The compound (E)-2-cyano-3-(1H-indol-3-yl)-N-phenylacrylamide (ICMD-01) was designed and developed based on the structures of clinically relevant drugs indomethacin and paracetamol through the molecular hybridization strategy. This derivative was obtained by an amidation reaction between substituted anilines and ethyl 2-cyanoacetate followed by a Knoevenagel-type condensation reaction with indole aldehyde that resulted in both a viable synthesis and satisfactory yield. In order to assess the immunomodulatory and anti-inflammatory activity, in vitro assays were performed in J774 macrophages, and significant inhibitions (p < 0.05) of the production of nitrite and the production of cytokines (IL-1β and TNFα) in noncytotoxic concentrations were observed. The anti-inflammatory effect was also studied via CFA-induced paw edema in vivo tests and zymosan-induced peritonitis. In the paw edema assay, ICMD01 (50 mg kg⁻¹) showed satisfactory activity, as did the group treated with dexamethasone, reducing edema in 2–6 h. In addition, there was no significant inhibition of PGE₂, IL-1β or TNFα in vivo. Moreover, in the peritonitis assay that assesses leukocyte migration, ICMD-01 exhibited promising results. Therefore, these preliminary studies demonstrate this compound to be a strong candidate for an anti-inflammatory drug together with an improved gastrointestinal safety profile when compared to the conventional anti-inflammatory drugs.

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.

Leishmaniasis is a neglected tropical disease caused by Leishmania sp. The therapeutic arsenal is reduced and limited. In this context, acridine derivatives present themselves as promising leishmanicidal compounds. This paper involved synthesizing and evaluating the antileishmanial and immunomodulatory potential of spiro-acridine derivatives. Six spiro-acridine derivatives were obtained through nucleophilic substitution reactions between the acetohydrazide/acetamide intermediates and 9-carbaldehydeacridine, followed by spontaneous cyclization. IR, NMR, and HRMS confirmed the structures. These were analyzed in vitro against L. infantum and L. amazonensis to determine anti-promastigote, anti-amastigote, and cytotoxicity effects. Immunomodulatory activity was evaluated using CBA, DCF-DA, and DAF-FM diacetate. In silico evaluation included molecular docking and dynamics. The spiro-acridines showed a wide range of anti-promastigote activities (IC₅₀ = 0.73–234.95 µM) and non-toxicity to red blood cells. AMTAC-02 and ACMD-03 demonstrated satisfactory anti-amastigote effect (IC₅₀ = 10.47–13.50 µM), low toxicity to macrophages (CC₅₀ = 27.22–569.50 µM), and cytokine and reactive species modulation. Molecular docking proposed cysteine protease B of L. amazonensis as a target, and molecular dynamics analysis highlighted the complex’s stability using RMSD, R_g, SASA, DCCM, PCA, and MM-PBSA (ΔG = −65.225 kJ/mol). Furthermore, QM-MM calculation provided the best energy for ACMD-03 (−199.30 au). Hence, AMTAC-02 and ACMD-03 demonstrated antileishmanial potential, making them promising entities for the development of leishmanicidal drug candidates.

Background: Heterocycle compounds with acridine, quinoline, indole, and pyridine nuclei are potentially active for anticancer activity since they can promote inhibition of vital enzymes, decreasing cell survival after binding to biomolecules. However, unspecific biological interactions can result in unwanted effects, which should be defined during the synthesis and proposition of new molecules. Thus, the objective of this study was to investigate the biological and teratogenic effects of four nitrogen heterocycles proposed for anticancer therapy. Methods: Four 2-cyano-N-phenylacrylamine type derivatives containing acridine (3a), quinoline (3b), indole (3c), and pyridine (3d) nuclei were synthesized and characterized. They were evaluated for their ability to interact with DNA, physicochemical and pharmacokinetic predictions, in vitro and in silico methodologies, besides in vitro inhibition of the Topoisomerase IIα enzyme, antiproliferative activity in tumor and non-tumor cells, hemolytic activity with human erythrocytes, and in vivo toxicological studies with zebrafish embryos. Results: UV–vis absorption studies with ssDNA revealed different spectroscopic effects, with binding constants (Kb) ranging from 1.41 × 10⁵ to 6.46 × 10⁴ M⁻¹. The fluorescence quenching constant (Ksv) with ethidium bromide (EB) varied between 0.53 and 0.67 × 10³ M⁻¹. The compounds intercalated into DNA base pairs, a mechanism confirmed by molecular docking, with 3b (quinoline) showing the most substantial interaction. All derivatives exhibited antitopoisomerase IIα activity at 100 μM and were cytotoxic against MCF-7 and T47-D breast tumor cells, particularly against the more aggressive T47-D lineage. No hemolytic activity was observed in human erythrocytes. In vivo assays in zebrafish embryos showed no toxicological or cardiotoxic effects. However, all compounds altered superoxide dismutase (SOD) and catalase (CAT) enzymatic activity, requiring further studies on reactive oxygen species (ROS) generation to assess potential adverse effects. Furthermore, significant results were observed in the physicochemical and pharmacokinetic parameters of the synthesized compounds. Conclusions: The findings highlight the quinoline derivative (3b) as the most promising nitrogen heterocycle due to its antiproliferative activity and biomolecular interactions without adverse effects in zebrafish embryos, distinguishing it from clinically available agents.

This study reports the synthesis of four derivatives containing acridine (3a), quinoline (3b), indole (3c), and pyridine (3d) nuclei, as well as their interactions with DNA, physicochemical and pharmacokinetic predictions, antiproliferative activity, in silico and in vivo effects in zebrafish, and enzyme inhibition assays. UV–vis absorption studies with ssDNA revealed different spectroscopic effects, with binding constants (Kb) ranging from 1.41 × 10⁵ to 6.46 × 10⁴ M⁻¹. The fluorescence quenching constant (Ksv) with ethidium bromide (EB) varied between 0.53 and 0.67 × 10³ M⁻¹. The compounds intercalated into DNA base pairs, a mechanism confirmed by molecular docking, with 3b (quinoline) showing the most substantial interaction. All derivatives exhibited antitopoisomerase IIα activity at 100 μM and were cytotoxic against MCF-7 and T47-D breast tumor cells, particularly against the more aggressive T47-D lineage. No hemolytic activity was observed in human erythrocytes. In vivo assays in zebrafish embryos showed no toxicological or cardiotoxic effects. However, all compounds altered superoxide dismutase (SOD) and catalase (CAT) enzymatic activity, requiring further studies on reactive oxygen species (ROS) generation to assess potential adverse effects. Furthermore, good results were observed in the physicochemical and pharmacokinetic parameters of the synthesized compounds. These findings highlight the quinoline derivative (3b) as the most promising nitrogen heterocycle due to its antiproliferative activity and biomolecular interactions without adverse effects in zebrafish embryos, distinguishing it from clinically available agents.