcosamine A (55) and microcosamine C (57) piperidine alkaloids isolated from the species Microcos paniculata L. showed cytotoxic activity in vitro against murine macrophage tumor cell lineage (RAW 264.7), with values of 31.5 µmol L^-1 and 39.8 µmol L^-1, respectively.

The alkaloids microgrewiapine A (58) isolated from Microcos paniculata⁵⁴ and quindolinone (75) isolated from Sida acuta showed cytotoxic activity.³⁹

Antibacterial and antifungal activities

The quinoline alkaloid vanessine (83) isolated from the Sida acuta showed antibacterial activity against strains of Escherichia coli (25.0 µg mL^-1), Salmonella setubal (50.0 µg mL^-1) and Klebsiella pneumoniae (25.0 µg mL^-1).³¹

The plant species Waltheria indica L. is extensively studied, having some major quinoline alkaloids in its metabolic composition demonstrated great antifungal activity, such as waltherione N (101), 8-deoxoantidesmone (19), antidesmone (33), waltherione E (92), waltherione G (94), waltherione I (96), waltherione J (97), waltherione F (93) and 5-(R)-vanessine (12), which presented a minimum inhibitory concentration MIC ≤ 32 µg mL^-1.⁷⁸

Antiparasitic activity

Among the secondary metabolites that present antiparasitic activity, we can highlight the alkaloids. Waltheria indica has shown a good anti-chagasic activity, being the alkaloids waltherione R (105), (8R)-8-hydroxywaltherione M (21), waltherione T (107), waltherione M (100), waltherione P (103) and waltherione Q (104) prominent for antiparasitic activity against the Trypanosoma cruzi parasite with IC₅₀ values of 2.1, 0.8, 2.1, 1.3, 0.5 and 0.1 µmol L^-1, respectively.⁷ In addition, waltherione C (90) showed a higher antitrypanosome activity against Trypanosoma cruzi (IC₅₀ 1.93 µmol L^-1) combined with a low cytotoxicity (IC₅₀ 101.23 µmol L^-1).²¹

Alkaloids waltherione A (88) and waltherione E (92) have been isolated from Triumfetta grandidens Hance and evaluated for nematocidal activity against the worm Meloidogyne incognita, known as cotton root nematode, which is considered as vermin in agriculture. These alkaloids showed a potency of inhibition against the egg hatching process of this worm, being 91.9 and 87.4%, respectively, after 7 days of exposure to a concentration of 1.25 µg mL^-1.⁹

Other activities

Some other activities of alkaloids are reported as vasorelaxant, hepatoprotective, antioxidant, hypoglycemic, antiviral and larvicide actions.

The vasorelaxant activity of quindolinone alkaloids (75), salt of cryptolepine (76)⁸ and cryptolepinone (37)⁴ against the mesenteric arteries of rodents were reported for the first time for Sida rhombifolia. These results justify the antihypertensive activity reported by Indian folk medicine of the species Sida rhombifolia.^4,8

Aleykutty & Akhila⁷⁹ performed a computational study (in silico) of the indolalkylamine alkaloid yohimbine (110) isolated from Helicteres isora L. This compound was designed using the Chem.Sketch software and the molecular docking was performed with the Autodock 4.0 program, making it possible to predict its antidiabetic (hypoglycemic) activity against the interaction with the enzyme aldose reductase, noting a better binding energy to insulin receptors (-10.08 kcal mol^-1), when compared to the standard compound pentadecane (-9.4 kcal mol^-1).

Studies with alkaloids have also led to promising activities such as antivirals and larvicides.

Alkaloids waltherione A (88) and waltherione C (90) isolated from Melochia odorata L.f. exhibited an in vitro anti-HIV antiviral activity, with cytoprotection at concentrations of 56.2 and 0.84 µmol L^-1 and inhibition of HIV P24 formation of more 50% at concentrations of 1.7 and 0.95 µmol L^-1, respectively. Waltherione C isolated from Melochia umbellata heartwood has also been reported as having anti-HIV antiviral activity with an EC₅₀ of 0.3 mg mL^-1.⁷²

For larvicidal activity, a study carried out by Feng et al.⁵⁹ showed that the alkaloids microcosamine A (55) and microcosamine B (56) isolated from Microcos paniculata would present potent activity against the larval stages of the mosquito Culex quinquefasciatus in lethal concentrations CL₅₀ of 5.2 and 17.0 µg mL^-1, respectively.

 

CONCLUSION

This review gathered information concerning the alkaloids found in different plant species belonging to the Malvaceae sensu lato family. Several medicinal properties come from these species widely used by the population for the treatment of illnesses.

After analyzing the literature, we concluded that the diversity of alkaloid nuclei found in Malvaceae species are responsible for characterizing the different pharmacological activities of these secondary metabolites from different parts of plants, presenting anti-inflammatory, analgesic, antimicrobial, antiparasitic, vasorelaxant and anticancer activities. This implies that such alkaloids, with extreme biological relevance, have great potential to be explored as sources of bioactive molecules, and species of Malvaceae sensu lato contribute to such importance.

 

ACKNOWLEDGMENTS

The authors are grateful to Coordenação de Aperfeiçoamento do Ensino Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the support to our researches.

 

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