Two new dilactonized glycerol glycosides of the dual anticholinesterase active extract from Ocotea daphnifolia using bioguided fractionation and molecular docking studies.

The dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) is considered as an important strategy for the treatment of Alzheimer's disease. In this study, we applied the bioguided fractionations of Ocotea daphinifolia ethyl acetate active extract to furnish a fraction with high inhibitory activity for AChE and BuChE (82% and 92%, respectively). High-performance liquid chromatography semipreparative purification of this fraction provided two new natural products: 1-ß-D-galactopyranosyl-glycerol-2,3-heptanedionate, (1) whose complete chemical structural elucidation was made with spectrometric analysis (MS, 1D, and 2D NMR) and its minor derivative 1-ß-D-gulopyranosyl-glycerol-2,3-heptanedionate; (2) which could be characterized by 2D 1 H-13 C heteronuclear single-quantum correlation spectra analysis. Investigation of the intermolecular interactions with cholinesterases was carried out by molecular docking studies, and results suggested that both compounds are capable to interact with the catalytic site of both enzymes. Compounds 1 and 2 interact with residues of catalytic domains and the peripheral anionic binding site of AChE and BuChE. The results are comparable to those achieved with rivastigmine and galantamine. Thus, this study provides evidence for consideration of the glycosylglycerol from O. daphnifolia as new valuable dual cholinesterases inhibitor.

Molecular targets for the development of new acaricides against Rhipicephalus microplus: a review.

The cattle tick Rhipicephalus microplus is an ectoparasite with high economic importance to bovine culture, mainly in tropical and subtropical regions. The resistance of the tick from the commercial acaricides has hindered its control, thus motivating the search for new strategies. The purpose of this study was to perform a critical review about the main molecular targets of R. microplus that are useful for the discovery of new acaricides. Bibliographic search was conducted in the databases PubMed, ScienceDirect and CAB Direct, using the following descriptors: 'Rhipicephalus microplus', 'Boophilus microplus', 'molecular targets' and 'action', published between 2010 and 2021. Out of the 212 publications identified, 17 articles were selected for study inclusion. This review described 14 molecular targets and among these 4 are targets from commercial acaricides. Most of them are enzymes to catalyse important reactions to tick survival, related to energetic metabolism, mechanisms of biotransformation and neurotransmission. The data will be helpful in the development of new more effective and selective acaricides.

Homology modeling, docking, molecular dynamics and in vitro studies to identify Rhipicephalus microplus acetylcholinesterase inhibitors.

Rhipicephalus microplus is an important ectoparasite of cattle, causing considerable economical losses. Resistance to chemical acaricides has stimulated the search for new antiparasitic drugs, including natural products as an eco-friendly alternative of control. Flavonoids represent a class of natural compounds with many biological activities, such as enzyme inhibitors. Acetylcholinesterase is an essential enzyme for tick survival that stands out as an important target for the development of acaricides. This work aimed to predict this 3D structure by homology modeling and use the model to identify compound with inhibitory activity. The model of R. microplus AChE1 (RmAChE1) was constructed using MODELLER program. The optimization and molecular dynamic investigation were performed in GROMACS program. The model developed was used, by molecular docking, to evaluate the anticholinesterase activity of flavonoids (quercetin, rutin, diosmin, naringin and hesperidin) and an acaricide synthetic (eserine). Additionally, in vitro inhibition of AChE and larval immersion tests were performed. The model of RmAChE1 showed to be sterically and energetically acceptable. In molecular dynamics simulations, the 3D structure remains stable with Root Mean Square Deviation = 3.58 Å and Root Mean Square Fluctuation = 1.43 Å. In molecular docking analyses, only eserine and quercetin show affinity energy to the RmAChE (Gridscore: -52.17 and -39.44 kcal/mol, respectively). Among the flavonoids, quercetin exhibited the best in vitro inhibition of AChE activity (15.8%) and mortality of larvae tick (30.2%). The use of in silico and in vitro techniques has shown that quercetin showed promising anti-tick activity and structural requirements to interact with RmAChE1. Communicated by Ramaswamy H. Sarma.