Biological assays of BF2-naphthyridine compounds: Tyrosinase and acetylcholinesterase activity, CT-DNA and HSA binding property evaluations.

The present work reports the biological assays between synthetic BF2-naphtyridine complexes and four proteins: human serum albumin (HSA), calf-thymus DNA (CT-DNA), tyrosinase and acetylcholinesterase enzymes via spectroscopic analysis at physiological conditions, combined with molecular docking simulations. The BF2-complexes presented spontaneous and moderate binding ability to HSA through the ground-state association (static fluorescence quenching mechanism). The main binding site is Sudlow's site I (subdomain IIA) and the binding does not perturb significantly both secondary and surface structure of HSA. Despite BF2-complexes showed good binding ability with HSA, these compounds presented weak intercalative ability with CT-DNA (the most conventional and simple model to preliminary studies), except in the case of 1 h, which suggested that the presence of electronic donor groups in both aromatic ring moieties of BF2-complex structure can increase the intercalative ability for DNA strands. Competitive binding displacement assays in the presence of methyl green and molecular docking calculations indicated that the studied compounds interact preferentially in the major groove of DNA. In addition, the assayed compounds presented the ability to activate or inhibit both tyrosinase (the decontrolled activity can induce melanoma carcinoma) or AChE (involved in reactions related to the function of neurotransmitters) enzymes.

In vitro tyrosinase, acetylcholinesterase, and HSA evaluation of dioxidovanadium (V) complexes: An experimental and theoretical approach.

The present study reports the biological evaluation of vanadium(V) complexes (1-3) against three different proteins: tyrosinase, acetylcholinesterase (AChE), and human serum albumin (HSA), which were studied by spectroscopic techniques and molecular docking. Despite the synthesis and characterization of complexes 1 and 2 having already previously described, complex 3 is a novel dioxidovanadium(V) derivative. Complex 1 can activate both tyrosinase and AChE enzymes in about 11.5 and 47.0%, respectively. On the other hand, complexes 2 and 3 inhibited the same enzymes (1.30 and 46.0% for tyrosinase and 20.0 and 21.9% for AChE, respectively). Molecular docking calculations suggested that the presence of the hydroxyl group in complex 1 is essential to activate tyrosinase enzymes. According to theoretical analysis, hydrogen bonding, van der Waals, and hydrophobic forces are the main binding interactions for each V(V) complex and AChE. Moreover, the interaction between HSA and vanadium(V) complexes occurs via ground-state association, being only enthalpically driven for complexes 1 and 2 and entropically and enthalpically driven for complex 3. The interaction is spontaneous for all samples and the binding modes do not perturb significantly the secondary and surface structures of the albumin. As there are few reported cases in the literature that explore vanadium complexes against these three proteins, the present results may contribute to future studies by offering different scaffolds to design new vanadium(V) complexes in the hyperpigmentation process and Alzheimer's disease.

Synthesis of new lophine-carbohydrate hybrids as cholinesterase inhibitors: cytotoxicity evaluation and molecular modeling.

In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate N-alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound 9a (a d-galactose derivative) being the most potent inhibitor (IC50 = 0.17 µM). According to the molecular modeling results, all the compounds indicated that the lophine moiety existed at the bottom of the BuChE cavity and formed a T-stacking interaction with Trp231, a residue accessible exclusively in the BuChE cavity. Noteworthily, only one compound exhibited activity against AChE (8b; IC50 = 2.75 µM). Moreover, the in silico ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, in vitro studies demonstrated that the two most potent compounds against BuChE (8b and 9a) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.

Design, synthesis, cholinesterase inhibition and molecular modelling study of novel tacrine hybrids with carbohydrate derivatives.

A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as d-xylose, d-ribose, and d-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the d-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50 = 2.2 nM for AChE and 4.93 nM for BuChE) was the most active compound for both enzymes. The d-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (d-ribose derivative) and 6b (d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.

Antimicrobial activity of Stomoxys calcitrans against Beauveria bassiana sensu lato isolates.

This study had the aims of evaluating the antimicrobial characteristics of Stomoxys calcitrans (Diptera: Muscidae) larvae against the fungal isolates CG138, CG228 and ESALQ986 of Beauveria bassiana sensu lato (Balsamo-Crivelli) Vuillemin, 1912 (Hypocreales: Cordycipitaceae). S. calcitrans eggs, larvae and pupae were exposed to these same isolates. Statistical analysis showed that the immature stages of S. calcitrans were not susceptible to the fungal isolates used, regardless of the exposure method. Diffusion test on solid culture medium reveled that macerated S. calcitrans larvae exposed to isolate CG138 reduced CG138 fungal development. The analysis of the chromatographic profiles indicated that the macerate or mucus of larvae of the control group and the groups exposed to the isolate CG138 presented different profiles. Reduced development of the isolate CG138 on the larvae cuticle was observed by means of scanning electron microscopy.

Antimicrobial activity of Stomoxys calcitransagainst Beauveria bassiana sensu lato isolates / Atividade antimicrobiana de Stomoxys calcitranscontra isolados de Beauveria bassiana sensu lato

This study had the aims of evaluating the antimicrobial characteristics of Stomoxys calcitrans (Diptera: Muscidae) larvae against the fungal isolates CG138, CG228 and ESALQ986 of Beauveria bassiana sensu lato (Balsamo-Crivelli) Vuillemin, 1912 (Hypocreales: Cordycipitaceae). S. calcitrans eggs, larvae and pupae were exposed to these same isolates. Statistical analysis showed that the immature stages of S. calcitrans were not susceptible to the fungal isolates used, regardless of the exposure method. Diffusion test on solid culture medium reveled that macerated S. calcitrans larvae exposed to isolate CG138 reduced CG138 fungal development. The analysis of the chromatographic profiles indicated that the macerate or mucus of larvae of the control group and the groups exposed to the isolate CG138 presented different profiles. Reduced development of the isolate CG138 on the larvae cuticle was observed by means of scanning electron microscopy.

Este estudo teve como objetivos avaliar as características antimicrobianas de larvas de Stomoxys calcitrans (Diptera: Muscidae) contra os isolados CG138, CG228 e ESALQ986 de Beauveria bassiana sensu lato (Balsamo-Crivelli) Vuillemin, 1912 (Hypocreales: Cordycipitaceae). Ovos, larvas e pupas de S. calcitrans foram expostos a estes mesmos isolados. Após análise estatística, foi verificado que os estágios imaturos de S. calcitrans não foram susceptíveis aos isolados utilizados, independentemente do método de exposição utilizado. O teste de difusão em meio sólido mostrou que quando o isolado CG138 foi exposto a macerado de larvas houve redução do desenvolvimento fúngico. A análise dos perfis cromatográficos mostrou que o macerado ou muco de larvas do grupo controle e dos grupos expostos ao isolado CG138 apresentaram diferenças nos perfis. Um desenvolvimento reduzido do isolado CG138 na cutícula de larvas foi observado pela microscopia eletrônica de varredura.

Nível de tiamina no miocárdio, área transversa e número de núcleos de cardiomiócitos de ratos em uso de furosemida / Myocardial thiamine level, cardiomyocyte cross-sectional area and nuclei number in furosemide-treated rats

Objetivo: Avaliar os níveis miocárdicos de tiamina e área transversa e número de núcleos de cardiomiócitos de ratos em uso de furosemida. Métodos: 24 ratos foram estratificados em 4 grupos: 2 grupos receberam furosemida por via intraperitoneal e 2 receberam solução salina, por 21 dias. Dois destes grupos receberam ração-padrão, e 2 ração pobre em tiamina. Os níveis miocárdicos de tiamina foram avaliados por: dosagem de tiamina pirofosfato (TPP) por HPLC, e medidas de atividade da transcetolase miocárdica(ATm) e do efeito da tiamina pirofosfato (ETPP). Métodos estereológicos foram utilizados para a obtenção da área transversa (Acmy) e número de núcleos (Ncmy) dos cardiomiócitos. Resultados: as médias e desvios-padrão de TPP, ATm, ETPP, Acmy e Ncmy foram, respectivamente: Grupo 1 - 133,7 maior ou menor que 17,9ng/100 microlitro de tecido homogeneizado; 173 maior ou menor que 20 micrograma.hexose/ml/h; 3,6 maior ou menor que 1,9 por cento; 808 maior ou menor que 8 milhões; Grupo 2 - 160,2 maior ou menor que 23,2ng/100 microlitro de tecido homogeneizado; 1634 maior ou menor que 137 micrograma.hexose/ml/h; 2,2 maior ou menor que 1,4 por cento; 961 maior ou menor que 59 micrometro2; 63 maior ou menor que 2 milhões; Grupo 3 - 73,5 maior ou menor que 8,6ng/100 microlitro de tecido homogeneizado; 715 maior ou menor que 123 micrograma.hexose/ml/h; 39,8 maior ou menor que 9,8 milhões por cento; 963 maior ou menor que 2 micrometro2; 59 maior ou menor que 4 milhões Grupo 4 - 82,1 maior ou menor que 9ng/100 microlitro de tecido homogeneizado; 863 maior ou menor que 75 micrograma.hexose/ml/h; 26,2 maior ou menor que 11,9 por cento; 1061 maior ou menor que 33 micrometro2; 63 maior ou menor que 5 milhões. Conclusão: A furosemida não reduziu o nível de tiamina no miocárdio, nem alterou a área transversa e o número de núcleos de cardiomiócitos nos animais estudados.