This Review discusses the isolation and bioactivity of marine alkaloids against protozoan parasite diseases, and chemical syntheses that enable the further development of these scaffolds as drug leads.

Chagas disease (CD) is a parasitic infection caused by Trypanosoma cruzi, endemic in Latin America and recently found in non-endemic countries of North America, Europe and Asia. The main form of transmission depends on the presence of a vector, being Triatoma infestans the most common 1. It is estimated that over eight million people are infected by the parasite and 70 million are at risk, living on endemic areas or in places where the control of other forms of transmission (oral, blood transfusion or organ transplant) is not rigid 2. CD is a two-stage disease: the acute phase, characterized by the high parasitaemia, and invasion by trypomastigote forms of different organs and the chronic phase, which may be latent for decades before appearance of clinical signs and usually associated with the development of cardiomyopathy 3,4. The available therapy for the treatment of CD is actually restricted to two approved drugs: benznidazole and nifurtimox, remains a controversial issue, with contradictory results in the chronic phase of the disease 5-8. Furthermore, these nitrocompounds showed several side effects associated to prolonged treatment regimens. Several clinical trials involving drug-repositioning (such as antifungal azoles) were carried out as well as studies involving new molecules, but none have reached the market yet 4. Therefore, new effective drugs for the treatment of CD are still needed. The Drugs for Neglected Diseases initiative (DNDi) defines that a desirable hit compound should present considerable efficacy (IC 50 < 10 µM), selectivity (>10-fold over mammalian cells) and adequate oral bioavailability 9. Natural products have always been a source of a great variety of bioactive molecules, mostly substances from the organism secondary metabolism. Many drugs available in the market are natural products as found in nature or compounds designed based on the structure and activity of these natural products (semi-synthetic or completely synthetic) 10. The biodiversity of plants makes them a commonly explored source of novel bioactive compounds, providing molecules with distinct structures, complex or simple, with huge chemical variety 11. Several research groups are focused on the isolation and identification of novel compounds with antimicrobial activity from plant extracts, aiming to use them as prototypes for drug discovery against Chagas disease 12. In this context, licarin A is a neolignan isolated from different plant species with reported activity against Mycobacterium tuberculosis 13,14 , Schistosoma mansoni 15 , Trypanosoma cruzi 15-17 , and Leishmania major 18. Considering the promising activity against T. cruzi and the considerable amounts of licarin A isolated from the leaves of Nectandra oppositifolia (Lauraceae), this compound was selected for preparation of semi-synthetic analogues to further pharmacophore exploitation. Thereafter, licarin A was obtained in pure form and five semi-synthetic and twenty-one analogues were designed by the molecular simplification approach. The main objective wa...

Chagas disease, caused by Trypanosoma cruzi , affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2′-de- N -methylaplysinopsin ( BMA ) was isolated and chemically characterized from the marine coral Tubastraea tagusensis . BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi , resulting in IC 50 values of 62 and 5.7 μM, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA , suggesting a different mechanism from benznidazole. In silico pharmacokinetic–pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations.

The SARS‐CoV‐2 virus, responsible for COVID‐19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID‐19, and their potential use in coronavirus‐related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID‐19.

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Background: Chagas disease (American Trypanosomiasis) is classified by the World Health Organization (WHO) as one of the seventeen neglected tropical diseases (NTD), affecting, mainly, several regions of Latin America. Introduction: However, immigration has expanded the range of this disease to other continents. Thousands of patients with Chagas disease die annually, yet no new therapeutics for Chagas disease have been approved, with only nifurtimox and benznidazole available. Treatment with these drugs presents several challenges, including protozoan resistance, toxicity, and low efficacy. Natural products, including the secondary metabolites found in plants, offer a myriad of complex structures that can be sourced directly or optimized for drug discovery. Method: Therefore, this review aims to assess the literature from the last 10 years (2011 – 2021) and present the anti-T. cruzi compounds isolated from plants in this period, as well as briefly discuss computational approaches and challenges in natural product drug discovery. Using this approach, more than 350 different metabolites were divided based on their biosynthetic pathway – alkaloids, terpenoids, flavonoids, polyketides, and phenylpropanoids which displayed activity against different forms of this parasite – epimastigote, trypomastigote and more important, the intracellular form, amastigote. Conclusion: In this aspect, there are several compounds with high potential which could be considered as a scaffold for the development of new drugs for the treatment of Chagas disease – for this, more advanced studies must be performed including pharmacokinetics (PK) and pharmacodynamics (PD) analysis as well as conduction of in vivo assays, these being important limitations in the discovery of new anti-T. cruzi compounds.

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Drimys brasiliensis (Winteraceae) has been investigated in traditional medicine for its anti-inflammatory properties to treat gastric ulcers and allergic and respiratory system diseases as well as for cancer treatment. In this work, we investigate the ability of the sesquiterpene polygodial, isolated from D. brasiliensis stem barks, to modulate the chronic inflammatory response induced by polyester-polyurethane sponge implants in C57BL/6J mice. Daily treatment with polygodial inhibited the macrophage content in the implants as determined by the activity of the N-acetyl-β-d-glucosaminidase enzyme as well as decreased the levels of CXCL1/KC and CCL2/JE/MCP-1 pro-inflammatory chemokines and the presence of mast cells along the formed fibrovascular tissue. Similarly, the deposition of a new extracellular matrix (total collagen and type I and III collagen fibers) as well as the production of the TGF-β1 cytokine were attenuated in implants treated with polygodial, showing for the first time its antifibrogenic capacity. The hemoglobin content, the number of newly formed vessels, and the levels of VEGF cytokine, which were used as parameters for the assessment of the neovascularization of the implants, did not change after treatment with polygodial. The anti-inflammatory and antifibrogenic effects of polygodial over the components of the granulation tissue induced by the sponge implant indicate a therapeutic potential for the treatment of inflammatory diseases associated with the development of fibrovascular tissue.