Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer's disease.

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), ß-secretase-1 (BACE-1), and inhibition of amyloid ß (Aß) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.

Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer's disease.

Cathepsin B is a cysteine protease lysosomal enzyme involved in several physiological functions. Overexpression of the enzyme enhances its proteolytic activity and causes the breakdown of amyloid precursor protein (APP) into neurotoxic amyloid ß (Aß), a characteristic hallmark of Alzheimer's disease (AD). Therefore, inhibition of the enzyme is a crucial therapeutic aspect for treating the disease. Combined structure and ligand-based drug design strategies were employed in the current study to identify the novel potential cathepsin B inhibitors. Five different pharmacophore models were developed and used for the screening of the ZINC-15 database. The obtained hits were analyzed for the presence of duplicates, interfering PAINS moieties, and structural similarities based on Tanimoto's coefficient. The molecular docking study was performed to screen hits with better target binding affinity. The top seven hits were selected and were further evaluated based on their predicted ADME properties. The resulting best hits, ZINC827855702, ZINC123282431, and ZINC95386847, were finally subjected to molecular dynamics simulation studies to determine the stability of the protein-ligand complex during the run. ZINC123282431 was obtained as the virtual lead compound for cathepsin B inhibition and may be a promising novel anti-Alzheimer agent.

Recent Advances in the Development of Near-Infrared Fluorescent Probes for the in Vivo Brain Imaging of Amyloid-ß Species in Alzheimer's Disease.

The deposition of ß-amyloid (Aß) plaques in the parenchymal and cortical regions of the brain of Alzheimer's disease (AD) patients is considered the foremost pathological hallmark of the disease. The early diagnosis of AD is paramount in order to effective management and treatment of the disease. Developing near-infrared fluorescence (NIRF) probes targeting Aß species is a potential and attractive approach suitable for the early and timely diagnosis of AD. The advantages of the NIRF probes over other tools include real-time detection, higher sensitivity, resolution, comparatively inexpensive experimental setup, and noninvasive nature. Currently, enormous progress is being observed in the development of NIRF probes for the in vivo imaging of Aß species. Several strategies, i.e., the classical push-pull approach, "turn-on" effect, aggregation-induced emission (AIE), and resonance energy transfer (RET), have been exploited for development. We have outlined and discussed the recently emerged NIRF probes with different design strategies targeting Aß species for ex vivo and in vivo imaging. We believe that understanding the recent development enables the prospect of the rational design of probes and will pave the way for developing future novel probes for early diagnosis of AD.

Discovery of triazole-bridged aryl adamantane analogs as an intriguing class of multifunctional agents for treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive brain disorder associated with slow loss of brain functions leading to memory failure and modest changes in behavior. The multifactorial neuropathological condition is due to a depletion of cholinergic neurons and accumulation of amyloid-beta (Aß) plaques. Recently, a multi-target-directed ligand (MTDL) strategy has emerged as a robust drug discovery tool to overcome current challenges. In this research work, we aimed to design and develop a library of triazole-bridged aryl adamantane analogs for the treatment of AD. All synthesized analogs were characterized and evaluated through various in vitro and in vivo biological studies. The optimal compounds 32 and 33 exhibited potent inhibitory activities against acetylcholinesterase (AChE) (32 - IC50 = 0.086 µM; 33 - 0.135 µM), and significant Aß aggregation inhibition (20 µM). N-methyl-d-aspartate (NMDA) receptor (GluN1-1b/GluN2B subunit combination) antagonistic activity of compounds 32 and 33 measured upon heterologous expression in Xenopus laevis oocytes showed IC50 values of 3.00 µM and 2.86 µM, respectively. The compounds possessed good blood-brain barrier permeability in the PAMPA assay and were safe for SH-SY5Y neuroblastoma (10 µM) and HEK-293 cell lines (30 µM). Furthermore, in vivo behavioral studies in rats demonstrated that both compounds improved cognitive and spatial memory impairment at a dose of 10 mg/kg oral administration. Together, our findings suggest triazole-bridged aryl adamantane as a promising new scaffold for the development of anti-Alzheimer's drugs.

Recent Applications of Bioinformatics in Target Identification and Drug Discovery for Alzheimer's Disease.

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease characterized by progressive memory loss. The main pathological features of the disease are extracellular deposition of amyloid ß (Aß) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Understanding factors contributing to AD progression, the number of molecular signatures, and the development of therapeutic agents played a significant role in the discovery of disease-modifying drugs to treat the disease. Bioinformatics has established its significance in many areas of biology. The role of bioinformatics in drug discovery, is emerging significantly and will continue to evolve. In recent years, different bioinformatics methodologies, viz. protein signaling pathway, molecular signature differences between different classes of drugs, interacting profiles of drugs and their potential therapeutic mechanisms, have been applied to identify potential therapeutic targets of AD. Bioinformatics tools were also found to contribute to the discovery of novel drugs, omics-based biomarkers, and drug repurposing for AD. The review aims to explore the applications of various advanced bioinformatics tools in the identification of targets, biomarkers, pathways, and potential therapeutics for the treatment of the disease.

Indole: A promising scaffold for the discovery and development of potential anti-tubercular agents.

Indole-containing small molecules have been reported to have diverse pharmacological activities. The aromatic heterocyclic scaffold, which resembles various protein structures, has received attention from organic and medicinal chemists. Exploration of indole derivatives in drug discovery has rapidly yielded a vast array of biologically active compounds with broad therapeutic potential. Nature is the major source of indole scaffolds, but various classical and advanced synthesis methods for indoles have also been reported. One-pot synthesis is widely considered an efficient approach in synthetic organic chemistry and has been used to synthesize some indole compounds. The rapid emergence of drug-resistant tuberculosis is a major challenge to be addressed. Identifying novel targets and drug candidates for tuberculosis is therefore crucial. Researchers have extensively explored indole derivatives as potential anti-tubercular agents or drugs. Indole scaffolds containing the novel non-covalent (decaprenylphosphoryl-ß-D-ribose2'-epimerase) DprE1 inhibitor 1,4-azaindole is currently in clinical trials to treat Mycobacterium tuberculosis. In addition, DG167 indazole sulfonamide with potent anti-tubercular activity is undergoing early-stage development in preclinical studies. Indole bearing cationic amphiphiles with high chemical diversity have been reported to depolarize and disrupt the mycobacterial membrane. Some indole-based compounds have potential inhibitory activities against distinct anti-tubercular targets, including the inhibition of cell wall synthesis, replication, transcription, and translation, as summarized in the graphical abstract. The success of computer-aided drug design in the fields of cancer and anti-viral drugs has accelerated in silico studies in antibacterial drug development. This review describes the sources of indole scaffolds, the potential for novel indole derivatives to serve as anti-tubercular agents, in silico findings, and proposed actions to facilitate the design of novel compounds with anti-tubercular activity.

Cathepsin B-A Neuronal Death Mediator in Alzheimer's Disease Leading to Neurodegeneration.

The lysosomal cysteine protease enzyme, named Cathepsin B, mainly degrades the protein and manages its average turnover in our body. The Cathepsin B active form is mostly present inside the lysosomal part at a cellular level, providing the slightly acidic medium for its activation. Multiple findings on Cathepsin B reveal its involvement in neurons' degeneration and a possible role as a neuronal death mediator in several neurodegenerative diseases. In this review article, we highlight the participation of Cathepsin B in the etiology/progress of AD, along with various other factors. The enzyme is involved in producing neurotoxic Aß amyloid in the AD brain by acting as the ß-secretase enzyme in the regulated secretory pathways responsible for APP processing. Aß amyloid accumulation and amyloid plaque formation lead to neuronal degeneration, one of the prominent pathological hallmarks of AD. Cathepsin B is also involved in the production of PGlu-Aß, which is a truncated and highly neurotoxic form of Aß. Some of the findings also revealed that Cathepsin B specific gene deletion decreases the level of PGlu-Aß inside the brain of experimental mice. Therefore, neurotoxicity might be considered a new pathological indication of AD due to the involvement of Cathepsin B. It also damages neurons present in the CNS region by producing inflammatory responses and generating mitochondrial ROS. However, Cathepsin B inhibitors, i.e., CA-074, can prevent neuronal death in AD patients. The other natural inhibitors are also equally effective against neuronal damage with higher selectivity. Its synthetic inhibitors are specific for their target; however, they lose their selectivity in the presence of quite a few reducing agents. Therefore, a humanized monoclonal antibody is used as a selective Cathepsin B inhibitor to overcome the problem experienced. The use of Cathepsin B for the treatment of AD and other neurodegenerative diseases could be considered a rational therapeutic target.

A systematic review of carbohydrate-based bioactive molecules for Alzheimer's disease.

The abundance, low cost, high density of functional groups and ease of purification of carbohydrates are among the most important features that make them a prime candidate for designing therapeutics. Several carbohydrate-based molecules, of both natural and synthetic origin, are known for their wide range of therapeutic activities. The incorporation of a carbohydrate moiety not only retains the pharmacological characteristics of a molecule but also improves its activity. Several sugar conjugates have been designed and reported to inhibit acetylcholinesterase, ß-amyloid and tau aggregation. This systematic review provides a brief overview of carbohydrate-based bioactive molecules having anti-Alzheimer's activity along with improved therapeutic potential. Most importantly, several reported carbohydrate-based molecules for Alzheimer's disease act on ß-amyloid aggregation, tau protein, cholinesterase and oxidative stress, with enhanced pharmacokinetic and mechanistic properties. The prospect of designing carbohydrate-based molecules for Alzheimer's disease will definitely provide potential opportunities to discover novel carbohydrate-based drugs.

Systematic review on role of structure based drug design (SBDD) in the identification of anti-viral leads against SARS-Cov-2.

The outbreak of existing public health distress is threatening the entire world with emergence and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel coronavirus disease 2019 (COVID-19) is mild in most people. However, in some elderly people with co-morbid conditions, it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multi organ dysfunction leading to death. COVID-19 has caused global panic in the healthcare sector and has become one of the biggest threats to the global economy. Drug discovery researchers are expected to contribute rapidly than ever before. The complete genome sequence of coronavirus had been reported barely a month after the identification of first patient. Potential drug targets to combat and treat the coronavirus infection have also been explored. The iterative structure-based drug design (SBDD) approach could significantly contribute towards the discovery of new drug like molecules for the treatment of COVID-19. The existing antivirals and experiences gained from SARS and MERS outbreaks may pave way for identification of potential drug molecules using the approach. SBDD has gained momentum as the essential tool for faster and costeffective lead discovery of antivirals in the past. The discovery of FDA approved human immunodeficiency virus type 1 (HIV-1) inhibitors represent the foremost success of SBDD. This systematic review provides an overview of the novel coronavirus, its pathology of replication, role of structure based drug design, available drug targets and recent advances in in-silico drug discovery for the prevention of COVID-19. SARSCoV- 2 main protease, RNA dependent RNA polymerase (RdRp) and spike (S) protein are the potential targets, which are currently explored for the drug development.