ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease majorly affecting old age populations. Various factors that affect the progression of the disease include, amyloid plaque formation, neurofibrillary tangles, inflammation, oxidative stress, etc. Herein we report of a new series of substituted (2-aminothiazol-5-yl)(imidazo[1,2-a]pyridin-3-yl)methanones. The designed compounds were synthesized and characterized by spectral data. In vivo anti-inflammatory activity was carried out for screening of anti-inflammatory potential of synthesized compounds. All the compounds were tested for acute inflammatory activity by using carrageenan induced acute inflammation model. Compounds 10b, 10c, and 10o had shown promising acute anti-inflammatory activity and they were further tested for formalin induced chronic inflammation model. Compound 10c showed both acute and chronic anti-inflammatory activity. Compound 10c also showed promising results in AlCl3 induced AD model. Studies on various behavioral parameters suggested improved amnesic performance of compound 10c treated rats. Compound 10c treated rats also exhibited excellent antioxidant and neuroprotective effect with inherent gastrointestinal safety.
Subject(s)
Alzheimer Disease/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Edema/drug therapy , Imidazoles/therapeutic use , Inflammation/drug therapy , Neuroprotective Agents/therapeutic use , Aluminum Chloride , Alzheimer Disease/chemically induced , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Dose-Response Relationship, Drug , Edema/chemically induced , Female , Formaldehyde , Imidazoles/chemical synthesis , Imidazoles/chemistry , Inflammation/chemically induced , Male , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Alzheimer's disease (AD) is the most prevalent disease of old age leading to dementia. Complex AD pathogenesis involves multiple factors viz. amyloid plaque formation, neurofibrillary tangles and inflammation. Herein we report of a new series of quinoxaline-bisthiazoles as multitarget-directed ligands (MTDLs) targeting BACE-1 and inflammation concurrently. Virtual screening of a library of novel quinoxaline-bisthiazoles was performed by docking studies. The most active molecules from the docking library were taken up for synthesis and characterized by spectral data. Compounds 8a-8n showed BACE-1 inhibition in micro molar range. One of the compounds, 8n showed BACE-1 inhibition at IC50 of 3⯱â¯0.07⯵M. Rat paw edema inhibition in acute and chronic models of inflammation were obtained at 69⯱â¯0.45% and 55⯱â¯0.7%, respectively. Compound 8n also showed noteworthy results in AlCl3 induced AD model. The treated rats exhibited excellent antiamnesic, antiamyloid, antioxidant, and neuroprotective properties. Behavioural parameters suggested improved cognitive functions which further validates the testimony of present study. Moreover, compound 8n was found to have inherent gastrointestinal safety. This new string of quinoxaline-bisthiazoles were identified as effective lead for the generation of potent MTDLs and compound 8n was found to showcase qualities to tackle AD pathogenesis.
Subject(s)
Anti-Inflammatory Agents/chemistry , Ligands , Quinoxalines/chemistry , Thiazoles/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/metabolism , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Antioxidants/chemistry , Antioxidants/pharmacology , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Brain/drug effects , Brain/metabolism , Brain/pathology , Catalytic Domain , Drug Design , Edema/chemically induced , Edema/drug therapy , Edema/pathology , Humans , Maze Learning/drug effects , Molecular Docking Simulation , Neuroprotective Agents/chemistry , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
Alzheimer's disease (AD) is associated with multiple neuropathological events including ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibition and neuronal inflammation, ensuing degeneracy, and death to neuronal cells. Targeting such a complex disease via a single target directed treatment was found to be inefficacious. Hence, with an intention to incorporate multiple therapeutic effects within a single molecule, multitarget-directed ligands (MTDLs) have been evolved. Herein, for the first time, we report the discovery of novel thiazolyl-thiadiazines that can serve as MTDLs as evident from the in vitro and in vivo studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the in vivo studies demonstrated efficient anti-inflammatory activity with inherent gastrointestinal safety. Moreover, compound 6d unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment.
