Shayenne Eduarda Ramos Vanderley

Alarming data on the neglected tropical disease leishmaniasis, especially for global visceral cases, have motivated the development of novel drugs to overcome the emergence of resistance. In this context, quinoline derivatives, especially quinoline-4- carboxylic acids, have shown promising antileishmanial activity. More recently, acetanilide linked quinoline derivatives revealed selective antileishmanial activity. Now, we are motivated to investigate the influence of the substituent group on antileishmanial and toxicity properties of sixteen 2-acetanilide 2-arylquinoline-4-carboxylates. To this end, the precursors, 2-arylquinoline-4-carboxylic acids, prepared from isatin through the Pfitzinger reaction, and 2-chloroacetanilides were used in an alkylation reaction to obtain the final products (5e-t) in yields of 40-88%. Next, 2-acetanilide 2-arylquinoline-4-carboxylates (5e-t) had their in silico/vitro activity evaluated against Leishmania infantum promastigotes. From the MolPredictX program, all compounds were predicted to be active, and only four halogenated compounds (5k, 5n, 5o, 5r) were active by in vitro assays, with the best result for the compound 5n (R/R’ = Br/Cl), IC50 = 17.08 ± 1.09 μM. From the pkCSM program, these compounds were predicted as non-mutagenic, hepatotoxic, and highly cytotoxic on Flathead Minnows. On the other hand, compounds showed moderate ecotoxicity on Artemia salina, with IC50 = 256-297 μg.mL-1. Finally, in contrast of Amphotericin B which caused relevant erythrocyte lysis starting from 50 μM, none of the compounds showed hemolytic activity. Furthermore, compounds were more selective against L. infantum promastigotes than against human erythrocytes, with a selectivity index (HC50/IC50) > 15.63, which demonstrates a promising therapeutic window for 2-acetanilide 2-arylquinoline-4-carboxylates.

Background: Visceral leishmaniasis (VL) is a neglected tropical disease with limited therapeutic options, often restricted by toxicity, high costs, and resistance. Chalcones are promising scaffolds for the development of antiparasitic agents. Objectives: This study aimed to synthesize novel acetamides derived from 4-hydroxychalcones and evaluate their antileishmanial activity, cytotoxicity, potential synergy with amphotericin B (AmB), and mechanisms of action through in silico analyses. Methods: Six chalcone–acetamides (3a–c, 4a–c) were synthesized and characterized by IR, NMR, and HRMS. In vitro activity against Leishmania infantum promastigotes and axenic amastigotes was assessed by colorimetric assays. Cytotoxicity was tested in human erythrocytes and PBMCs. Synergy with AmB was analyzed by the combination index. Molecular docking targeted parasite enzymes, and ADMET tools predicted pharmacokinetic and safety profiles. Results: Phenyl-substituted derivatives (3a–c) were inactive, while cyclohexyl-substituted analogs (4a–c) were active. Compound 4b displayed the strongest effect (IC₅₀: 7.02 μM for promastigotes, 3.4 μM for amastigotes), with low cytotoxicity and high Selectivity Indices. In combination with AmB, compound 4b reduced the effective dose (DRI: 2.87) and increased the therapeutic window. Docking revealed favorable interactions of compound 4b with deubiquitinase DUB16 and tryparedoxin peroxidase I, suggesting enzyme inhibition. ADMET predictions supported good absorption and low toxicity. Conclusions: Compound 4b demonstrated potent and selective antileishmanial activity, synergism with AmB, and predicted safety. These findings highlight chalcone derivative 4b as a promising lead for future preclinical development in VL therapy.

Violacein, a bluish-purple pigment formed from the condensation of two tryptophan molecules, acts as a secondary metabolite important for the fitness of its producers in a given ecosystem. These microorganisms are distributed in various environments, including oceans, glaciers, rivers, and soil. Violacein is bioactive and important for the ecological relationships between organisms that coexist with producers. Therefore, the pharmacological potential of the compound can be prospected and the literature provides many examples of how violacein can be used in therapy. This chapter deals with these applications, as well as their obtaining and extraction. The text was prepared by students of the Graduate Program in Natural, Synthetic and Bioactive Products at UFPB, as a final project of the course. DOI:https://doi.org/10.56238/sevened2024.003-037 A violaceína, um pigmento roxo-azulado formado a partir da condensação de duas moléculas de triptofano e atua como um metabólito secundário importante para o fitness de seus produtores num dado ecossistema. Estes microrganismos estão distribuídos em vários ambientes, incluindo oceanos, glaciares, rios e solo. A violaceína é bioativa e importante para as relações ecológicas entre os organismos que coexistem com os produtores. Visto isso, o potencial farmacológico do composto pode ser prospectado e a literatura traz muitos exemplos de como a violaceína pode ser utilizada na terapêutica. Este capítulo trata dessas aplicações, bem como de sua obtenção e extração. O texto foi elaborado por discentes do Programa de Pós-Graduação em Produtos Naturais, Sintéticos e Bioativos da UFPB, como projeto final de disciplina. DOI:https://doi.org/10.56238/sevened2024.003-037

Leishmaniasis is a group of neglected infectious, non-contagious diseases caused by parasites of the Leishmania genus which affects millions of people worldwide. The drugs available for its treatment, especially in cases of visceral leishmaniasis, are old, outdated, have serious side effects and in many cases are ineffective due to the emergence of resistant strains. In this context, the search for new candidates for more effective and safer drugs which can become new therapeutic alternatives is a constant need. In this work, 10 new chalcones were synthesized in high yields through Claisen-Schmidt condensation and were evaluated in vitro against Leishmania infantum promastigotes and amastigotes. CP04 and CP06 compounds were the most promising, respectively showing IC50 values = 13.64 ± 0.25 and 11.19 ± 0.22 against promastigotes, and IC50 = 18.92 ± 0.05 and 22.42 ± 0.05 against amastigotes. The compounds did not show cytotoxicity in erythrocytes, showing selectivity indexes greater than 74 and 90. Molecular docking studies carried out under the sterol 14-alpha demethylase (CYP-51) (PDB: 3L4D) and trypanothione reductase (PDB: 5EBK) enzymes from L. infantum evidenced the great affinity of the CP04 molecule for these targets, showing Moldock score values of -94.0758 and -50.5692 KJ/mol-1, with these values being much lower than the co-crystallized ligand energies. Molecular dynamics simulations demonstrated great stability of CP04 in its targets, thus indicating a real interaction possibility. Our findings confirm the potential that chalcones have as candidates for anti-leishmania drugs, and suggest that the CP04 compound may become a promising drug candidate to design and develop novel chalcone-based analogs for leishmaniosis therapy.

Mycobacterium tuberculosis complex causes tuberculosis (TB), a disease that causes pulmonary inflammation but can also affect other tissues. Despite macrophages having a defined role in TB immunopathogenesis, other innate immune cells, such as neutrophils, are involved in this process. These cells have high phagocytic ability and a microbial-killing machine comprised of enzymes, antimicrobial peptides, and reactive oxygen species. In the last two decades, a new neutrophil immune response, the neutrophil extracellular traps (NETs), has been intensely researched. NETs comprise DNA associated with histones, enzymes, and antimicrobial peptides. These structures are related to antimicrobial immune response and some immuno-pathogenesis mechanisms. This mini review highlights the role of NETs in tuberculosis and how they can be helpful as a diagnostic tool and/or therapeutic target.

Leishmaniasis is a complex infectious parasitic disease caused by protozoa of the genus Leishmania, belonging to a group of neglected tropical diseases. It establishes significant global health challenges, particularly in socio-economically disadvantaged regions. Macrophages, as innate immune cells, play a crucial role in initiating the inflammatory response against the pathogens responsible for this disease. Macrophage polarization, the process of differentiating macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, is essential for the immune response in leishmaniasis. The M1 phenotype is associated with resistance to Leishmania infection, while the M2 phenotype is predominant in susceptible environments. Notably, various immune cells, including T cells, play a significant role in modulating macrophage polarization by releasing cytokines that influence macrophage maturation and function. Furthermore, other immune cells can also impact macrophage polarization in a T-cell-independent manner. Therefore, this review comprehensively examines macrophage polarization’s role in leishmaniasis and other immune cells’ potential involvement in this intricate process.

O objetivo deste trabalho foi identificar algumas classes de compostos do metabolismo secundário de Zingiber officinale R., através de testes qualitativos dos extratos brutos de gengibre. Na preparação dos extratos etanólico e aquoso de gengibre, os rizomas da planta foram cortados em pequenos cubos e imergidos em água destilada aquecida (37 °C) ou etanol por três dias, no escuro, para extração. Os extratos então foram filtrados e rotaevaporados para concentração dos compostos de interesse. Os extratos brutos foram avaliados quanto às características fitoquímicas. No final do processo extrativo, obteve-se cerca de 2,84% e 3,23% de rendimento dos extratos brutos etanólico e aquoso, respectivamente. Na caracterização, foi observado a presença de saponinas, polifenóis/taninos, terpenos, esteroides, flavonoides, glicosídeos cardiotônicos e alcaloides no grupo etanólico, e, em contrapartida, apenas terpenos e esteroides na amostra aquosa. Baseado no exposto, os compostos observados nos extratos brutos de gengibre, em sua maioria, podem ser utilizados como alternativa vegetal às substâncias sintéticas em segmentos diversos da indústria alimentícia.

A algarobeira (Prosopis juliflora) é uma planta xerófila muito encontrada na região Nordeste do Brasil devido a sua facilidade em florescer em regiões áridas e produzir uma vagem de polpa doce muito apreciada na região e com alto potencial biotecnológico. Diversos trabalhos já demonstraram esse potencial, principalmente na produção de pães, aguardente, vinagre, bioetanol, dentre outros. Com isso, este trabalho objetivou caracterizar qualitativamente os compostos metabólitos secundários presentes no extrato aquoso da vagem da algarobeira. O extrato de algaroba foi preparado e 20 mL deste extrato aquoso foi rotaevaporado a vácuo, pesado e submetido às análises fitoquímicas, para verificar a presença de alcaloides, esteroides, flavonoides, glicosídeos, polifenóis, taninos, saponinas e terpenos. O peso final do extrato foi de 11,22 g. No extrato aquoso de algaroba não foi possível detectar a presença de alcaloides, esteróis, flavonoides, glicosídeos, polifenóis e taninos, apenas saponinas e terpenos. Estes achados podem estar relacionados à sensibilidade da técnica empregada. Outro possível fator é a obtenção do extrato, que comumente utiliza o álcool, que tem maior efeito extrativo comparado à água. Apesar dos achados serem satisfatórios, considerando a água como extrator, novas análises com metodologias mais sensíveis são necessárias para demonstrar o potencial dessa planta e sua utilização no setor industrial.