Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(9), P. 1828 - 1881

Published: April 22, 2024

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), hydrazine monohydrate (NH2NH2•H2O) for regioselective preparation some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis characterization mentioned cinnolines (3a–h), in silico multi-targeting inhibitory properties these heterocyclic scaffolds investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, hDHODH, which confirmed their functions roles neurodegenerative (NDs), based on molecular docking studies, obtained results were compared with wide range approved drugs well-known (with IC50, EC50, etc.) compounds. addition, ADMET prediction analysis was performed examine prospective drug synthesized compounds The from studies ADMET-related data demonstrated that series heteroaryl)-5,6-dihydrobenzo[h]cinnolines especially hit ones, can really be turned into potent core new treatment and/or due having reactionable locations, they able further organic reactions (such as cross-coupling reactions), expansion (for example, using other types monohydrates) makes avenue designing novel efficient purpose.

Language: Английский

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Design and synthesis of 2-amino-4,6-diarylpyrimidine derivatives as potent α-glucosidase and α-amylase inhibitors: structure–activity relationship, in vitro , QSAR, molecular docking, MD simulations and drug-likeness studies

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: 42(1), P. 244 - 260

Published: April 25, 2023

In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their

Language: Английский

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

Journal of Biochemical and Molecular Toxicology, Journal Year: 2023, Volume and Issue: 38(1)

Published: Sept. 14, 2023

Abstract N ‐substitued anthranilic acid derivatives are commonly found in the structure of many biologically active molecules. In this study, new members hydrazones derived from (1−15) were synthesized and investigated their effect on some metabolic enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α‐glycosidase (α‐Gly). Results indicated that all molecules exhibited potent inhibitory effects against targets compared to standard inhibitors, revealed by IC 50 values. K i values compounds for AChE, BChE, α‐Gly obtained ranges 66.36 ± 8.30–153.82 13.41, 52.68 6.38–113.86, 2.13 0.25–2.84 nM, respectively. The molecular docking study was performed most determination ligand–enzyme interactions. Binding affinities compound at range –9.70 –9.00 kcal/mol –11.60 –10.60 −10.30 −9.30 α‐Gly. Molecular simulations showed novel had preferential interaction with Drug‐likeness properties ADMET (absorption, distribution, metabolism, excretion, toxicity) analyzes estimated toxic evaluated well therapeutic properties. Moreover, dynamics carried out understand accuracy studies.

Language: Английский

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Investigation of Pivalic Acid-Derived Organotin(IV) Carboxylates: Synthesis, Structural Insights, Interaction with Biomolecules, and Computational Studies

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: unknown, P. 140444 - 140444

Published: Oct. 1, 2024

Language: Английский

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Design, Synthesis, and Pharmacological Evaluation of Embelin–Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood–Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer’s Disease: Discovery of SB-1448

ACS Chemical Neuroscience, Journal Year: 2023, Volume and Issue: 14(6), P. 1193 - 1219

Published: Feb. 22, 2023

The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways combat its outrageous prevalence. Embelin is major secondary metabolite Embelia ribes Burm f., one the oldest herbs in Indian traditional medicine. It micromolar inhibitor cholinesterases (ChEs) β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, excretion (ADME) properties. Herein, we synthesize series embelin-aryl/alkyl amine hybrids improve physicochemical properties therapeutic potency against targeted enzymes. most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), butyrylcholinesterase (hBChE), BACE-1 (hBACE-1) IC50 values 0.15, 1.6, 0.6 μM, respectively. both ChEs noncompetitively ki 0.21 1.3 orally bioavailable, crosses blood-brain barrier (BBB), Aβ self-aggregation, possesses good ADME properties, protects neuronal cells from scopolamine-induced cell death. oral administration at 30 mg/kg attenuates cognitive impairments C57BL/6J mice.

Language: Английский

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Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 252, P. 115301 - 115301

Published: March 22, 2023

Language: Английский

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Hydrazone–Sulfonate Hybrids as Potential Cholinesterase Inhibitors: Design, Synthesis and Molecular Modeling Simulation

Future Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 15(24), P. 2269 - 2287

Published: Nov. 23, 2023

Design and synthesis of a series hydrazone-sulfonate hybrids,

Language: Английский

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Design of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insights

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(15), P. 2853 - 2869

Published: July 22, 2024

Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, it closely associated with the dysregulation cholinergic neurotransmission. Since acetylcholinesterase (AChE) critical enzyme in nervous system, responsible for breaking down neurotransmitter acetylcholine, its inhibition holds significant interest treatment various neurological disorders. Therefore, crucial to develop efficient AChE inhibitors capable increasing acetylcholine levels, ultimately leading improved The results reported here represent step forward development novel thiazoloindazole-based compounds that have potential serve as effective inhibitors. Molecular docking studies revealed certain evaluated nitroindazole-based outperformed donepezil, well-known inhibitor used treatment. Sustained these findings, two series were synthesized. One included triazole moiety (Tl45a–c), while other incorporated carbazole (Tl58a–c). These isolated yields ranging from 66 87% through nucleophilic substitution Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among synthesized compounds, 6b core derivatives emerged selective inhibitors, exhibiting remarkable IC50 values less than 1.0 μM. Notably, derivative Tl45b displays superior performance an inhibitor, boasting lowest (0.071 ± 0.014 μM). Structure–activity relationship (SAR) analysis indicated containing bis(trifluoromethyl)phenyl-triazolyl group demonstrated most promising activity against AChE, when compared more rigid substituents such carbazolyl moiety. combination molecular experimental synthesis provides suitable strategy new

Language: Английский

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Development of Activity Rules and Chemical Fragment Design for In Silico Discovery of AChE and BACE1 Dual Inhibitors against Alzheimer’s Disease

Molecules, Journal Year: 2023, Volume and Issue: 28(8), P. 3588 - 3588

Published: April 20, 2023

Multi-target drug development has become an attractive strategy in the discovery of drugs to treat Alzheimer's disease (AzD). In this study, for first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied rational design novel dual-target acetylcholinesterase (AChE) and β-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds AChE BACE1 measurements were curated ChEMBL database. The best global accuracies training/external validation 0.85/0.80 0.83/0.81, respectively. rules then screen dual inhibitors original databases. Based on obtained each tree, set potential identified, active fragments extracted using Murcko-type decomposition analysis. More than 250 designed silico based predicted inhibitory activity consensus QSAR models docking validations. ML study may be useful screening new against AzD.

Language: Английский

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Piperazine-2-carboxylic acid derivatives as MTDLs anti-Alzheimer agents: Anticholinesterase activity, mechanistic aspect, and molecular modeling studies

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 142, P. 106916 - 106916

Published: Oct. 21, 2023

Language: Английский

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