RESUMO

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.

Assuntos

RESUMO

The herbicide glyphosate [N- (phosphonomethyl) glycine; PMG] and the insecticide chlorpyrifos [O, O-diethyl O- (3,5,6-trichloro-2-pyridinyl) -phosphorothioate, CPF] are widely used in agricultural practices around the world and can reach aquatic environments. Therefore, it is necessary to characterize the toxicity of these pesticides on non-target species. The use of biomarkers as a tool to assess responses of organisms exposed to pollutants requires the understanding of their natural fluctuation and the dose-response relationship. In the present work, the effect of the exposure to PMG and CPF on the acetylcholinesterase activity (AChE, biomarker of neurotoxicity) in Cnesterodon decemmaculatus, a native teleost, was evaluated in different environmental conditions. Semi-static bioassays of acute toxicity were carried out under controlled conditions during the four weather seasons of the year using animals of homogeneous size. Circannual rhythms in the basal levels of AChE activity in homogenates of the anterior section were confirmed. Statistically significant average inhibition of AChE activity (47.1 ±â€¯0.7% for 1 µg CPF × L-1; 69.7 ±â€¯2.5% for 5 µg CPF × L-1; 23.1 ±â€¯1.1% for 1 mg PMG × L-1 and 32.9 ±â€¯3.3% for 10 mg PMG × L-1) was determined during summer, winter and spring weather seasons. Interestingly, animals exhibit an increased susceptibility to exposure during the autumn season (inhibition of 55.4 ±â€¯0.6% for 1 µg CPF × L-1; 81.9 ±â€¯3.3% for 5 µg CPF × L-1; 41.4 ±â€¯1.7% for 1 mg PMG × L-1 and 61.1 ±â€¯0.3% for 10 mg PMG × L-1). A different sensitivity of the enzyme between seasons was evaluated by in vitro tests. The inhibition pattern for chlorpyrifos-oxon (CPF-oxon, the active metabolite of CPF) was not affected when test was performed using homogenates of unexposed specimens of summer or autumn. Otherwise, PMG in vitro inhibitory effect was not observed in a wide range of concentrations. The results confirm that AChE activity is a sensitive biomarker for exposure to CPF and PMG, even at environmentally relevant concentrations. Finally, this work highlights the existence of seasonal variations in the dose-response relationship, which could be due to variations in the metabolism of the pollutants.

Assuntos

RESUMO

We synthesized a series of compounds bearing pharmacologically important 1,3,4-oxadiazole and piperidine moieties. Spectral data analysis by 1H-NMR, 13C-NMR, IR and EI-MS was used to elucidate the structures of the synthesized molecules. Docking studies explained the different types of interaction of the compounds with amino acids, while bovine serum albumin (BSA) binding interactions showed their pharmacological effectiveness. Antibacterial screening of these compounds demonstrated moderate to strong activity against Salmonella typhi and Bacillus subtilis but only weak to moderate activity against the other three bacterial strains tested. Seven compounds were the most active members as acetyl cholinesterase inhibitors. All the compounds presented displayed strong inhibitory activity against urease. Compounds 7l, 7m, 7n, 7o, 7p, 7r, 7u, 7v, 7x and 7v were highly active, with respective IC50 values of 2.14±0.003, 0.63±0.001, 2.17±0.006, 1.13±0.003, 1.21±0.005, 6.28±0.003, 2.39±0.005, 2.15±0.002, 2.26±0.003 and 2.14±0.002 µM, compared to thiourea, used as the reference standard (IC50 = 21.25±0.15 µM). These new urease inhibitors could replace existing drugs after their evaluation in comprehensive in vivo studies.

Assuntos

RESUMO

Alzheimer disease (AD) is characterized by a low level of acetylcholine, beta-amyloid (Aβ) aggregation and oxidative stress. Donepezil is the core medicine used for the treatment of AD. Various structural modifications of donepezil have been carried out. Benzylpiperidine part of donepezil has been replaced with benzylpyridine, pyridyl methylpiperidine, benzylpiperazine, pyrimidyl piperazine. These derived molecules showed promising activities as anti-Alzheimer agents. Replacement of indanone part by other heterocyclic rings such as pyridine resulted in the formation of compounds which exhibited monoamine oxidase (MAO) as well as acetylcholinesterase (AChE) inhibition. Propargylamine containing derivatives displayed AChE as well as MAO inhibition properties. Attachment of donepezil with natural compounds like ferulic acid, flavonoids, and curcumin showed antioxidant activities in addition to inhibition of the AChE. Benzylpiperidine and benzylpiperazine have also been combined with condensed heterocyclic rings and these compounds displayed promising anti-Alzheimer properties. This review highlights the important structural modifications of donepezil and their influence on biological activities as anti-Alzheimer agents.

RESUMO

Two new species of flatworm, collected from a beach at eastern Shenzhen, China, were studied through an integrative approach by combining morphological, histological, histochemical (acetylcholinesterase, AChE), and molecular (18S r- DNA) data. These species belong to two genera of marine triclads, previously unrecorded from China, viz. Nerpa Marcus, 1948 and Paucumara Sluys, 1989.        Nerpa fistulata Wang Chen, sp. nov. is characterized by: transparent body; principally pentamerous intestine with three distinct commissures; two very large, prepharyngeal testis follicles; a semi-circular lens in each eye cup; a penis papilla provided with a chitinized, pointed stylet; lateral bursae communicating with the oviduct and opening ventrally to the exterior via a duct. Phylogenetically N. fistulata groups with one member of the family Bdellouridae. This new, Chinese species of Nerpa introduces a major geographic disjunction, as the type species N. evelinae was described from the bay of Santos, Brazil, so that the genus is now known from both Atlantic as well as Pacific coasts.        The species Paucumara falcata Wang Li, sp. nov. is characterized by: three distinct pale yellow transverse pigmentation bands on its dorsal side, between which some snowflake-like specks are randomly distributed, and a brown transverse band anteriorly to the eyes; 8-11 testicular follicles on either side of the body, the follicles extending from immediately behind the ovaries to half-way along the pharyngeal pocket; a musculo-parenchymatic organ with a sclerotic, curved tip projecting from the anterior wall of the male atrium, ventrally to the root of the penis papilla. Phylogenetically P. falcata groups with its congener P. trigonocephala, with the genus Paucumara forming the sister taxon of the genus Ectoplana. Comparison of the nerve structure of P. falcata, as revealed by AChE histochemistry, with that of eight other species of triclad suggested that the nervous system of marine planarians is simpler than that of species of freshwater planarians, but revealed also that the nerve structure is rather variable among species.        The copulatory position exhibited by two partners in Paucumara falcata is remarkable in that they intertwine, with their heads pointing downwards and the tails pointing upwards, the entire process lasting about 10 min. Such a copulatory position has never before been reported for triclad flatworms.

Assuntos

RESUMO

Organophosphorus-induced delayed neuropathy (OPIDN) is a central and peripheral distal axonopathy characterized by ataxia and paralysis. Trichlorfon and acephate are two organophosphorus compounds (OPs) used worldwide as insecticide and which cause serious effects to non-target species. Despite that, the neuropathic potential of these OPs remains unclear. The present study addressed the neurotoxic effects and the neuropathic potential of trichlorfon and acephate in SH-SY5Y human neuroblastoma cells, by evaluating inhibition and aging of neuropathy target esterase (NTE), inhibition of acetylcholinesterase (AChE), neurite outgrowth, cytotoxicity and intracellular calcium. Additionally, the effects observed were compared to those of two well-studied OPs: mipafox (known as neuropathic) and paraoxon (known as non-neuropathic). Trichlorfon and mipafox presented the lowest percentage of reactivation of inhibited NTE and the lowest ratio IC50 NTE/IC50 AChE. Moreover, they caused inhibition and aging of at least 70% of the activity of NTE at sub-lethal concentrations. All these effects have been associated with induction of OPIDN. When assayed at these concentrations, trichlorfon and mipafox reduced neurite outgrowth and increased intracellular calcium, events implicated in the development of OPIDN. Acephate caused effects similar to those caused by paraoxon (non-neuropathic OP) and was only able to inhibit 70% of NTE activity at lethal concentrations. These findings suggest that trichlorfon is potentially neuropathic, whereas acephate is not.

Assuntos

RESUMO

Alzheimer's disease (AD) is a fast growing neurodegenerative disorder of the central nervous system and anti-oxidants can be used to help suppress the oxidative stress caused by the free radicals that are responsible for AD. A series of selected synthetic indole derivatives were biologically evaluated to identify potent new antioxidants. Most of the evaluated compounds showed significant to modest antioxidant properties (IC50 value 399.07 140.0±50 µM). Density Functional Theory (DFT) studies were carried out on the compounds and their corresponding free radicals. Differences in the energy of the parent compounds and their corresponding free radicals provided a good justification for the trend found in their IC50 values. In silico, docking of compounds into the proteins acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), which are well known for contributing in AD disease, was also performed to predict anti-AD potential.

A doença de Alzheimer (DA) é uma doença neurodegenerativado sistema nervoso central, em rápido crescimento, e antioxidantes ajudam a suprimir o estresse oxidativo causado por radicais livres, responsávies pela DA. Avaliou-se, biologicamente, série de derivados sintéticos de indol selecionados para identificar novos antioxidantes. A maioria dos compostos avaliados apresentou de significativa a boa propriedade antioxidante (valor de IC50 399,07140.0 ± 50 µM). Eftuaram-se estudos de Teoria do Funcional de Densidade (DFT) com os compostos e os seus correspondentes radicais livres. As diferenças de energia entre os compostos protótipos e os radicais livres correspondentes proporcionaram boa justificativa para a tendência encontrada nos seus valores de IC50. O ancoramento in silico dos compostos com a acetilcolinesterase (AChE) e com a butirilcolinesterase (BChE), que contribuem para a DA, foi, também, realizado para prever o seu potencial anti-DA.

Assuntos

RESUMO

Several studies have shown the mechanisms and importance of immune responses against Toxoplasma gondii infection and the notable role of cholinesterases in inflammatory reactions. However, the association between those factors has not yet been investigated. Therefore, the aim of this study was to evaluate the acetylcholinesterase (AChE) activity in blood and lymphocytes and the activity of butyrylcholinesterase (BChE) in serum of rats experimentally infected with T. gondii during the acute phase of infection. For that, an in vivo study was performed with evaluations of AChE and BChE activities on days 5 and 10 post-infection (PI). The activity of AChE in blood was increased on day 5 PI, while in lymphocytes its activity was enhanced on days 5 and 10 PI (P<0.05). No significant difference was observed between groups regarding to the activity of BChE in serum. A positive (P<0.01) correlation was observed between AChE activity and number of lymphocytes. The role of AChE as an inflammatory marker is well known in different pathologies; thus, our results lead to the hypothesis that AChE has an important role in modulation of early immune responses against T. gondii infection.

Assuntos