Novel hydrazones derived from anthranilic acid as potent cholinesterases and α-glycosidase inhibitors: Synthesis, characterization, and biological effects.

N-substitued anthranilic acid derivatives are commonly found in the structure of many biologically active molecules. In this study, new members of hydrazones derived from anthranilic acid (1-15) were synthesized and investigated their effect on some metabolic enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glycosidase (α-Gly). Results indicated that all the molecules exhibited potent inhibitory effects against all targets as compared to the standard inhibitors, revealed by IC50 values. Ki values of compounds for AChE, BChE, and α-Gly enzymes were obtained in the ranges 66.36 ± 8.30-153.82 ± 13.41, 52.68 ± 6.38-113.86, and 2.13 ± 0.25-2.84 nM, respectively. The molecular docking study was performed for the most active compounds to the determination of ligand-enzyme interactions. Binding affinities of the most active compound were found at the range of -9.70 to -9.00 kcal/mol for AChE, -11.60 to -10.60 kcal/mol for BChE, and -10.30 to -9.30 kcal/mol for α-Gly. Molecular docking simulations showed that the novel compounds had preferential interaction with AChE, BChE, and α-Gly. Drug-likeness properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyzes of all synthesized compounds (1-15) were estimated and their toxic properties were evaluated as well as their therapeutic properties. Moreover, molecular dynamics simulations were carried out to understand the accuracy of the most potent derivatives of docking studies.

Novel Quinazolinone Derivatives: Potential Synthetic Analogs for the Treatment of Glaucoma, Alzheimer's Disease and Diabetes Mellitus.

Quinazolinones, which represent an important part of nitrogen-containing six-membered heterocyclic compounds, are frequently used in drug design due to their wide biological activity properties. Therefore, the novel quinazolinones were synthesized from the reaction of acylated derivatives of 4-hydroxy benzaldehyde with 3-amino-2-alkylquinazolin-4(3H)-ones with good yields (85-94 %) and their structures were characterized using Fourier-transform Infrared (FT-IR), Nuclear Magnetic Resonance (1 H-NMR, 13 C-NMR), and High-Resolution Mass Spectroscopy (HR-MS). As the application of the synthesized compounds, their inhibition properties of the synthesized compounds on α-Glucosidase (α-Glu), Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and Carbonic anhydrase I-II (hCA I-II) metabolic enzymes were investigated. All compounds showed inhibition at nanomolar level with the Ki values in the range of 12.73±1.26-93.42±9.44 nM for AChE, 8.48±0.92-25.84±2.59 nM for BChE, 66.17±5.16-818.06±44.41 for α-Glu, 2.56±0.26-88.23±9.72 nM for hCA I, and 1.68±0.14-85.43±7.41 nM for hCA II. Molecular docking study was performed to understand the interactions of the most potent compounds with corresponding enzymes. Also, absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties of the compounds were investigated.

New 4-phenylpiperazine-carbodithioate-N-phenylacetamide hybrids: Synthesis, in vitro and in silico evaluations against cholinesterase and α-glucosidase enzymes.

A series of novel 4-phenylpiperazine-carbodithioate-N-phenylacetamide hybrids (6a-n) was designed, synthesized, and evaluated for their in vitro inhibitory activity against the metabolic enzymes, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The obtained results showed that most of the synthesized compounds exhibited high to good anti-AChE and anti-BChE activity in the range of nanomolar concentrations in comparison to tacrine as a positive control. Molecular modeling of the most potent compounds 6e and 6i demonstrated that these compounds interacted with important residues of the AChE and BChE active sites. Moreover, all the newly synthesized compounds 6a-n had significant Ki values against α-glucosidase when compared with the positive control acarbose. Representatively, N-2-fluorophenylacetamide derivative 6l, with a Ki value of 0.98 nM as the most potent compound, was 126 times more potent than acarbose with a Ki value of 123.70 nM. This compound also fitted in the α-glucosidase active site and interacted with key residues. An in silico study of the druglikeness/absorption, distribution, metabolism, and excretion (ADME)/toxicity profile of the selected compounds 6e, 6i, and 6l predicts that these compounds are drug-like and have the appropriate properties in terms of ADME and toxicity.

Impact of Iontophoresis and PACK-CXL Corneal Concentrations of Antifungals in an In Vivo Model.

PURPOSE: To investigate voriconazole (VRZ) penetration and fungal load in the cornea after applying VRZ therapy with various treatment combinations in a fungal keratitis model. METHODS: Fifty-four eyes of 27 young albino rabbits were provided for this experimental study. Twelve corneas were inoculated with Candida albicans, 12 corneas were inoculated with Fusarium solani, and 6 eyes were selected as controls. Infected corneas received various treatment combinations including VRZ 1% drop therapy alone, VRZ 1% plus amphotericin B 1% drop combination therapy, iontophoretic VRZ therapy, and VRZ 1% drop therapy after corneal cross-linking. Fungal load was measured by log reduction, and VRZ levels were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Iontophoresis-assisted VRZ application showed the highest antifungal activity against F. solani keratitis (4-log reduction) and C. albicans keratitis (5-log reduction) compared with other treatment applications. VRZ levels were also found to be the highest in corneas that received iontophoretic VRZ treatment (3.6313 ± 0.0990 ppb for F.solani keratitis and 1.7001 ± 0.0065 ppb for C. albicans keratitis) compared with other treatment applications. CONCLUSIONS: Iontophoresis seems to provide the highest VRZ concentration and highest antifungal activity in the cornea compared with other treatment applications for C. albicans and F. solani keratitis.