Design and Synthesis of Novel Imidazo Pyridine Derivatives and their Bioisosteres in the Management of Alzheimer Disease

Abstract

Abstract newlineAlzheimer s disease (AD) is a neurodegenerative disease of the old age and it has become an important medico-socioeconomic problem worldwide. The approved drugs for AD give only symptomatic relief of the disease but they cannot elicit disease modifying effects. Hence, there is an urgent need to develop agents that have profound effect on the pathology of AD. For that reason, the novel approach of multi-target directed ligands have been emerged to target complex nature of AD. newlineThe present work focuses on the major pathophysiology of the AD viz. Beta site Amyloid Precursor Protein (APP) Cleaving Enzyme (BACE)-1 and inflammation. In this study, imidazo[1,2-a]pyridine derivatives and their bioisosteres were designed. Virtual library of compounds was screened by docking studies. From the docking studies, top ranked 40 molecules targeting BACE-1 and inflammatory pathway enzymes were taken further for synthesis. Three different series namely thiazolyl-imidazo[1,2-a]pyridines, quinoxalines-bisthiazoles and thiazolyl-thiadiazines were synthesized and characterized by spectroscopic data. newlineFurther, these 40 molecules were evaluated using in vitro BACE-1 inhibition assay and in vivo acute inflammation study. Afterwards, most active molecules from these studies were taken further for screening in chronic inflammation rat paw edema model. Overall, most active 3 molecules from these studies were tested for aluminium chloride induced AD model. Based on the findings of these studies, PMCSRS3A, PMCSRS10Q and PMCSRSTD4 showed promising multi-target profile for the AD treatment. Although our compounds showed promising anti-inflammatory activity, they were found to be gastrointestinal safe when compared with the standard non-steroidal anti-inflammatory drugs (NSAIDs). newlineBased on these results, it can be concluded that multi-target drug design proved to be an advantageous approach over single target directed therapy. One of the compounds, PMCSRSTD4 turned out to be the most potent MTDL. The outcome of the present work may lead to