A series of new heterocycle hybrids incorporating pyrazole
and
isoxazoline rings was successfully synthesized, characterized, and
evaluated for their antimicrobial responses. The synthesized compounds
were obtained utilizing N-alkylation and 1,3-dipolar
cycloaddition reactions, as well as their structures were established
through spectroscopic methods and confirmed by mass spectrometry.
To get more light on the regioselective synthesis of new hybrid compounds,
mechanistic studies were performed using DFT calculations with B3LYP/6-31G(d,p)
basis set. Additionally, the results of the preliminary screening
indicate that some of the examined hybrids showed potent antimicrobial
activity, compared to standard drugs. The results confirm that the
antimicrobial activity is strongly dependent on the nature of the
substituents linked pyrazole and isoxazoline rings. Furthermore, molecular
docking studies were conducted to highlight the interaction modes
between the investigated hybrid compounds and the Escherichia
coli and Candida albicans receptors.
Notably, the results demonstrate that the investigated compounds have
strong protein binding affinities. The stability of the formed complexes
by the binding between the hybrid compound 6c, and the
target proteins was also confirmed using a 100 ns molecular dynamics
simulation. Finally, the prediction of ADMET properties suggests that
almost all hybrid compounds possess good pharmacokinetic profiles
and no signs of observed toxicity, except for compounds 6e, 6f, and 6g.
Currently, anti‐butyrylcholinesterase (anti‐BuChE)is among the greatest therapeutic agents for the treatment of Alzheimer's disease. In this research, a series of 36 carbamate derivatives were subjected to a quantitative structure–activity relationships study using DFT and Lipinski's descriptors. Multiple linear regression (MLR) was used to explore the relationships between the structural features of these compounds and BuChE inhibitory activity. In order to generate results applicable in the experimental plan, the Organization of Economic Cooperation and Development guidelines were adopted. The quality of MLR model was evaluated by several statistical parameters including internal and external validation parameters (R2, R2adj, F, VIF, R2test, Q2CV, R2Rand, Q2CV [Rand], and cRp2). The built model displayed a high predictive power (R2test = 0.817). What is more, the internal validation parameters (Q2CV = 0.774; average R2Rand = 0.118; average Q2CV [Rand] = −0.438; cRp2 = 0.820) highlight the robustness of our built model. Besides, the obtained result revealed that anti‐BuChE activity is mainly attributed to the following molecular descriptors: octanol–water partition (log P), highest occupied molecular orbital energy (EHOMO), total energy (ET), and dipole moment (μ). Based on these findings, a series of newer synthesizable compounds with enhanced anti‐BuChE activities were designed and their ADMET and drug‐likeness properties were further predicted to filter out compounds likely to fail during drug development stages. Finally, molecular docking and molecular dynamics were performed to identify the binding types between the best designed compounds and BuChE enzyme.
Cholinesterase enzymes are promising drug targets for the symptomatic treatment of Alzheimer's disease. Indeed, the activity inhibition of these acetylcholine-degrading enzymes leads to improved neurocognitive function. The present work, attempted to identify eugenol derivatives possibly capable of inhibiting the acetylcholine enzymes, by implementing density functional theory (DFT), docking and molecular dynamics methods. The investigated compounds exhibited moderate to high affinity toward the target proteins with free binding energy values ranging from À6.3 to À11.5 kcal/mol. The best ligands in terms of binding energy were evaluated for their pharmacokinetic properties. Furthermore, molecular dynamics studies were performed to assess the stability under aqueous environment of ligands having shown good pharmacokinetic properties. The obtained results revealed that 4-alkyl-2-methoxyphenyl 3-bromobenzoate strongly tended to act as dual inhibitor of Acetylcholinesterase and Butyrylcholinesterase, leading to a good alternative for the treatment of AD. The highlighting of this study can be of great support for the Alzheimer treatment development.
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