Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes.

The termneglected diseasesrefers to a group of infections caused by various classes of pathogens, including protozoa, viruses, bacteria, and helminths, most often affecting impoverished populations without adequate sanitation living in close contact with infectious vectors and domestic animals. The fact that these diseases were historically not considered priorities for pharmaceutical companies made the available treatments options obsolete, precarious, outdated, and in some cases nonexistent. The use of plants for medicinal, religious, and cosmetic purposes has a history dating back to the emergence of humanity. One of the principal fractions of chemical substances found in plants are essential oils (EOs). EOs consist of a mixture of volatile and hydrophobic secondary metabolites with marked odors, composed primarily of terpenes and phenylpropanoids. They have great commercial value and were widely used in traditional medicine, by phytotherapy practitioners, and in public health services for the treatment of several conditions, including neglected diseases. In addition to the recognized cytoprotective and antioxidative activities of many of these compounds, larvicidal, insecticidal, and antiparasitic activities have been associated with the induction of oxidative stress in parasites, increasing levels of nitric oxide in the infected host, reducing parasite resistance to reactive oxygen species, and increasing lipid peroxidation, ultimately leading to serious damage to cell membranes. The hydrophobicity of these compounds also allows them to cross the membranes of parasites as well as the blood-brain barrier, collaborating in combat at the second stage of several of these infections. Based on these considerations, the aim of this review was to present an update of the potential of EOs, their fractions, and their chemical constituents, against some neglected diseases, including American and African trypanosomiasis, leishmaniasis, and arboviruses, specially dengue.

Cancer represents the main cause of morbidity and mortality worldwide, constituting a serious health problem. In this context, melanoma represents the most aggressive and fatal type of skin cancer, with death rates increasing every year. Scientific efforts have been addressed to the development of inhibitors targeting the tyrosinase enzyme as potential anti-melanoma agents due to the importance of this enzyme in melanogenesis biosynthesis. Coumarin-based compounds have shown potential activity as anti-melanoma agents and tyrosinase inhibitors. In this study, coumarin-based derivatives were designed, synthesized, and experimentally evaluated upon tyrosinase. Compound FN-19, a coumarin–thiosemicarbazone analog, exhibited potent anti-tyrosinase activity, with an IC₅₀ value of 42.16 ± 5.16 µM, being more active than ascorbic acid and kojic acid, both reference inhibitors. The kinetic study showed that FN-19 acts as a mixed inhibitor. Still, for this compound, molecular dynamics (MD) simulations were performed to determine the stability of the complex with tyrosinase, generating RMSD, RMSF, and interaction plots. Additionally, docking studies were performed to elucidate the binding pose at the tyrosinase, suggesting that the hydroxyl group of coumarin derivative performs coordinate bonds (bidentate) with the copper(II) ions at distances ranging from 2.09 to 2.61 Å. Then, MM/PBSA calculations revealed that van der Waals interactions are the most relevant intermolecular forces for complex stabilization. Furthermore, it was observed that FN-19 has a binding energy (ΔE_MM) value similar to tropolone, a tyrosinase inhibitor. Therefore, the data obtained in this study will be useful for designing and developing novel coumarin-based analogs targeting the tyrosinase enzyme.

A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1β-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC₅₀ = 7.1 ± 0.8 and 3.3 ± 0.5 μM, respectively against A549 and H2170 cells) and CC₅₀ value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1β-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1β. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1β-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines.

Neglected parasitic diseases are a group of infections currently considered as a worldwide concern. This fact can be attributed to the migration of these diseases to developed and developing countries, associated with therapeutic insufficiency resulted from the low investment in the research and development of new drugs. In order to overcome this situation, bioprospecting supports medicinal chemistry in the identification of new scaffolds with therapeutically appropriate physicochemical and pharmacokinetic properties. Among them, we highlight the nitrogenous heterocyclic compounds, as they are secondary metabolites of many natural products with potential biological activity. The objective of this work was to review studies within a 10-year timeframe (2009- 2019), focusing on the pharmacological application of nitrogen bioprospectives (pyrrole, pyridine, indole, quinoline, acridine, and their respective derivatives) against neglected parasitic infections (malaria, leishmania, trypanosomiases, and schistosomiasis), and their application as a template for semi-synthesis or total synthesis of potential antiparasitic agents. In our studies, it was observed that among the selected articles, there was a higher focus on the attempt to identify and obtain novel antimalarial compounds, in a way that an extensive amount of studies involving all heterocyclic nitrogen nuclei were found. On the other hand, the parasites with the lowest number of publications up until the present date have been trypanosomiasis, especially those caused by Trypanosoma cruzi, and schistosomiasis, where some heterocyclics have not even been cited in recent years. Thus, we conclude that despite the great biodiversity on the planet, little attention has been given to certain neglected tropical diseases, especially those that reach countries with a high poverty rate.