Chromenone: An emerging scaffold in anti-Alzheimer drug discovery.

Alzheimer's disease (AD) presents a growing global health concern. In recent decades, natural and synthetic chromenone have emerged as promising drug candidates due to their multi-target potential. Natural chromenone, quercetin, scopoletin, esculetin, coumestrol, umbelliferone, bergapten, and methoxsalen (xanthotoxin), and synthetic chromenone hybrids comprising structures like acridine, 4-aminophenyl, 3-arylcoumarins, quinoline, 1,3,4-oxadiazole, 1,2,3-triazole, and tacrine, have been explored for their potential to combat AD. Key reactions used for synthesis of chromenone hybrids include Perkin and Pechmann condensation. The activity of chromenone hybrids has been reported against several drug targets, including AChE, BuChE, BACE-1, and MAO-A/B. This review comprehensively explores natural, semisynthetic, and synthetic chromenone, elucidating their synthetic routes, possible mode of action/drug targets and structure-activity relationships (SAR). The acquired knowledge provides valuable insights for the development of new chromenone hybrids against AD.

Protective effect of rutin on acrylamide induced ovarian inflammation, oxidative stress, DNA damage, and hormonal changes: Based on in silico and in vivo study.

Acrylamide (AA) is a carcinogenic compound that affects people due to its frequent use in laboratories and industry as well as the high-temperature cooking of foods with high hydrocarbon content. AA is known to cause severe reproductive abnormalities. The main aim of this study is to evaluate the protective effect of rutin (RU), a phytoactive compound, against AA-induced reproductive toxicity in female rats. Initially, rats were exposed to AA (40 mg/kg for 10 days). Therapy of RU was given after AA intoxication consecutively for 3 days. After 24 h of the last treatment, all the animals were sacrificed. The study evaluated reproductive hormones, oxidative stress markers, membrane-bound enzymes, DNA damage, histological findings, and an in silico approach to determine the protective efficacy of RU. The results indicated that RU significantly protected against inflammation, oxidative stress, and DNA damage induced by AA, likely due to its antioxidant properties.

Impact of GSK-3ß and CK-1δ on Wnt signaling pathway in alzheimer disease: A dual target approach.

Alzheimer's disease (AD) is an enigmatic neurological illness that offers few treatment options. Recent exploration has highlighted the crucial connection of the Wnt signaling pathway in AD pathogenesis, shedding light on potential therapeutic targets. The present study focuses on the dual targeting of glycogen synthase kinase-3ß (GSK-3ß) and casein kinase-1δ (CK-1δ) within the framework of the Wnt signaling pathway as a possible technique for AD intervention. GSK-3ß and CK-1δ are multifunctional kinases known for their roles in tau hyperphosphorylation, amyloid processing, and synaptic dysfunction, all of which are major hallmarks of Alzheimer's disease. They are intricately linked to Wnt signaling, which plays a pivotal part in sustaining neuronal function and synaptic plasticity. Dysregulation of the Wnt pathway in AD contributes to cognitive decline and neurodegeneration. This review delves into the molecular mechanisms by which GSK-3ß and CK-1δ impact the Wnt signaling pathway, elucidating their roles in AD pathogenesis. We discuss the potential of small-molecule inhibitors along with their SAR studies along with the multi-targetd approach targeting GSK-3ß and CK-1δ to modulate Wnt signaling and mitigate AD-related pathology. In summary, the dual targeting of GSK-3ß and CK-1δ within the framework of the Wnt signaling pathway presents an innovative and promising avenue for future AD therapies, offering new hope for patients and caregivers in the quest to combat this challenging condition.

Design and evaluation of sustained release mucoadhesive film of sumatriptan succinate containing grafted co-polymer as the platform.

Purpose: The primary goal of this research is to improve the bioavailability and efficacy of Sumatriptan succinate by incorporating it in the mucoadhesive film for the treatment of migraine. Mucoadhesive film offers an excellent substitute to deliver the drug in the systemic circulation and eliminate the chance of first-pass metabolism. Method: Using central composite design (CCD), various formulations were created by incorporating polymer, plasticizer, and water, and an optimized preparation was created using statistical screening. The optimization has been performed by applying a 34 factorial method based on dependent variables such as Drug content (%), Swelling index (%), Folding endurance (Number of times), and Mucoadhesive strength (g). Results: The actual experimental values obtained were compared with those predicted by the mathematical models. Formulation S9 was selected as an optimized formulation because it showed the lowest standard deviation between predicted and actual values compared to other formulations. In the case of the S9 formulation, approximately 77.12% of the drug was released within 24 h, but initially, it showed burst release. In addition, the in-vitro release of pure drug suspension showed 99.32% drug release within 2 h. That signified that the developed formulation provides sustained release due to presence of grafted co-polymer. Conclusion: Formulation holding drug-loaded grafted film showed decent sustained and controlled drug release characteristics compared to a pure drug suspension. S9 formulation showed better results than other formulations in drug content, swelling index, folding endurance, and mucoadhesive strength, which is further used to treat migraine.

Targeting cryptic-orthosteric site of PD-L1 for inhibitor identification using structure-guided approach.

Approved mAbs that block the protein-protein interaction (PPI) interface of the PD-1/PD-L1 immune checkpoint axis have led to significant improvements in cancer treatment. Despite having drawbacks of mAbs only few a compounds are reported till date against this axis. Inhibiting PPIs using small molecules has emerged as a significant therapeutic opportunity, demanding for the identification of drug-like molecules at an accelerated pace under the hit-to-lead campaigns. Due to the PD-L1's cross-talk with PD-1/CD80 and its overexpression on cancer cells, as well as the availability of its crystal structures with small molecules, it is an enticing therapeutic target for structure-assisted small molecule design. Furthermore, the selection of chemical databases enriched with focused designing for PPI interfaces is crucial. Therefore, in this study we have utilized the Asinex signature library for structure-assisted virtual screening to find the potential PD-L1 inhibitors by targeting the cryptic PD-L1 interface, followed by induced fit docking for pose refinements in the pocket. The obtained hits were then subjected to interaction fingerprinting and ligand-based drug-likeness investigations in order to evaluate and analyze their drug-like qualities (ADME). Twelve compounds qualified for molecular dynamics simulations, followed by thermodynamic calculations for evaluation of their stability and energetics inside the pocket. Two novel compounds with different chemical moieties have been identified that are consistent throughout the simulation, mimicking the interactions and binding energies with BMS-1166. These compounds appear as potential therapeutic candidates to be explored experimentally, thereby paving the way for the development of novel leads as immunomodulators.

Interplay among Structural Stability, Plasticity, and Energetics Determined by Conformational Attuning of Flexible Loops in PD-1.

The dynamics and plasticity of the PD-1/PD-L1 axis are the bottlenecks for the discovery of small-molecule antagonists to perturb this interaction interface significantly. Understanding the process of this protein-protein interaction (PPI) is of fundamental biological interest in structure-based drug designing. Food and Drug Administration (FDA)-approved anti-PD-1 monoclonal antibodies (mAbs) are the first-in-class with distinct binding modes to access this axis clinically; however, their mechanistic aspects remain elusive. Here, we have unveiled the interactive interfaces with PD-L1 and mAbs to investigate the native plasticity of PD-1 at global (structural and dynamical) and local (residue side-chain orientations) levels. We found that the structural stability and coordinated Cα movements are increased in the presence of PD-1's binding partners. The rigorous analysis of these PPIs using computational biophysical approaches revealed PD-1's intrinsic plasticity, its concerted loops' movement (BC, FG, and CC'), distal side-chain motions, and the thermodynamic landscape, which are perturbed remarkably from its unbound to bound states. Based on intra-/inter-residues' contact networks and energetics, the hot-spots have been identified that were found to be essential to arrest the dynamical motions of PD-1 significantly for the rational design of therapeutic agents by mimicking the mAbs mechanism.

Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection.

Angiotensin-converting enzyme 2 (ACE2), the host cell-binding site for SAR-CoV-2, poses two-fold drug development problems. First, the role of ACE2 itself is still a matter of investigation, and no specific drugs are available targeting ACE2. Second, as a consequence of SARS-CoV-2 interaction with ACE2, there is an impairment of the renin-angiotensin system (RAS) involved in the functioning of vital organs like the heart, kidney, brain, and lungs. In developing antiviral drugs for COVID-19, ACE2, RNA-dependent RNA polymerase (RdRp), and the specific enzymes involved in the viral and cellular gene expression have been the primary targets. SARS-CoV-2 being a new virus with unusually high mortality, there has been a need to get medicines in an emergency, and the drug repurposing has been a primary strategy. Considering extensive mortality and morbidity throughout the world, we have made a maiden attempt to discover the drugs interacting with RAS and identify the lead compounds from herbal plants using molecular docking. Both host ACE2 and viral RNA-dependent RNA polymerase (RdRp) and ORF8 appear to be the primary targets for the treatment of COVID-19. While the drug repurposing of currently approved drugs seems to be one strategy for the treatment of COVID-19, purposing phytochemicals may be another essential strategy for discovering lead compounds. Using in silico molecular docking, we have identified a few phytochemicals that may provide insights into designing herbal and synthetic therapeutics to treat COVID-19.

Therapeutic potential and recent progression of BTK inhibitors against rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex chronic inflammatory illness that affects the entire physiology of human body. It has become one of the top causes of disability worldwide. The development and progression of RA involves a complex interplay between an individual's genetic background and various environmental factors. In order to effectively manage RA, a multidisciplinary approach is required, as this disease is complicated and its pathophysiological mechanism is not fully understood yet. In majority of arthritis patients, the presence of abnormal B cells and autoantibodies, primarily anti-citrullinated peptide antibodies and rheumatoid factor affects the progression of RA. Therefore, drugs targeting B cells have now become a hot topic in the treatment of RA which is quite evident from the recent trends seen in the discovery of various B cell receptors (BCRs) targeting agents. Bruton's tyrosine kinase (BTK) is one of these recent targets which play a role in the upstream phase of BCR signalling. BTK is an important enzyme that regulates the survival, proliferation, activation and differentiation of B-lineage cells by preventing BCR activation, FC-receptor signalling and osteoclast development. Several BTK inhibitors have been found to be effective against RA during the in vitro and in vivo studies conducted using diverse animal models. This review focuses on BTK inhibition mechanism and its possible impact on immune-mediated disease, along with the types of RA currently being investigated, preclinical and clinical studies and future prospective.

The recent update and advancements of natural products in targeting the Wnt/ß-Catenin pathway for cancer prevention and therapeutics.

The Wnt/ß-Catenin pathway (Wnt/ß-CatP) is implicated in accelerating carcinogenesis and cancer progression, contributing to increased morbidity and treatment resistance. Even though it holds promise as a focus for cancer treatment, its intricate nature and diverse physiological effects pose significant challenges. Recent years have witnessed significant advancements in this domain, with numerous natural products demonstrating promising preclinical anti-tumor effects and identified as inhibitors of the Wnt/ß-CatP through various upstream and downstream mechanisms. This study provides a comprehensive overview of the current landscape of Wnt/ß-Cat-targeted cancer therapy, examining the impact of natural products on Wnt/ß-Cat signaling in both cancer prevention and therapeutic contexts. A comprehensive search was conducted on scientific databases like SciFinder, PubMed, and Google Scholar to retrieve relevant literature on Wnt-signaling, natural products, ß-Catenin (ß-Cat), and cancer from 2020 to January 2024. As per the analysis of the relevant reference within the specified period, it has been noted that a total of 58 phytoconstituents, predominantly phenolics, followed by triterpenoids and several other classes, along with a limited number of plant extracts, have exhibited activity targeting the Wnt/ß-CatP. Most ß-Cat regulating modulators restrict cancer cell development by suppressing ß-Cat expression, facilitating proteasomal degradation, and inhibiting nuclear translocation. Multiple approaches have been devised to block the activity of ß-Cat in cancer therapy, a key factor in cancer progression, leading to the discovery of various Wnt/ß-CatP regulators. However, their exploration remains limited, necessitating further research using clinical models for potential clinical use in cancer prevention and therapeutics.

The hidden threat: Environmental toxins and their effects on gut microbiota.

The human gut microbiota (GM), which consists of a complex and diverse ecosystem of bacteria, plays a vital role in overall wellness. However, the delicate balance of this intricate system is being compromised by the widespread presence of environmental toxins. The intricate connection between contaminants in the environment and human well-being has garnered significant attention in recent times. Although many environmental pollutants and their toxicity have been identified and studied in laboratory settings and animal models, there is insufficient data concerning their relevance to human physiology. Consequently, research on the toxicity of environmental toxins in GM has gained prominence in recent years. Various factors, such as air pollution, chemicals, heavy metals, and pesticides, have a detrimental impact on the composition and functioning of the GM. This comprehensive review aims to comprehend the toxic effects of numerous environmental pollutants, including antibiotics, endocrine-disrupting chemicals, heavy metals, and pesticides, on GM by examining recent research findings. The current analysis concludes that different types of environmental toxins can lead to GM dysbiosis and have various potential adverse effects on the well-being of animals. We investigate the alterations to the GM composition induced by contaminants and their impact on overall well-being, providing a fresh perspective on research related to pollutant exposure.

Harnessing the druggability at orthosteric and allosteric sites of PD-1 for small molecule discovery by an integrated in silico pipeline.

The PD-1/PD-L1 interaction is a promising target for small molecule inhibitors in cancer immunotherapy, but targeting this interface has been challenging. While efforts have been made to identify compounds that target the orthosteric sites, no reports have explored the potential of small molecules to target the allosteric region of PD-1. Therefore, our study aims to establish a pipeline to identify small molecules that can effectively bind to either the orthosteric or allosteric pockets of PD-1. We categorized the PD-1 interface into two hot-spot zones (P-and N-zones) based on extensive analysis of its structural, dynamical, and energetic properties. These zones correspond to the orthosteric and allosteric PPI sites, respectively, targeted by monoclonal antibodies. We used a guided virtual screening workflow to identify hits from ∼7 million compounds library, which were then clustered based on structural similarity and assessed by interaction fingerprinting. The selective and diverse chemical representatives were subjected to MD simulations and binding energetics calculations to filter out false positives and identify actual binders. Binding poses metadynamics calculations confirmed the stability of the final hits in the pocket. This study emphasizes the need for an integrated pipeline that uses molecular dynamics simulations and binding energetics to identify potential binders for the dynamic PD-1/PD-L1 interface, due to the lack of small molecule co-crystals. Only a few potential binders were discovered from a large pool of molecules targeting both the allosteric and orthosteric zones. Our results suggest that the allosteric site has more potential than the orthosteric site for inhibitor design. The identified "computational hits" hold potential as starting points for in vitro evaluations followed by hit-to-lead optimization. Overall, this study represents an effort to establish a computational pipeline for exploring and enriching both the allosteric and orthosteric sites of PPI interfaces, "a tough but indispensable nut to crack".

Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease.

The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain cellular homeostasis. The mTOR signaling cascade consists of two distinct multi-subunit complexes named mTOR complex 1/2 (mTORC1/2). mTOR catalyzes the phosphorylation of several critical proteins like AKT, protein kinase C, insulin growth factor receptor (IGF-1R), 4E binding protein 1 (4E-BP1), ribosomal protein S6 kinase (S6K), transcription factor EB (TFEB), sterol-responsive element-binding proteins (SREBPs), Lipin-1, and Unc-51-like autophagy-activating kinases. mTOR signaling plays a central role in regulating translation, lipid synthesis, nucleotide synthesis, biogenesis of lysosomes, nutrient sensing, and growth factor signaling. The emerging pieces of evidence have revealed that the constitutive activation of the mTOR pathway due to mutations/amplification/deletion in either mTOR and its complexes (mTORC1 and mTORC2) or upstream targets is responsible for aging, neurological diseases, and human malignancies. Here, we provide the detailed structure of mTOR, its complexes, and the comprehensive role of upstream regulators, as well as downstream effectors of mTOR signaling cascades in the metabolism, biogenesis of biomolecules, immune responses, and autophagy. Additionally, we summarize the potential of long noncoding RNAs (lncRNAs) as an important modulator of mTOR signaling. Importantly, we have highlighted the potential of mTOR signaling in aging, neurological disorders, human cancers, cancer stem cells, and drug resistance. Here, we discuss the developments for the therapeutic targeting of mTOR signaling with improved anticancer efficacy for the benefit of cancer patients in clinics.

Metal-based nanomaterials and nanocomposites as promising frontier in cancer chemotherapy.

Cancer is a disease associated with complex pathology and one of the most prevalent and leading reasons for mortality in the world. Current chemotherapy has challenges with cytotoxicity, selectivity, multidrug resistance, and the formation of stemlike cells. Nanomaterials (NMs) have unique properties that make them useful for various diagnostic and therapeutic purposes in cancer research. NMs can be engineered to target cancer cells for early detection and can deliver drugs directly to cancer cells, reducing side effects and improving treatment efficacy. Several of NMs can also be used for photothermal therapy to destroy cancer cells or enhance immune response to cancer by delivering immune-stimulating molecules to immune cells or modulating the tumor microenvironment. NMs are being modified to overcome issues, such as toxicity, lack of selectivity, increase drug capacity, and bioavailability, for a wide spectrum of cancer therapies. To improve targeted drug delivery using nano-carriers, noteworthy research is required. Several metal-based NMs have been studied with the expectation of finding a cure for cancer treatment. In this review, the current development and the potential of plant and metal-based NMs with their effects on size and shape have been discussed along with their more effective usage in cancer diagnosis and treatment.

Traversing through the Dynamic Protein-Protein Interaction Landscape and Conformational Plasticity of PD-1 for Small-Molecule Discovery.

Monoclonal antibodies (mAbs) blocking the PD-1/PD-L1 interface have shown remarkable success in treating malignancies, but they may also initiate lethal immune-related adverse events. Small molecules may circumvent the mAb limitations; however, none has entered clinical trials targeting PD-1. Its complex protein-protein interaction interfaces necessitate an atomic-level understanding of recognition and binding mechanisms. Hence, we have aimed to highlight the PD-1's sequence-structure-dynamic-function link with its cognate ligands and diversely reported inhibitors. We focus primarily on the anti-PD-1 mAbs, their mode of actions, and interactions with PD-1 epitopes. The comparison of co-crystals showed that these ligands/inhibitors harness the PD-1's conformational plasticity and structural determinants differentially. The relationship between modulator binding patterns and biological activity is demonstrated using interaction fingerprinting of all reported human PD-1 co-crystals. The significant dynamical events and hot-spot residues underpinned from crystallographic wealth and computational studies have been highlighted to expedite small-molecule discovery.

Stability Indicating Assay Method for the Quantitative Determination of Olaparib in Bulk and Pharmaceutical Dosage Form.

Objectives: Olaparib is an orally active poly (ADP-ribose) PARP (polymerases) inhibitor known to destroy cancer cells with BRCA1 or BRCA2 deficiency. An authentic, fast, distinct, and reliable reverse phase-high performance liquid chromatography (RP-HPLC) method was developed and promptly validated in tablet formulations for olaparib estimation. Materials and Methods: The proposed method focuses on the separation of olaparib in reverse phase mode using a Waters symmetry C18 (150 x 4.6 mm, 5 µm) analytical column with a flow rate of 1.0 mL/min and the injection volume was kept at 20 µL. The optimized mobile phase consists of ammonium acetate buffer (pH adjusted to 3.5 by glacial acetic acid): methanol in the ratio of 50:50 v/v. Results: The eluents were measured at 254 nm and the retention time for the drug encircled was about 4.32 min. The stress degradation studies of olaparib were conducted under acidic, alkaline, oxidative, photolytic and thermal conditions to demonstrate the stability of the drug. The regression value of 0.998 showed that the developed method was linear over the range of 80 µg/mL to 120 µg/mL. The developed RP-HPLC method is accurate and precise. The method was statistically validated as per International Conference on Harmonization guidelines. Conclusion: The proposed method is suitable and can be applied for the quantitative estimation of olaparib without any interference of the excipients used in the drug formulations.

Quinoline-derivatives as privileged scaffolds for medicinal and pharmaceutical chemists: A comprehensive review.

The quinoline scaffolds are privileged for their numerous biological activities in the pharmaceutical field. This moiety constitutes a well-known space in several marketed preparations. The quinoline scaffolds gained attention in modern days being an important chemical moiety in the identification, designing, and synthesis of novel potent derivatives. The current review is developed to shine the light on critical and significant insights on the quinoline derivatives possessing diverse biological activities such as analgesic, anti-inflammatory, antialzheimer, anti-convulsant, anti-oxidant, antimicrobial, anti-cancer activities and so on. A detailed summary of quinoline ring from its origin to the recent advancements regarding its synthesis, green chemistry approaches, patented methods, and its marketed drugs is presented in the review. We attempted to review the literature compiling the critical information that has potential to encourage fellow researchers and scientists for the design and development of quinoline scaffold based active molecules that have improved therapeutic performance along with profound pharmacological properties.

Withdrawal Notice: S.A.R.S Covid-19 A Medicinal Chemistry Approach

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Management of Glioblastoma Multiforme by Phytochemicals: Applications of Nanoparticle-Based Targeted Drug Delivery System.

The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhorts tumors of star-shaped glial cells in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorders like neurofibromatosis and schwannomatosis, which develop the tumor in the nervous system. The management of GBM with chemo-radiotherapy leads to resistance, and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind the failure of drugs are due to DNA alkylation in the cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bioactive compounds from plants referred as phytochemicals, serve as vital sources for anti-cancer drugs. Some prototypical examples include taxol analogs, vinca alkaloids (vincristine, vinblastine), podophyllotoxin analogs, camptothecin, curcumin, aloe-emodin, quercetin, berberine etc. These phytochemicals often regulate diverse molecular pathways, which are implicated in the growth and progression of cancers. However, the challenges posed by the presence of BBB/BBTB to restrict the passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review, we integrated nanotech as a novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.

Therapeutic Potential of Cinnoline Core: A Comprehensive Review.

Cinnoline or Benzo-pyridazine has its place in the family of fairly well-known benzfuseddiazine heterocycles. Because of its natural occurrence and synthetic exploration, cinnoline compounds validated its thought-provoking bioactivity through a number of research publications and patents during last few decades. A creative consideration has been rewarded to the synthesis of cinnoline based heterocyclic compounds, mostly due to their wide range of diverse pharmacological activities. The present review covers the principle approaches to the synthesis of cinnoline nucleus and almost all biological properties of 115 cinnoline derivatives reported during the last 65 years from natural and synthetic origin with 140 references.

Role of Forkhead Transcription Factors of the O Class (FoxO) in Development and Progression of Alzheimer's Disease.

In the Central Nervous System (CNS), a specific loss of focal neurons leads to mental and neurological disorders like dementia, Alzheimer's Disease (AD), Huntington's disease, Parkinson's disease, etc. AD is a neurological degenerative disorder, which is progressive and irreversible in nature and is the widely recognized reason for dementia in the geriatric populace. It affects 10% of people above the age of 65 and is the fourth driving reason for death in the United States. Numerous evidence suggests that the neuronal compartment is not the only genesis of AD, but transcription factors also hold significant importance in the occurrence and advancement of the disease. It is the need of the time to find the novel molecular targets and new techniques for treating or slowing down the progression of neurological disorders, especially AD. In this article, we summarised a conceivable association between transcriptional factors and their defensive measures against neurodegeneration and AD. The mammalian forkhead transcription factors of the class O (FoxO) illustrate one of the potential objectives for the development of new methodologies against AD and other neurocognitive disorders. The presence of FoxO is easily noticeable in the "cognitive centers" of the brain, specifically in the amygdala, hippocampus, and the nucleus accumbens. FoxO proteins are the prominent and necessary factors in memory formation and cognitive functions. FoxO also assumes a pertinent role in the protection of multiple cells in the brain by controlling the involving mechanism of autophagy and apoptosis and also modulates the process of phosphorylation of the targeted protein, thus FoxO must be a putative target in the mitigation of AD. This review features the role of FoxO as an important biomarker and potential new targets for the treatment of AD.