The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological illness that causes dementia mainly in the elderly. The challenging obstacles related to AD has freaked global healthcare system to encourage scientists in developing novel therapeutic startegies to overcome with the fatal disease. The current treatment therapy of AD provides only symptomatic relief and to some extent disease-modifying effects. The current approach for AD treatment involves designing of cholinergic inhibitors, Aß disaggregation inducing agents, tau inhibitors and several antioxidants. Hence, extensive research on AD therapy urgently requires a deep understanding of its pathophysiology and exploration of various chemical scaffolds to design and develop a potential drug candidate for the treatment. Various issues linked between disease and therapy need to be considered such as BBB penetration capability, clinical failure and multifaceted pathophisiology requires a proper attention to develop a lead candidate. This review article covers all probable mechanisms including one of the recent areas for investigation i.e., lipid dyshomeostasis, pathogenic involvement of P. gingivalis and neurovascular dysfunction, recently reported molecules and drugs under clinical investigations and approved by FDA for AD treatment. Our summarized information on AD will attract the researchers to understand and explore current status and structural modifications of the recently reported heterocyclic derivatives in drug development for AD therapy.

Sars-cov-2 host entry and replication inhibitors from Indian ginseng: an in-silico approach.

COVID-19 has ravaged the world and is the greatest of pandemics in modern human history, in the absence of treatment or vaccine, the mortality and morbidity rates are very high. The present investigation identifies potential leads from the plant Withania somnifera (Indian ginseng), a well-known antiviral, immunomodulatory, anti-inflammatory and a potent antioxidant plant, using molecular docking and dynamics studies. Two different protein targets of SARS-CoV-2 namely NSP15 endoribonuclease and receptor binding domain of prefusion spike protein from SARS-CoV-2 were targeted. Molecular docking studies suggested Withanoside X and Quercetin glucoside from W. somnifera have favorable interactions at the binding site of selected proteins, that is, 6W01 and 6M0J. The top-ranked phytochemicals from docking studies, subjected to 100 ns molecular dynamics (MD) suggested Withanoside X with the highest binding free energy (ΔGbind = -89.42 kcal/mol) as the most promising inhibitor. During MD studies, the molecule optimizes its conformation for better fitting with the receptor active site justifying the high binding affinity. Based on proven therapeutic, that is, immunomodulatory, antioxidant and anti-inflammatory roles and plausible potential against n-CoV-2 proteins, Indian ginseng could be one of the alternatives as an antiviral agent in the treatment of COVID 19. Communicated by Ramaswamy H. Sarma.

Design, synthesis and pharmacological evaluation of N3 aryl/ heteroaryl substituted 2-((benzyloxy and phenylthio) methyl) 6,7- dimethoxyquinazolin-4(3H)-ones as potential anticonvulsant agents.

Novel N3 aryl/heteroaryl substituted 2-((benzyloxy and phenylthio) methyl) 6,7-dimethoxyquinazolin-4(3H)- ones (8a-8l) were synthesized and evaluated for their anticonvulsant activity using various models of epilepsy, such as maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and intracerebroventricular AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in mice. The rotarod test has been used to determine the acute neurotoxicity. Further, the serum enzymatic activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assessed along with histopathological examination of liver. Among all the derivatives, compound 8f displayed significant activity profile based on the overall magnitude of activity and minimum neurotoxicity.