Quinazolinone-Hydrazine Cyanoacetamide Hybrids as Potent Multitarget-Directed Druggable Therapeutics against Alzheimer's Disease: Design, Synthesis, and Biochemical, In Silico, and Mechanistic Analyses.

The discovery of effective multitarget-directed ligands (MTDLs) against multifactorial Alzheimer's disease (AD) remnants has been focused in an incessant drug discovery pursuit. In this perception, the current study explores the rational design, synthesis, and evaluation of 26 quinazolinone-hydrazine cyanoacetamide hybrids , , and as MTDLs against AD. These new compounds were synthesized in four-step processes using simple phthalimide as the starting material without any major workup procedures and were characterized by different spectroscopic techniques.

Unveiling the molecular basis of lobeline's allosteric regulation of NMDAR: insights from molecular modeling.

Neurological and psychiatric disorders contribute significantly to the global disease burden, adversely affecting the quality of life for both patients and their families. Impaired glutamatergic signaling is considered to be a major cause for most of the neurological and psychiatric disorders. Glutamate receptors are over activated in excitotoxic conditions, leading to dysregulation of Ca homeostasis, triggering the production of free radicals and oxidative stress, mitochondrial dysfunction and eventually cell death.

Lobeline: A multifunctional alkaloid modulates cholinergic and glutamatergic activities.

Developing drugs for Alzheimer's disease (AD) is an extremely challenging task due to its devastating pathology. Previous studies have indicated that natural compounds play a crucial role as lead molecules in the development of drugs. Even though, there are remarkable technological advancements in the isolation and synthesis of natural compounds, the targets for many of them are still unknown.

Binding of rosmarinic acid curcumin and capsaicin with PLA2: A comparative study.

Phospholipase A2 (PLA2) is a key enzyme involved in the formation of pro-inflammatory mediators like eicosanoids. Inhibition of PLA2 is regarded as one of the effective methods of controlling inflammation. The present study investigated the binding potentials of three natural compounds, rosmarinic acid (RA), capsaicin (CAP), and curcumin (CUR) by means of in silico and in vitro methods.

Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation.

The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer's disease (AD). Tacrine, a potent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD.

Exploring the binding mode of PQ912 against secretory glutaminyl cyclase through systematic exploitation of conformational ensembles.

Secretory glutaminyl cyclase (sQC) plays an important role in the formation of the pyroglutamate-amyloid beta (pGlu-Aβ) peptide, one of the most abundant variants of Aβ found in the Alzheimer's disease (AD) brain. This post-translationally modified pGlu-Aβ possesses high toxicity and rapid aggregation propensity when compared to the wild-type Aβ (WT-Aβ). Since pGlu-Aβ acts as seed for WT-Aβ, the inhibition of sQC limits the formation of pGlu-Aβ and reduces the overall load of Aβ plaques in the AD brain.

Chemical similarity assisted search for acetylcholinesterase inhibitors: Molecular modeling and evaluation of their neuroprotective properties.

Alzheimer's disease (AD) is an obstinate and progressive neurodegenerative disorder, mainly characterized by cognitive decline. Increasing number of AD patients and the lack of promising treatment strategies demands novel therapeutic agents to combat various disease pathologies in AD. Recent progresses in understanding molecular mechanisms in AD helped researchers to streamline the various therapeutic approaches.

Crystal structure of phospholipase A in complex with 1-naphthaleneacetic acid.

Phospholipase A (PLA ) is one of the rate limiting enzymes involved in the production of arachidonic acid, a potent inflammatory mediator. PLA is widely distributed all over the animal kingdom. It is also seen in inflammatory exudation and venoms of different organisms.

Cellular calcium signaling in the aging brain.

Aging in the biological system is an irreversible process. In the initial stages of lifespan aging improves survival skills of an organism while in the later stages aging reduce the survival skills. Aging is associated with changes in several cellular and molecular functions among which calcium signaling is a prominent one.

Novel tacrine derivatives exhibiting improved acetylcholinesterase inhibition: Design, synthesis and biological evaluation.

A novel series of twenty four tacrine derivatives were designed and synthesised. Among these, thirteen were taken for the acetylcholinesterase (AChE) inhibition studies. Three compounds such as 4c, 6c and 6f were found to possess significant AChE inhibitory properties with IC values 12.

Interactions of selected indole derivatives with phospholipase A₂: in silico and in vitro analysis.

Phospholipase A2 (PLA₂) is one of the key enzymes involved in the formation of inflammatory mediators. Inhibition of PLA₂ is considered to be one of the efficient methods to control inflammation. In silico docking studies of 160 selected indole derivatives performed against porcine pancreatic PLA₂ (ppsPLA2) suggested that, CID2324681, CID8617 (indolebutyric acid or IBA), CID22097771 and CID802 (indoleacetic acid or IAA) exhibited highest binding energies.

In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile.

Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer's disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors.