Jamerson Ferreira de Oliveira

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.

Molecular hybridization is used in the development of drug prototypes through the combination of bioactive compounds, being useful in the development of new drugs with antitumor action, given the high complexity of the disease. Thiosemicarbazones are interesting structures for the development of hybrids, enabling the discovery of unexplored mechanisms of action and new alternatives in cancer treatment. In this study, we report data on new thiosemicarbazone hybrids from the last 10 years (2015-2025), identifying the main bioactive groups, pharmacological targets, and cell lines of interest. The study indicates a strong trend towards hybridization with nitrogenous heterocycles (52%), with emphasis on indole, quinoline, and pyridine groups. Regarding targets, VEGFR-2 (Vascular Endothelial Growth Factor Receptor 2) and different topoisomerases are particularly prominent. The main cell lines used in cytotoxicity studies were MCF-7 (36 studies), MDA-MB-231 (21 articles), A549 (21 articles), and HepG-2 (20 articles). Only 20 compounds showed IC50 values below 2 µM, with emphasis on those hybridized with nitrogenous groups. Thus, thiosemicarbazone hybrids, especially those conjugated with nitrogenous compounds, show promise for exploration in the development of antitumor prototypes.

A crescente busca por terapias mais seguras e eficazes tem impulsionado a investigação de plantas medicinais, como Allium sativum e Zingiber officinale, amplamente reconhecidas por suas propriedades terapêuticas no saber popular. Diante disso, este estudo teve como objetivo explorar o perfil fitoquímico, as propriedades bioativas e o potencial farmacológico dessas espécies, com foco em sua atividade antimicrobiana in silico e citotoxicidade. Os bulbos de A. sativum e rizomas de Z. officinale foram submetidos à extração hidroetanólica por maceração, com análise dos extratos quanto à densidade, rendimento e presença de metabólitos secundários. Além disso, testes in silico investigaram a interação de 19 fitoconstituintes dessas plantas com a enzima KPC-2, enquanto ensaios in vitro avaliaram a citotoxicidade utilizando hemácias de carneiro. Os resultados mostraram a presença de flavonoides, saponinas e cumarinas como principais metabólitos secundários. O fitoconstituinte curcumina, proveniente de Z. officinale, apresentou elevada afinidade de ligação com a enzima KPC-2 (-9,1 kcal/mol). Compostos promissores também foram identificados em A. sativum, como a alicina (-5,7 kcal/mol). Ambos os extratos demonstraram baixa citotoxicidade nas concentrações analisadas. Assim, concluiu-se que A. sativum e Z. officinale são fontes promissoras de compostos bioativos com potencial antimicrobiano e baixa toxicidade. Estudos futuros devem focar na otimização desses compostos para desenvolver terapias mais seguras e eficazes.

Indole-thiosemicarbazones have different biological activities. The present study evaluated the preliminary interaction of these compounds with biomolecules, specifically human serum albumin (HSA) and DNA, using fluorescence techniques. The suppression results (K_sv) for HSA ranged from 3.5 x 10⁴ to 4.6 x 10⁵ L/mol, while for DNA, they ranged from 1.4 x 10⁴ to 5.9 x 10⁴ L/mol. The suppression was classified as weak to strong for HSA and moderate for DNA. The bimolecular suppression constant (K_q) showed values between 6.0 x 10¹² and 8.2 x 10¹³ L/mol/s for HSA and from 1.4 x 10¹² to 5.9 x 10¹² L/mol/s for DNA, suggesting a static suppression mechanism. Compound PR09 stood out, presenting a binding constant (K_a) greater than 10⁵ L/mol for HSA, indicating a strong interaction. Additionally, PR05, PR06, PR07, and PR09 demonstrated strong interactions with DNA. The values of the number of binding sites (n) indicated that PR01, PR02, and PR09 bind to multiple sites on HSA, while PR04, PR05, PR06, and PR09 interact with more than one site on DNA. All interactions were spontaneous, with ∆G negative. The distance between the compounds and tryptophan on HSA was less than 8 nm, suggesting high energy transfer efficiency. In molecular docking studies, PR05 showed the highest affinity for DNA (-11.15 kcal/mol), while PR09 had the highest affinity for HSA (-10.00 kcal/mol). PR07 exhibited the lowest binding energies for DNA (-8.21 kcal/mol) and for HSA (-7.38 kcal/mol). This study demonstrates that the evaluated compounds have potential as new drug candidates.

Cancer is a complex and multifactorial disease characterized by uncontrolled cell growth and is one of the main causes of death in the world. This work aimed to evaluate a small series of 10 different indole-thiosemicarbazone compounds as potential antitumor agents. This is a pioneering study. For this, the antioxidant and cytotoxic capacity against normal and tumor cells was evaluated. The results showed that the compounds were able to promote moderate to low antioxidant activity for the ABTS radical scavenging assay. ADMET in silico assays showed that the compounds exhibited good oral bioavailability. As for toxicity, they were able to promote low cytotoxicity against normal cells, in addition to not being hemolytic. The compounds showed promising in vitro antitumor activity against the T47D, MCF-7, Jurkat and DU-145 strains, not being able to inhibit the growth of the Hepg2 strain. Through this in vitro study, it can be concluded that the compounds are potential candidates for antitumor agents.

In this work, an in silico study and evaluation of the cytotoxicity of 4-(4-chlorophenyl)thiazole compounds against mouse splenocytes and the chloroquine-sensitive Plasmodium falciparum 3D7 strain are reported. The in silico results showed that the compounds have important pharmacokinetic properties for compounds with potential drug candidates. Regarding cytotoxicity assays against splenocytes, the compounds have low cytotoxicity. In addition, they were able to promote activation of these cells by increasing nitric oxide production without promoting cell death. Finally, they were able to promote cell proliferation. Regarding the in vitro anti-P. falciparum activity assays, it was observed that the compounds were able to inhibit the parasite’s growth, presenting IC₅₀ values ​​ranging from 0.79 to greater than 10 µM. These results are promising when compared to chloroquine. Therefore, this study showed that 4-(4-chlorophenyl)thiazole compounds are promising candidates for antimalarials.

Neglected tropical diseases are a diverse group of communicable pathologies that mainly prevail in tropical and subtropical regions. Thus, the objective of this work was to evaluate the biological potential of eight 4-(4-chlorophenyl)thiazole compounds. Tests were carried out in silico to evaluate the pharmacokinetic properties, the antioxidant, cytotoxic activities in animal cells and antiparasitic activities were evaluated against the different forms of Leishmania amazonensis and Trypanosoma cruzi in vitro. The in silico study showed that the evaluated compounds showed good oral availability. In a preliminary in vitro study, the compounds showed moderate to low antioxidant activity. Cytotoxicity assays show that the compounds showed moderate to low toxicity. In relation to leishmanicidal activity, the compounds presented IC50 values that ranged from 19.86 to 200 µM for the promastigote form, while for the amastigote forms, IC50 ranged from 101 to more than 200 µM. The compounds showed better results against the forms of T. cruzi with IC50 ranging from 1.67 to 100 µM for the trypomastigote form and 1.96 to values greater than 200 µM for the amastigote form. This study showed that thiazole compounds can be used as future antiparasitic agents.

Background In this article, a series of 20 new thiosemicarbazone derivatives containing indole were synthesized and evaluated for their anti-inflammatory potential. Methods The compounds were obtained through a synthetic route of only two steps, with yields that varied between 33.6 and 90.4%, and characterized by spectroscopic and spectrometric techniques. Results An initial screening through the lymphoproliferation assay revealed that compounds LT76, LT81, and LT87 were able to inhibit lymphocyte proliferation, with CC₅₀ of 0.56 ± 0.036, 0.9 ± 0.01 and 0.5 ± 0.07 µM, respectively, better results than indomethacin (CC₅₀ > 12 µM). In addition, these compounds were able to suppress the in-vitro production of TNF-α and NO, in addition to stimulating the production of IL-4. Reinforcing in-vitro assays, the compounds were able to inhibit COX-2 similar to Celecoxib showing greater selectivity for this isoform (LT81 SI: 23.06 versus Celecoxib SI: 11.88). Animal studies showed that compounds LT76 (64.8% inhibition after 6 h), LT81 (89% inhibition after 6 h) and LT87 (100% inhibition after 4 h) were able to suppress edema in mice after inoculation carrageenan with greater potency than indomethacin, and immunohistochemistry revealed that the groups treated with LT76, LT81 and LT87 reduced the expression of COX-2, similar or better results when compared to indomethacin. Complementarily, in-silico studies have shown that these compounds have a good pharmacokinetic profile, for respecting the parameters of Lipinski and Veber, showing their good bioavailability. Conclusions These results demonstrate the potency of thiosemicarbazone derivatives containing indole and confirm their importance as scaffolds of molecules with notorious anti-inflammatory activity.