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Item Unveiling the potential of novel indol-3-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors: a combined in silico, synthesis and in vitro study(RSC, 2024-07) Jadhav, Hemant R.Alzheimer's disease (AD) is a complex and debilitating neurological disorder that primarily affects the brain, leading to cognitive decline and memory loss. AD is a chronic and progressive disease that gradually impairs an individual's ability to function independently, affecting their daily activities and quality of life.1 Worldwide, as of 2023, the current estimate of 50 million people worldwide with dementia is expected to increase to 78 million by 2030 and a staggering 139 million by 2050.2 The disease is characterized by several neuro-pathological features such as reduced levels of acetylcholine (ACh), accumulation of amyloid-β, formation of neurofibrillary tangles made of hyperphosphorylated tau-protein, oxidative stress, and imbalanced biometal levels.3 The current approach to treating neurological disorders involves the use of medication that aims to enhance cognitive functions or alleviate symptoms by targeting the mechanisms of neurotransmitters in the brain using cholinesterase inhibitors (such as donepezil, galantamine, and rivastigmine see Fig. 1) and N-methyl-D-aspartate (NMDA) receptor antagonist i.e. memantine.4,5 Patients with declining cognitive functions who are prescribed cholinesterase inhibitors or similar medications have not shown any significant improvement in preventing the advancement of AD.6 Despite ongoing efforts to develop drugs that modify the course of AD and slow its progression, there are still potential obstacles that may impede success, such as unanticipated toxicity or inadequate effectiveness in human clinical trials.7 The complexity of AD and its multifaceted nature have rendered the existing single-targeted drugs ineffective in producing the desired therapeutic effect. It is widely believed that compounds with the ability to modulate multiple targets are more effective than those that only act on a single target, due to the inadequate results of the one drug one target (ODOT) strategy. Therefore, there is a need for the development of multi-targeted therapies to slow down the progression of the diseaseItem Design, synthesis, in silico, and in vitro evaluation of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors(RSC, 2024-08) Jadhav, Hemant R.Alzheimer's disease (AD) manifests as a progressive decline in cognitive function and mental behavior. Targeting two crucial enzymes associated with AD, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), in combination, holds promise for therapeutic breakthroughs. In this study, 40 derivatives of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide were designed based on prior research. These derivatives underwent synthesis and assessment for their inhibitory potential against AChE and BACE 1. ADME predictions indicated favorable physicochemical properties for these compounds. The findings offer novel avenues for exploring the dual inhibition of AChE and BACE 1 as a promising therapeutic strategy for AD.Item Structure-based virtual screening and biological characterization of novel bace-1 and amyloid-β aggregation inhibitors(Wiley, 2024-12) Jadhav, Hemant R.Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening. The top 45 compounds, based on docking scores and binding affinities, were tested for BACE-1 inhibitory activity using a FRET assay. Four compounds, 18 (5353320), 20 (5262831), 29 (5784196) and 32 (5794006) demonstrated more than 35 % inhibitory activity at 10 μM. Notably, pyrazole-5-carbohydrazide 29 (5784196) exhibited BACE-1 inhibition with an IC50 value of 14.5 μM and a ki value of 0.25 μM. Additionally, it also inhibits the self-aggregation of β-amyloid, with IC50 value of 14.87 μM. Molecular modeling and dynamics simulations provided insights into its interaction pattern and stability of the enzyme-inhibitor complex. These findings suggest that virtual screening is an efficient and cost-effective method for identifying potential leads for ADItem Recent advancements in the therapeutic approaches for Alzheimer's disease treatment: current and future perspective(RSC, 2024-12) Jadhav, Hemant R.Alzheimer's disease (AD) is a complex, incurable neurological condition characterized by cognitive decline, cholinergic neuron reduction, and neuronal loss. Its exact pathology remains uncertain, but multiple treatment hypotheses have emerged. The current treatments, single or combined, alleviate only symptoms and struggle to manage AD due to its multifaceted pathology. The developmental drugs target pivotal disease factors involved in the envisaged hypotheses and include targets such as amyloid aggregation, hyperphosphorylated tau proteins, and receptors like cholinergic, adrenergic, etc. Present-day research focuses on multi-target directed ligands (MTDLs), which inhibit multiple factors simultaneously, helping slow the disease's progression. This review attempts to collate the recent information related to proposed hypotheses for AD etiology. It systematically organizes the advances in various therapeutic options for AD, with a particular emphasis on clinical candidates. Also, it is expected to help medicinal chemists design novel AD treatments based on available information, which could be helpful to AD patients.