Promising Inhibitors of Endocannabinoid Degrading Enzymes Sharing a Carbamate Scaffold.

Carbamate has been extensively used as a scaffold in the recent era of drug discovery and is a common structural motif of many approved drugs. The carbamate moiety's unique amide-ester hybrid (-O-CO-NH-) feature offers the designing of specific drug-target interactions. Despite the discovery of numerous carbamate derivatives that act on the endocannabinoid system (ECS), the development of clinically effective carbamates remains a challenge.

Design, synthesis and evaluation of benzothiazole-derived phenyl thioacetamides as dual inhibitors of monoamine oxidases and cholinesterases.

A series of rationally designed benzothiazole-derived thioacetamides was synthesized and investigated for monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) inhibition properties. The tested compounds 18-31 inhibited MAO-A and MAO-B in the micromolar to nanomolar range and AChE in the submicromolar range. Compound 28 was identified as the most potent MAO-A inhibitor with an IC = 0.

Identification of new small molecule allosteric SHP2 inhibitor through pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation studies, synthesis and evaluation.

Src homology-2 (SH2) domain-containing phosphatase-2 (SHP2) is the first identified protooncogene and is a promising target for developing small molecule inhibitors as cancer chemotherapeutic agents. Pharmacophore-based virtual screening (PBVS) is a pharmacoinformatics methodology that employs physicochemical knowhow of the chemical space into the dynamic environs of computational technology to extract virtual molecular hits that are precise and promising for a drug target. In the current study, PBVS has been applied on Enamine Advanced Collection of 551,907 molecules by using a pharmacophore model developed upon by Molecular Operating Environment (MOE) software to identify potential small molecule allosteric SHP2 inhibitors.

Development and validation of machine learning models for the prediction of SH-2 containing protein tyrosine phosphatase 2 inhibitors.

Discovery and development of a new drug to the market is a highly challenging and resource consuming process. Although, modern drug discovery technologies have enabled the rapid identification of lead compounds, translation of the lead compounds into successful clinical candidates remains a big challenge. In recent years, the availability of massive structural and biological data of diverse small molecules and macromolecules has helped the researchers to deep mine the multidimensional data with the help of artificial intelligence-based predictive tools to draw useful insights on the structural features of biological or therapeutic significance.

Benzimidazole-derived carbohydrazones as dual monoamine oxidases and acetylcholinesterase inhibitors: design, synthesis, and evaluation.

A series of novel benzimidazole-derived carbohydrazones was designed, synthesized and evaluated for their dual inhibition potential against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) using multitarget-directed ligand approach (MTDL). The investigated compounds have exhibited moderate to excellent MAOs/AChE inhibitory activity at micromolar to nanomolar concentrations. Compound , 2-(1-Benzo[d]imidazol-1-yl)--[1-(4-hydroxyphenyl) ethylidene]acetohydrazide has emerged as a lead dual MAO-AChE inhibitor by exhibiting superior multi-target activity profile against MAO-A (IC = 0.

Anti-nociceptive potential of an isatin-derived dual fatty acid amide hydrolase-monoacylglycerol lipase inhibitor.

Background: Recently, we have reported an isatin-derived carbohydrazone, 5-chloro-N'-(6-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (SIH 3) as dual nanomolar FAAH (fatty acid amide hydrolase)-MAGL (monoacylglycerol lipase) inhibitor with good CNS penetration and neuroprotective activity profile. In this study, we further investigated the pharmacological profile of compound SIH 3 in the neuropathic pain model along with acute toxicity and ex vivo studies.

Methods: Chronic constrictive injury (CCI) was used to induce neuropathic pain in male Sprague-Dawley rats and the anti-nociceptive activity of the compound SIH 3 was investigated at 25, 50, and 100 mg/kg ip.

Lead optimization study on indoline-2,3-dione derivatives as potential fatty acid amide hydrolase inhibitors.

Based on the known isatin-based fatty acid amide hydrolase (FAAH) inhibitor , we designed and synthesized two small sets ( and ) of N-1 and C-3 substituted isatin derivatives and evaluated them for their FAAH inhibition properties. The lead simplification by modification of bulky aryl moiety at N-1 with a flexible allyl group produced a nanomolar (IC = 6.7 nM, = 5 nM) inhibitor (Z)-3-((1H-benzo[d]imidazol-2-yl)imino)-1-allylindolin-2-one which exhibited a reversible and competitive FAAH inhibition with 1500 times more potency to (1.

Exploration of a library of piperonylic acid-derived hydrazones possessing variable aryl functionalities as potent dual cholinesterase and monoamine oxidase inhibitors.

A library of piperonylic acid-derived hydrazones possessing variable aryl moiety was synthesized and investigated for their multifunctional properties against cholinesterases (ChEs) and monoamine oxidases (MAOs). The in vitro enzymatic assay results revealed that the tested hydrazones have exhibited excellent cholinesterase inhibition profile. Compound 4i, (E)-N'-(2,3-dichlorobenzylidene)benzo[d][1,3]dioxole-5-carbohydrazide showed promising dual inhibitory profile against AChE (0.

Tracing the Anti-cancer Mechanism of Pleurotus osteratus by the Integrative Approach of Network Pharmacology and Experimental Studies.

The present study identified the probable mechanism behind the anti-cancer activity of the hexane fraction of Pleurotus osteratus (HFPO) using network pharmacology and experimental validation. HFPO myco-metabolites targets and targets related to the cancer were mined from the online web server, and overlapping targets were screened. Out of the 74 overlapping targets, 33 targets were identified in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of cancer.

Identification of new small molecule monoamine oxidase-B inhibitors through pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation studies.

The discovery of a safe and efficacious drug is a complex, time-consuming, and expensive process. Computational methodologies driven by cheminformatics tools play a central role in the high-throughput lead discovery and optimization process especially when the structure of the biological target is known. Monoamine oxidases are the membrane-bound FAD-containing enzymes and the isoform monoamine oxidase-B (MAO-B) is an attractive target for treating diseases like Alzheimer's disease, Parkinson's disease, glioma, etc.

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.

Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors.

Role of Lysine-specific Demethylase 1 and Its Small Molecule Inhibitors in Glioblastoma Multiforme Therapy.

Glioblastoma multiforme (GBM) is among the most critical and aggressive carcinomas of CNS, characterised by poor prognosis, low survival rate and difficult clinical correlations. Current treatment opportunities have proved to be insufficient due to high chemoresistance and relapse of the disease with enhanced malignancy. Molecular diagnostics and epigenetic profiling of GBM have discovered several signaling pathways and cellular mediators, which play key roles in triggering GBM phenotypic manifestations via somatic and genetic aberrations and recruitment of GBM stem-like cells (GSCs).

Emerging three-dimensional neuronal culture assays for neurotherapeutics drug discovery.

Introduction: Development of in vitro models mimicking the physiology and pathophysiology of the brain is essential and remains a major challenge for the discovery of neurotherapeutics. Intensive research efforts over the past two decades led to the development of various two-dimensional/three-dimensional (3D) in vitro models of the central nervous system, and these models have been found to be very promising for studying the pathology of several neurological disorders and for the screening of neurotherapeutics.

Areas Covered: This review highlights various in vitro 3D neuronal cell culture (3DNCC) techniques that exhibit tremendous potential in the screening and development of new chemical entities for neurodegenerative disorders.

Discovery of Isatin-Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase.

Using ligand-based design strategy, a set of isatin-3-carbohydrazones was designed, synthesized and evaluated for dual fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition properties. Compound 5-chloro-N'-(5-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 b) emerged as a potent MAGL inhibitor with nanomolar activity (IC =3.33 nM), while compound 5-chloro-N'-(1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 j) was the most potent selective FAAH inhibitor (IC =37 nM).

Anticancer Potential of Small-Molecule Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase.

Recently fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors have been in the limelight due to their anticancer potential. Both FAAH and MAGL are the endocannabinoid degrading enzymes that hydrolyze several endogenous ligands, mainly anandamide (AEA) and 2-arachidonic glycerol (2-AG), which regulate various pathophysiological conditions in the body such as emotion, cognition, energy balance, pain sensation, neuroinflammation, and cancer cell proliferation. FAAH and MAGL inhibitors block the metabolism of AEA and 2-AG, increase endogenous levels of fatty acid amides, and exert various therapeutic effects including chronic pain, metabolic disorders, psychoses, nausea and vomiting, depression, and anxiety disorders.

Small-Molecule Inhibitors of Shp2 Phosphatase as Potential Chemotherapeutic Agents for Glioblastoma: A Minireview.

Glioblastoma multiforme (GBM) is a dreadful cancer characterised by poor prognosis, low survival rate and difficult clinical correlations. Several signalling pathways and molecular mediators are known to precipitate GBM, and small-molecular targets of these mediators have become a favoured thrust area for researchers to develop potent anti-GBM drugs. Shp2, an important phosphatase of the nonreceptor type protein tyrosine phosphatase (PTPN) subfamily is responsible for master regulation of several such signalling pathways in normal and glioma cells.

Emerging chemical scaffolds with potential SHP2 phosphatase inhibitory capabilities - A comprehensive review.

The drug discovery panorama is cluttered with promising therapeutic targets that have been deserted because of inadequate authentication and screening failures. Molecular targets formerly tagged as "undruggable" are nowadays being more cautiously cross-examined, and whilst they stay intriguing, numerous targets are emerging more accessible. Protein tyrosine phosphatases (PTPs) excellently exemplifies a class of molecular targets that have transpired as druggable, with several small molecules and antibodies recently turned available for further development.

Exploration of dual fatty acid amide hydrolase and cholinesterase inhibitory potential of some 3-hydroxy-3-phenacyloxindole analogs.

The dual inhibition of fatty acid amide hydrolase (FAAH) and cholinesterases (ChEs) has recently egressed as a novel strategy for the management of neurodegeneration. In the present work, a library of 3-hydroxy-3-phenacyloxindole analogs was screened for FAAH and ChEs (acetylcholinesterase [AChE]/butyrylcholinesterase [BuChE]) inhibition. 1-Benzyl-3-hydroxy-3-(2',4'-dibromophenacyl)oxindole (16), the most promising compound, showed a balanced multifunctional profile with FAAH (IC  = 8.

Monoamine oxidase-B inhibitors as potential neurotherapeutic agents: An overview and update.

Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery.

Scaffold hopping-guided design of some isatin based rigid analogs as fatty acid amide hydrolase inhibitors: Synthesis and evaluation.

Fatty acid amide hydrolase (FAAH) represents a potential therapeutic target for number of peripheral and nervous system related disorders including neuropathic pain and neuroinflammation. A library of N-(2,4-dichlorobenzoyl) isatin Schiff bases 7a-7l and 8a-8c were designed using the contemporary scaffold-hopping approach, synthesized and investigated for their ability to inhibit human FAAH enzyme using fluorescence based Cayman assay kit. The synthesized compounds inhibited FAAH with IC values in the range from 1.

Design, synthesis, and pharmacological evaluation of 2-amino-5-nitrothiazole derived semicarbazones as dual inhibitors of monoamine oxidase and cholinesterase: effect of the size of aryl binding site.

A series of 2-amino-5-nitrothiazole derived semicarbazones were designed, synthesised and investigated for MAO and ChE inhibition properties. Most of the compounds showed preferential inhibition towards MAO-B. Compound 4, (1-(1-(4-Bromophenyl)ethylidene)-4-(5-nitrothiazol-2-yl)semicarbazide) emerged as lead candidate (IC = 0.

Anticonvulsant activity, organotypic hippocampal neuroprotection assay and in-silico sodium channel blocking potential of 2-amino-6-nitrobenzothiazole derived semicarbazones.

Epilepsy is one of the dreadful neurodegenerative disorder characterized by recurrent, unprovoked seizures. Currently available antiepileptic drugs are still associated with enormous side effects resulting in search of newer, more effective and safer agents. In view of this, we have investigated anticonvulsant activity of 2-amino-6-nitrobenzothiazole derived semicarbazones (7-32) in various in-vivo animal seizure models viz.

Design, Synthesis, and Evaluation of 2-Amino-6-nitrobenzothiazole-Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group.

A series of 2-amino-6-nitrobenzothiazole-derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO-A/MAO-B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO-B isoform.

Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation.

A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.

Discovery of 3-Hydroxy-3-phenacyloxindole Analogues of Isatin as Potential Monoamine Oxidase Inhibitors.

A series of 3-hydroxy-3-phenacyloxindole analogues of isatin were designed, synthesized, and evaluated in vitro for their inhibitory activity toward monoamine oxidase (MAO) A and B. Most of the synthesized compounds proved to be potent and selective inhibitors of MAO-A rather than MAO-B. 1-Benzyl-3-hydroxy-3-(4'-hydroxyphenacyl)oxindole (compound 18) showed the highest MAO-A inhibitory activity (IC50 : 0.