Hybridization of the effective pharmacophores for treatment of epilepsy: design, synthesis, in vivo anticonvulsant activity, and in silico studies of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids.

BACKGROUND: Epilepsy is a common neurological disorder. The available drugs for this disease only control convulsions in nearly 70% of patients, while bearing many side effects. In this study, a new series of phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid hybrids 8a-m was designed, synthesized, and evaluated as potent anticonvulsant agents. METHODS: Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid derivatives 8a-m were synthesized with well-known chemical reactions and anticonvulsant activity of them was determined by pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Phenoxyphenyl-1,3,4-oxadiazole-thio-N-phenylacetamid scaffold has the necessary pharmacophores to be a benzodiazepine (BZD) receptor agonist, thus, the most potent anticonvulsant compounds were assayed in vivo and in silico as BZD receptor agonist. Furthermore, in vivo neurotoxicity evaluation and in silico physicochemical, pharmacokinetic, and toxicity study on the most potent compounds were also performed. RESULTS: Obtained results demonstrated that two compounds among the title new compounds have anticonvulsant activity in PTZ test while all of the new compounds are active in the MES test. The best anticonvulsant activities were obtained with nitro derivatives 8k and 8L. In vivo evaluation of flumazenil effect (a BZD receptor antagonist) on anticonvulsant activity of compound 8k confirmed that this compound is a BZD receptor agonist. The most potent compounds 8k and 8L interacted with the important residues of BZD-binding site of GABAA receptor. Furthermore, neurotoxicity of the latter compounds was lower than positive control diazepam. CONCLUSION: According to these results, our designed scaffold can be a valuable lead structure for further structural developments and assessments to obtain a new potent anticonvulsant agent.

Nitroenediamines (EDAMs), and N-methyl-1-(methylthio)-2-nitroethenamine (NMSM) derivatives: scaffolds for heterocycle molecular diversity (update from 2012 to 2021).

Nitro-1,1-enediamines (EDAMs) and 1,1-bis(methylthio)-2-nitroethene (NMSN) have proven to be a class of attractive and useful synthetic building blocks for use in the synthesis of heterocyclic and fused heterocyclic compounds. The bicyclic or tricyclic heterocycles derived from these frames widely exist in natural and synthetic drugs. To comprehend the reaction properties of EDAMs and NMSN and to design other novel fused heterocycles with biological effects in the future, it is essential to investigate their recent reactions. The current review envisions highlighting some recent and remarkable examples of nitroenediamine reactions categorized by catalyst-assisted and catalyst-free reactions from 2012 onward.

Recent Developments in Arylation of N-Nucleophiles via Chan-Lam Reaction: Updates from 2012 Onwards.

''Chan-Evans-Lam'' (CEL) reaction is the copper-mediated cross-coupling of N-nucleophiles with boronic acids that was independently reported in 1998 by Chan, Evans, and Lam for the first time. This reaction is accomplished at room temperature with a remarkably wide range of nucleophiles. In the recent decade, it has been particularly attractive as a convenient method for constructing the various C- N bonds in organic synthesis. Therefore, a comprehensive survey through all reported process was crucial. In this review, we summarized research progress about N-Arylation, based on the type of N-nucleophile involved in this reaction and catalysts from 2012 onwards.

Recent Opportunities and Challenges in Selective C-H Functionalization of Methyl Azaarenes: A Highlight from 2010 to 2020 Studies.

Azaarenes are unique scaffolds that are frequently found in pharmaceuticals. Herein we have summarized the recent synthetic available methods in C-H functionalization of methylazaarenes from 2010 to 2020. Multiple approaches involving halogenation, alkylation via different methods, alkenylation, oxidative functionalization, and cyclization of the methylazaarenes will be discussed in this review.

The recent development of donepezil structure-based hybrids as potential multifunctional anti-Alzheimer's agents: highlights from 2010 to 2020.

Dementia is a term used to define different brain disorders that affect memory, thinking, behavior, and emotion. Alzheimer's disease (AD) is the second cause of dementia that is generated by the death of cholinergic neurons (especially acetylcholine (ACh)), which have a vital role in cognition. Acetylcholinesterase inhibitors (AChEI) affect acetylcholine levels in the brain and are broadly used to treat Alzheimer's. Donepezil, rivastigmine, and galantamine, which are FDA-approved drugs for AD, are cholinesterase inhibitors. In addition, scientists are attempting to develop hybrid molecules and multi-target-directed ligands (MTDLs) that can simultaneously modulate multiple biological targets. This review highlights recent examples of MTDLs and fragment-based strategy in the rational design of new potential AD medications from 2010 onwards.

Recent strategies in the synthesis of thiophene derivatives: highlights from the 2012-2020 literature.

Thiophene-based analogs have been fascinated by a growing number of scientists as a potential class of biologically active compounds. Furthermore, they play a vital role for medicinal chemists to improve advanced compounds with a variety of biological effects. The current review envisioned to highlight some recent and particularly remarkable examples of the synthesis of thiophene derivatives by heterocyclization of various substrates from 2012 on.

Synthesis and biological evaluation of a new series of benzofuran-1,3,4-oxadiazole containing 1,2,3-triazole-acetamides as potential α-glucosidase inhibitors.

A series of new benzofuran-1,3,4-oxadiazole containing 1,2,3-triazole-acetamides 12a-n as potential anti-α-glucosidase agents were designed and synthesized. α-Glucosidase inhibition assay demonstrated that all the synthesized compounds 12a-n (half-maximal inhibitory concentration [IC50 ] values in the range of 40.7 ± 0.3-173.6 ± 1.9 µM) were more potent than standard inhibitor acarbose (IC50 = 750.0 ± 12.5 µM). Among them, the most potent compound was compound 12c, with inhibitory activity around 19-fold higher than acarbose. Since the most potent compound inhibited α-glucosidase in a competitive mode, a docking study of this compound was also performed into the active site of α-glucosidase. In vitro and in silico toxicity assays of the title compounds were also performed.

Synthesis and cholinesterase inhibitory activity of new 2-benzofuran carboxamide-benzylpyridinum salts.

A series of benzofuran-2-carboxamide-N-benzyl pyridinium halide derivatives (6a-o) are synthesized as new cholinesterase inhibitors. The synthetic pathway involves the reaction of salicylaldehyde derivatives and ethyl bromoacetate, followed by hydrolysis and amidation with 3- and 4-picolyl amine. Subsequently, N-((pyridin-4-yl) methyl) benzofuran-2-carboxamide and substituted N-((pyridin-3-yl) methyl) benzofuran-2-carboxamides reacts with benzyl halides to afford target compounds (6a-o). The chemical structures of all derivatives were confirmed by spectroscopic methods. The studies reveal that some of the synthesized compounds are potent butyrylcholinesterase inhibitors with IC50 values in the range of 0.054-2.7 µM. In addition, good inhibitory effects on Aß self-aggregation are observed for 6h and 6k (33.1 and 46.4% at 100 µM, respectively).