Diabetology and Nanotechnology: A Compelling Combination.

The convergence of diabetology and nanotechnology has emerged as a promising synergy with the potential to revolutionize the management and treatment of diabetes mellitus. Diabetes, a complex metabolic disorder affecting millions worldwide, necessitates innovative approaches to enhance monitoring, diagnosis, and therapeutic interventions. Nanotechnology, a burgeoning field that manipulates materials at the nanoscale, offers unprecedented opportunities to address the challenges posed by diabetes. This abstract explores the multifaceted interface between diabetology and nanotechnology, highlighting key areas of integration. Nanotechnology has paved the way for the development of advanced glucose monitoring systems with enhanced accuracy, sensitivity, and patient convenience. Miniaturized biosensors and implantable devices equipped with nanoscale materials enable continuous and real-time glucose monitoring, empowering individuals with diabetes to make timely and informed decisions about their dietary and insulin management. Furthermore, nanotechnology has facilitated breakthroughs in targeted drug delivery, addressing the limitations of conventional therapies in diabetes treatment. Nano-sized drug carriers can improve bioavailability, enable controlled release, and enhance the selectivity of therapeutic agents, minimizing side effects and optimizing treatment outcomes. Moreover, nanoengineered materials have opened avenues for tissue engineering and regenerative medicine, offering the potential to restore damaged pancreatic islets and insulin-producing cells. The amalgamation of diabetology and nanotechnology also holds promise for early disease detection and prevention. Nanoscale diagnostic tools, such as biomarker-based nanoprobes and lab-onchip devices, offer rapid and accurate detection of diabetes-related biomolecules, enabling timely interventions and reducing the risk of complications. However, this compelling combination also presents challenges that warrant careful consideration. Safety, biocompatibility, regulatory approval, and ethical implications are crucial factors that demand meticulous evaluation during the translation of nanotechnology-based solutions into clinical practice. In conclusion, the integration of diabetology and nanotechnology represents a transformative paradigm that has the potential to reshape the landscape of diabetes management. By harnessing the unique properties of nanoscale materials, researchers and clinicians are poised to usher in an era of personalized and precise diagnostics, therapeutics, and preventive strategies for diabetes mellitus. As advancements in nanotechnology continue to unfold, the journey towards realizing the full potential of this compelling combination remains an exciting frontier in medical science.

Understanding Alzheimer's Disease and its Metal Chelation Therapeutics: A Narrative Review.

The neurodegenerative disorders are age-related illnesses that cause the morphology or activity of neurons to deteriorate over time. Alzheimer's disease is the most frequent neurodegenerative illness in the long run. The rate of advancement might vary, even though it is a progressive neurological illness. Various explanations have been proposed, however the true etiology of Alzheimer's disease remains unclear. Most pharmacological interventions are based on the cholinergic theory, that is earliest idea. In accordance with the amyloid hypothesis, the buildup of beta-amyloid in brain regions is the primitive cause of illness. There is no proof that any one strategy is useful in avoiding Alzheimer's disease, though some epidemiological studies have suggested links within various modifiable variables, such as cardiovascular risk, diet and so on. Different metals like zinc, iron, and copper are naturally present in our bodies. In metal chelation therapy drugs are used to jam the metal ions from combining with other molecules in the body. Clioquinol is one of the metal chelation drugs used by researchers. Research on metal chelation is still ongoing. In the present review, we go over the latest developments in prevalence, incidence, etiology, or pathophysiology of our understanding of Alzheimer's disease. Additionally, a brief discussion on the development of therapeutic chelating agents and their viability as Alzheimer's disease medication candidates is presented. We also assess the effect of clioquinol as a potential metal chelator.

Recent updates in the development of small molecules as potential clinical candidates for Alzheimer's disease: A review.

Alzheimer's disease (AD) is one of the prominent causes for disability and lowered quality of life worldwide in elderly population. It has fostered immense burden to AD patients, families and society. Burgeoning progress in the field of pathogenesis over last two decades has persuaded the investigation of novel pharmacological therapeutics that focuses towards the pathophysiological events of AD. Miscellaneous clinical trials, development and testing of interventions aimed at various targets, such as anti-tau and anti-amyloid interventions, neurotransmitter modification, neuroprotection and anti-neuroinflammation interventions, cognitive enhancement and interventions to palliate behavioural symptoms have been carried out. Despite massive efforts to find disease-modifying therapies, there lingers a vital need for continuing the advancement in progress of the AD research. This review features the new developments of small molecule compounds that will be beneficial in evolution of new AD therapies. In particular, this review briefly describes summary of mechanistic causes chiefly associated with AD and focuses on medicinal approach via small molecule inhibitors that can manage cognitive impairment and dysfunction and may combat Alzheimer's development.

Naphthalene-triazolopyrimidine hybrid compounds as potential multifunctional anti-Alzheimer's agents.

In an attempt to construct potential anti-Alzheimer's agents Naphthalene-triazolopyrimidine hybrids were synthesized and screened in vitro against the two cholinesterases (ChE)s, amyloid ß aggregation and for antioxidation activity. Single-crystal X-ray crystallography was utilized for crystal structure determination of one of the compounds. In vitro study of compounds revealed that most of the compounds are capable of inhibiting acetylcholinesterase and Butyrylcholinesterase activity. Particularly, the compounds 4e and 4d exhibited IC50 values ranging from 8.6 to 14 nM against AChE lower than the standard drug Donepezil (IC50 49 nM). Best result was found for compound 4e with IC50 of 8.6 nM (for AChE) and 150 nM (for BuChE). Selectivity upto that of Donepezil and even more was observed for 4a, 4c and 4h. Investigation by electron microscopy, transmission electron microscopy and ThT fluorescence assay unveils the fact that synthesized hybrids exhibit amyloid ß self-aggregation inhibition. The compounds 4i and 4j revealed highest inhibitory potential, 85.46% and 72.77% at 50 µM respectively; above the standard Aß disaggregating agent, Curcumin. Their antioxidation profile was also analyzed. Studies from DPPH free radical scavenging assay and ORAC assay depicts molecules to possess low antioxidation profile. Results suggest that triazolopyrimidines are potential candidate for Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), and amyloid ß aggregation inhibition. In silico ADMET profiling indicates drug-like properties with a very low toxic influence. Such synthesized compounds provide a strong vision for further development of potential anti-Alzheimer's agents.

A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease.

2-(piperazin-1-yl)N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid ß aggregation inhibitors. Formation of synthesized compounds (P1P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aß aggregation and Cu(II)-mediated Aß aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced ß-amyloid (Aß) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aß1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aß disaggregation, antioxidation, metal-chelation activity.

New amyloid beta-disaggregating agents: synthesis, pharmacological evaluation, crystal structure and molecular docking of N-(4-((7-chloroquinolin-4-yl)oxy)-3-ethoxybenzyl)amines.

In the journey towards the development of potent multi-targeted ligands for the treatment of Alzheimer's disease, a series of Aß aggregation inhibitors having quinoline scaffold were designed utilizing computational biology tools, synthesized and characterized by various spectral techniques including single-crystal X-ray crystallography. Organic syntheses relying upon convergent synthetic routes were employed. Investigations via ThT fluorescence assay, electron microscopy and transmission electron microscopy revealed the synthesized derivatives to exhibit Aß self-aggregation inhibition. Molecules 5g and 5a showed the highest inhibitory potential, 53.73% and 53.63% at 50 µM respectively; higher than the standard Aß disaggregating agent, curcumin. Molecules 5g and 5a disaggregated AChE-induced (58.26%, 47.36%) Aß aggregation more than two fold more than the standard drug-donepezil (23.66%) and inhibited Cu2+-induced Aß aggregation. A docking study significantly showed their interaction with key residues of Aß and the results were in accordance with the study. Besides, these compounds also exhibited potential antioxidant activity (5a, 2.7240 Trolox equivalent by ORAC assay) and metal chelating property. Furthermore, the stoichiometric ratio of Cu (ii)-5a and Cu(ii)-5g complexes were found by Job's method (0.5 : 1 for 5a and 0.8 : 1 for 5g). In silico ADMET profiling showed these derivatives to have drug like properties with very low toxicity effects in the pharmacokinetic study. Overall, these results displayed a multi-activity profile with promising Aß aggregation inhibition and antioxidation and metal chelation activity that could be helpful for developing new multifunctional agents against Alzheimer's disease.

Alzheimer's Disease: A Systemic Review of Substantial Therapeutic Targets and the Leading Multi-functional Molecules.

Alzheimer's Disease (AD) is a fatal neurodegenerative disorder, having a complex aetiology with numerous possible drug targets. There are targets that have been known for years while more new targets and theories have also emerged. Beta amyloid and cholinesterases are the most significant biological targets for finding curative treatment of AD. The major class of drugs used for AD till now has been the Cholinesterase (ChE) inhibitors. Other prevailing models of molecular pathogenesis in AD include Neurofibrillary Tangles (NFTs) and amyloid deposition, tryptophan degradation pathway, kinase and phosphatase activity imbalance and neuroinflammation. The beta amyloid aggregation initiates flow of events resulting in neurotoxicity and finally clinical pathogenesis of AD. Furthermore, ApoE is another very significant entity involved in repairing and maintaining the neurons and has important role in neurodegeneration. Neuroinflammation being the primmest symptom for AD is essential to focus on. Multiple factors and complexity in interlinking disease progression pose huge challenge to find one complete curing drug. With so many promising molecules having multiform pharmacological profile from all over the world however facing failures in clinical trials indicates the need to consider all aspects of the old as well as new therapeutic targets of AD. Until the disease mechanism is better understood, it is likely that multiple targeting, symptomatic and diseasemodifying, is the way forward. Most recent approaches to find anti-Alzheimer's agents have focused on multi-target directed agents that include targeting all glorious targets hypothesized against AD. New identification of prototype candidates that could be starting point of a new way of thinking drug design has been done and many drug candidates are under preclinical evaluation. The main focus of this review is to discuss the recent understanding of key targets and the development of potential therapeutic agents for the treatment of AD. It also documents the current therapeutic agents in clinical trials and under development based on their main mode of action.

Identification of lead BAY60-7550 analogues as potential inhibitors that utilize the hydrophobic groove in PDE2A: a molecular dynamics simulation study.

The phosphodiesterase (PDE) family of proteins are important regulators of signal transduction, which they achieve by controlling the secondary messengers cyclic AMP (cAMP) and cyclic GMP (cGMP). cAMP and cGMP are involved in many critical intracellular processes such as gene transcription, kinase activation, signal transduction in learning and memory, and channel function as secondary messengers. The involvement of PDEs in neuronal communication has made them important therapeutic targets. Considering the recent discovery that PDE2A inhibition can improve cognitive functioning, a combined molecular dynamics simulation and scoring and docking study was carried out to identify selective inhibitors of PDE2A that specifically interact with the recently discovered hydrophobic groove in PDE2A. Using the X-ray crystal structure of PDE2A (from PDB ID: 4HTX), we investigated the binding modes of a range of promising inhibitors based on the known PDE2A inhibitor BAY60-7550 to PDE2A. Graphical abstract The lead molecule showing highest MMPBSA binding energy with 2D and 3D binding pose in hydrophobic groove.

Coumarin: A Privileged Scaffold for the Design and Development of Antineurodegenerative Agents.

Drug development for neurodegenerative diseases (NDs) is foremost task for the medicinal chemists in the 21st century. Coumarins are exemplary of an assorted and aptitudinally useful set of drugs. Coumarins play a momentous role in several pharmacological and medicinal aspects. Its analogues are anticipated to play a significant role in the development of new therapeutic leads for NDs. Their promising applications in the field of ND medication are exemplified by clinical candidates such as nodakenin that have been potent for demoting memory impairment. Apart from ND, clinically used anticoagulant warfarin, anticoagulant dicoumarol, and antibiotic coumermycin, novobiocin and chartesium grab the interest of researchers in coumarins. It would be worthwhile to look at the different biological processes that could cause neurodegeneration, thereby establishing a link with distinct coumarin derivatives to serve the purpose of medication. This review undertakes estimation of the wide spectrum of studies focusing coumarin to the domain of drug research for ND. Herein, we search for multitarget coumarin-based inhibitors and their scope for NDs. Future challenges in coumarin-based drug development have been discussed, and emphases have been laid on the future perspectives of coumarins as possible drugs in the future for the treatment of NDs.