PRODUTOS NATURAIS COMO PROMISSORES INIBIDORES DA ACETILCOLINESTERASE:: UM ESTUDO IN SILICO

Um grupo de seis produtos naturais, usados como ponto de partida no estudo de novos derivados estruturais, foram analisados frente a inibição da enzima acetilcolinesterase (AChE) in silico e previsão sobre o modelo de Absorção, Distribuição, Metabolismo, Eliminação e Toxicidade (ADMET). Usando ferramentas de modelagem molecular para verificar as interações de 6-gingerol, 6-shagaol, curcumina, piperina, β-lapachona e lapachol, em comparação com a galantamina padrão com a enzima AChE. Os resultados mostraram que os compostos 6-gingerol e 6-shogaol apresentam as melhores interações in silico e as melhores propriedades ADMET com potencial terapêutico sobre o Sistema Nervoso Central (SNC)comparados ao padrão galatamina (GNT), além de fazerem interações químicas in silico adicionais interessantes com o sitío ativo da enzima. Este trabalho traz resultados preliminares que são base para novos estudos com variações estruturais nos compostos com melhores interações in silico

Design, synthesis and antiproliferative evaluation of new acridine-thiosemicarbazone derivatives as topoisomerase IIα inhibitors

Thiosemicarbazone-acridine hybrids are prominent inhibitors of topoisomerases II. This study reports the design, synthesis, and antiproliferative evaluation of eighteen new acridine–thiosemicarbazone derivatives as possible inhibitors of topoisomerase IIα. In general, compounds showed moderate to low cytotoxicity in the first screening performed on three cell lines, with emphasis on the DT-3OCH3 series, in which five of the six compounds have been active. Further studies against resistant leukemic cells indicated an interesting profile for derivatives DT-3OCH3-H (IC50 = 8.83 µM) and DT-3OCH3-3OH (IC50 = 10.69 µM) in the resistant cell Lucena-1, with relative resistance (RR) index of 0.11 and 0.10, respectively. A cytotoxicity assay on Vero cells showed low toxicity for most of the antileukemic compounds, with only DT-3OCH3-3OH derivative indicating a highlighted reduction in cell viability at a concentration of 61.25 µM. Five compounds were selected for topoisomerase IIα inhibition and all presented enzyme inhibition activity. Also, Topo IIα-DNA docking and molecular dynamics studies indicated that better scores were obtained for compounds interacting with residues Arg487 and Asp463, presenting electron donor groups on the acridine nucleus, as well as the presence of the hydroxyl substituents in the benzylidene. Finally, two selected compounds had their in vitro gastrointestinal absorption profile evaluated in Caco-2 cells, indicating good membrane permeation, with an apparent permeability coefficient greater than 10 × 10-6 cm/s for both

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

The present study proposed the synthesis of a novel acridine derivative not yet described in the literature, chemical characterization by NMR, MS, and IR, followed by investigations of its antileishmanial potential. In vitro assays were performed to assess its antileishmanial activity against L. amazonensis strains and cytotoxicity against macrophages through MTT assay and annexin V-FITC/PI, and the ability to perform an immunomodulatory action using CBA. To investigate possible molecular targets, its interaction with DNA in vitro and in silico targets were evaluated. As results, the compound showed good antileishmanial activity, with IC50 of 6.57 (amastigotes) and 94.97 (promastigotes) µg mL−1, associated with non-cytotoxicity to macrophages (CC50 > 256.00 µg mL−1). When assessed by flow cytometry, 99.8% of macrophages remained viable. The compound induced an antileishmanial effect in infected macrophages and altered TNF-α, IL-10 and IL-6 expression, suggesting a slight immunomodulatory activity. DNA assay showed an interaction with the minor grooves due to the hyperchromic effect of 47.53% and Kb 1.17 × 106 M−1, and was sustained by docking studies. Molecular dynamics simulations and MM-PBSA calculations propose cysteine protease B as a possible target. Therefore, this study demonstrates that the new compound is a promising molecule and contributes as a model for future works