Design, Green Synthesis and in silico Studies of New Substituted Naphtho[1,2-e][1,3]Oxazines as Potential Acetylcholinesterase Inhibitors.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors as the primary pharmacotherapy for numerous neurodegenerative conditions, leveraging their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, oxazines  have brought worthy synthetic interest due to their extensive biological activities including, anti-tubercular, anti-convulsant, and anti-cancer activities. In this study, a series of novel naphtho[1,2-e][1,3]oxazine derivatives has been designed  and synthesized with potential of acetylcholinesterase (AChE) inhibition. The target products have been prepared by a one-pot and three-component condensation reaction of 2-naphthol, aromatic aldehydes, and arylmethanimine in the presence of 3-methyl-1-sulfonic acid imidazolium chloride ([Msim]Cl) as an effective and recyclable catalyst under microwave irradiation solvent-free condition. The molecular docking studies has also been performed to investigate the synthetic compounds in the the AChE active site gorge. The results showed that all these derivatives interact with the enzymes with high affinity in binding pocket. The MM-GBSA studies were performed for all synthesized derivatives and among them, compound 3-(4-Chlorophenyl)-1-phenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine 5f, showed the lowest the binding free energy (-48.04 kcal mol-1). In general, oxazine derivatives could be proposed as the strong AChE inhibitors.

Biological Evaluation of Anti-Cholinesterase Activity, in Silico Molecular Docking Studies, and DFT Calculations of Green Synthesized Thiadiazolo[3,2-a]pyrimidine Derivatives.

A series of [1,3,4] thiadiazolo[3,2-a]pyrimidine-6-carboxylate derivatives 4(a-n) have been designed and synthesized as inhibitors of acetylcholinesterase (AChE). Synthesizing of thiadiazolo[3,2-a] pyrimidines was carried out in a single step, one-pot reaction using aromatic aldehydes, ethyl acetoacetate and different derivatives of 1,3,4-thiadiazoles (with molar ratio of 1 : 2 : 1, respectively) in conjunction with the catalyst, anhydrous iron(III) chloride by a grinding method under solvent-free conditions at room temperature. The in-vitro studies exhibited good potency for inhibiting AChE comparable with donepezil as the reference drug. The best results were obtained by Ethyl 2-(4-nitroophenyl)-7-methyl-5-(pyridin-3-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylate 4n with IC50 value of 0.082±0.001 µM which was comparable with AChE inhibitory effects of donepezil (IC50 =0.079 µM).

Facile green synthesis of CaO NPs using the Crataegus pontica C.Koch extract for photo-degradation of MB dye.

In this research, a novel synthesis of CaO nanoparticles via a green, environmentally, and economical method is developed. Crataegus pontica C.Koch leaves extract was used as a green reducing and stabilizing agent to synthesize the calcium oxide nanoplates ranging from 40 to 65 nm. The synthesized CaO NPs are characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRD), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy. The CaO NPs were evaluated successfully for photocatalytic degradation of methylene blue (MB) dye with 98.99% degradation efficiency under sunlight by a simple technique. The recoverability and reusability of the CaO photocatalyst were considered under the optimized reaction conditions, which are showed high chemical stability after at least five runs.

Green and four-component cyclocondensation synthesis and in silico docking of new polyfunctionalized pyrrole derivatives as the potential anticholinesterase agents.

Synthesis of new substituted pyrrole scaffolds containing substituted thiadiazol-2-amine moiety was successfully developed through one-pot and multi-component tandem condensation reaction utilizing of triethyl ammonium hydrogen sulfate ([Et3NH][HSO4]) ionic liquid as a green media under solvent-free conditions. The chemical structures of all newly synthesized compounds were fully characterized by spectroscopic methods (IR, 1H NMR, 13C NMR) and elemental analyzes. The molecular docking studies were also performed to predict the possible binding sites of the derivatives on the active site gorge of cholinesterase enzymes (AChE and BuChE). The results showed that all the seventeen derivatives interact with the enzymes with high affinity and among them 7d and 7f possess the greatest ability to bind to AChE and BuChE, respectively.

Unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with benzylidene thiazolidinediones: synthesis of pharmacologically active spiroindoline oxazepine derivatives and theoretical study.

An unexpected regio- and stereoselective [4 + 3] cycloaddition reaction of azomethine ylides with 5-benzylidenethiazolidine-2,4-diones has been successfully developed for the synthesis of the novel pharmacologically active 4',5'-dihydro-3'H-spiro[indoline-3,2'-[1, 3] oxazepin]-2-one derivatives in basic condition. Easy purification, high yield, short experimental time and operational simplicity are specific advantages of this protocol. Furthermore, all the synthesized compounds have been evaluated for antioxidant and antibacterial activities. According to the results, most of the synthesized compounds exhibited DPPH radical scavenging activity and nine of them showed antibacterial properties. The reaction mechanism and 1H NMR spectrum have been evaluated by B3LYP/6311G method.

Design, synthesis and biological assessment of acridine derivatives containing 1,3,4-thiadiazole moiety as novel selective acetylcholinesterase inhibitors.

A novel series of acridine derivatives containing substituted thiadiazol-2-amine moiety was synthesized via multi-component condensation reaction of dimedone, aromatic aldehyde and 5-aryl-1,3,4-thiadiazol-2-amines in the presence of LaCl3 as a catalyst under solvent-free conditions. Anticholinesterase (AChE and BuChE) activity evaluation of the derivatives showed that all the derivatives are capable of inhibiting both enzymes and are highly selective towards AChE. Among them, the ability of 4i and 4d with respective IC50 values of 0.002 and 0.006 µM to inhibit AChE was higher than the reference compound tacrine (IC50 = 0.016 µM). The kinetics studies demonstrated that 4i and 4d inhibit AChE through a competitive/non-competitive mixed mechanism. The HEPG2 cell viability assay evidenced that 4i and 4d significantly exhibit lower hepatotoxicity compared with tacrine. Blind docking experiments performed on TcAChE (PDB ID: 2ACE) indicated that an unknown site is preferred for binding by all the derivatives over classic binding site of the enzyme, site 1 (CAS/PAS). Identification of the residues by protein structure alignment confirmed that this site is site 2 which was recently recognized as a new allosteric site of hAChE. The binding modes of 4i and 4d were also investigated using local docking studies on site 1 and site 2.

A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy.

The identification of molecular agents inhibiting specific functions in cancer cells progression is considered as one of the most successful plans in cancer treatment. The epidermal growth factor receptor (EGFR) over-activation is observed in a vast number of cancers, so, targeting EGFR and its downstream signaling cascades are regarded as a rational and valuable approach in cancer therapy. Several synthetic EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in recent years, mostly exhibited clinical efficacy in relevant models and categorized into first, second, third and fourth-generation. However, studies are still ongoing to find more efficient EGFR inhibitors in light of the resistance to the current inhibitors. In this review, the importance of targeting EGFR signaling pathway in cancer therapy and related epigenetic mutations are highlighted. The recent advances on the discovery and development of different EGFR inhibitors and the use of various therapeutic strategies such as multi-targeting agents and combination therapies have also been reviewed.

Facile, efficient and one-pot access to diverse new functionalized aminoalkyl and amidoalkyl naphthol scaffolds via green multicomponent reaction using triethylammonium hydrogen sulfate ([Et3NH][HSO4]) as an acidic ionic liquid under solvent-free conditions.

An efficient, clean and one-pot multicomponent synthesis of divers kind of new functionalized aminoalkyl naphthol and amidoalkyl naphthol derivatives via tandem condensation reaction of 2-naphthol, aromatic aldehydes and 5-methyl-1,3,4-thiadiazol-2-amine/5-aryl-1,3,4-thiadiazol-2-amines urea/acetamide under solvent-free conditions is reported. Following this protocol, it was possible to synthesize novel 1-(((5-methyl-1,3,4-thiadiazol-2-yl)amino)(aryl)methyl)naphthalen-2-ol, 1-(aryl((5-aryl-1,3,4-thiadiazol-2-yl)amino)methyl)naphthalen-2-ol and amidoalkyl naphthol derivatives. This protocol includes some salient features, such as the use of triethylammonium hydrogen sulfate ([Et3NH][HSO4]) ionic liquid as a green, clean and reusable catalyst, no column chromatographic separation, high atom economy, good yields, low cost and finally no need for a complex procedure.

Synthesis and anticholinesterase activity of new substituted benzo[d]oxazole-based derivatives.

A series of novel benzo[d]oxazole derivatives (6a-n) have been synthesized and biologically evaluated as potential inhibitors of acetylcholinesterases (AChE) and butyrylcholinesterase (BChE). The chemical structures of all final compounds were confirmed by spectroscopic methods. In vitro studies showed that most of the synthesized compounds are potent acetylcholinesterase and butyrylcholinesterase inhibitors. Among them, compounds 6a and 6j strongly inhibited AChE and BChE activities with IC50 values of 1.03-1.35 and 6.6-8.1 µm, respectively. Docking studies also provided the binding modes of action and identified hydrophobic pi forces as the main interaction.