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, 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.

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...

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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