Targeting Abnormal Tau Phosphorylation for Alzheimer's Therapeutics.

Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive memory and cognitive decline, posing a formidable public health challenge. This review explores the intricate interplay between two pivotal players in AD pathogenesis: ß-amyloid (Aß) and tau protein. While the amyloid cascade theory has long dominated AD research, recent developments have ignited debates about its centrality. Aß plaques and tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal antibodies targeting Aß, have been approved, albeit amidst controversy, raising questions about the therapeutic efficacy of Aß-focused interventions. On the other hand, tau, specifically its hyperphosphorylation, disrupts microtubule stability and contributes to neuronal dysfunction. Various post-translational modifications of tau drive its aggregation into NFTs. Emerging treatments targeting tau, such as GSK-3ß and CDK5 inhibitors, have shown promise in preclinical and clinical studies. Restoring the equilibrium between protein kinases and phosphatases, notably protein phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily regulated by its phosphorylation state. Activation of tau-specific phosphatases offers potential for mitigating tau pathology. The evolving landscape of AD drug development emphasizes tau-centric therapies and reevaluation of the amyloid cascade hypothesis. Additionally, exploring the role of neuroinflammation and its interaction with tau pathology present promising research directions.

Molecular interactions of dioxins and DLCs with the xenosensors (PXR and CAR): An in silico risk assessment approach.

Dioxins and dioxin-like compounds (DLCs) are known to cause endocrine disruption in humans and animals. Being lipophilic xenobiotic chemicals, they can be easily absorbed into the biological system from the surrounding environments, thereby causing various health dysfunctions. In the present study, a total of 100 dioxins and DLCs were taken, and their binding pattern was assessed with the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in comparison with the corresponding known inhibitors and a well-studied endocrine disrupting xenobiotic, bisphenol A (BPA). The nuclear receptors CAR and PXR are known to play a significant role in handling potential toxins by coordinating cellular transport and metabolic functions of the same. Among different endocrine-disrupting chemicals used in the present study, DLCs (PCDFs and PCBs) elicited better interactions in comparison with the parent dioxin (polychlorinated dibenzodioxins) compounds. On comparing D scores of all the compounds against both the receptors, PCDF 8-hydroxy-3,4-dichlorodibenzofuran (8-OH-DCDF) and PCB tetrachlorobenzyltoluene (TCBT) exhibited significant molecular interactions against PXR (-7.633 kcal mol-1 ) and CAR (-8.389 kcal mol-1 ), respectively. Predominant interactions were found to be H-bonding, π-π stacking, hydrophobic, polar, and van der Waals. By contrast, BPA and some natural ligands tested in this study showed lower binding affinities with these receptors than certain DLCs reported herein, ie, certain DLCs might be more toxic than the proven toxic agent, BPA. Such studies play a pivotal role in the risk assessment of exposure to dioxins and DLCs on human health.

Targeting oncogenic kinases: Insights on FDA approved tyrosine kinase inhibitors.

Protein kinases play pivotal roles in various biological functions, influencing cell differentiation, promoting survival, and regulating the cell cycle. The disruption of protein kinase activity is intricately linked to pathways in tumor development. This manuscript explores the transformative impact of protein kinase inhibitors on cancer therapy, particularly their efficacy in cases driven by targeted mutations. Focusing on key tyrosine kinase inhibitors (TKIs) like Bcr-Abl, Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR), it targets critical kinase families in cancer progression. Clinical trial details of these TKIs offer insights into their therapeutic potentials. Learning from FDA-approved kinase inhibitors, the review dissects trends in kinase drug development since imatinib's paradigm-shifting approval in 2001. TKIs have evolved into pivotal drugs, extending beyond oncology. Ongoing clinical trials explore novel kinase targets, revealing the vast potential within the human kinome. The manuscript provides a detailed analysis of advancements until 2022, discussing the roles of specific oncogenic protein kinases in cancer development and carcinogenesis. Our exploration on PubMed for relevant and significant TKIs undergoing pre-FDA approval phase III clinical trials enriches the discussion with valuable findings. While kinase inhibitors exhibit lower toxicity than traditional chemotherapy in cancer treatment, challenges like resistance and side effects emphasize the necessity of understanding resistance mechanisms, prompting the development of novel inhibitors like osimertinib targeting specific mutant proteins. The review advocates thorough research on effective combination therapies, highlighting the future development of more selective RTKIs to optimize patient-specific cancer treatment and reduce adverse events.

In silico Approaches for Exploring the Pharmacological Activities of Benzimidazole Derivatives: A Comprehensive Review.

BACKGROUND: This article reviews computational research on benzimidazole derivatives. Cyotoxicity for all compounds against cancer cell lines was measured and the results revealed that many compounds exhibited high inhibitions. This research examines the varied pharmacological properties like anticancer, antibacterial, antioxidant, anti-inflammatory and anticonvulsant activities of benzimidazole derivatives. The suggested method summarises in silico research for each activity. This review examines benzimidazole derivative structure-activity relationships and pharmacological effects. In silico investigations can anticipate structural alterations and their effects on these derivative's pharmacological characteristics and efficacy through many computational methods. Molecular docking, molecular dynamics simulations and virtual screening help anticipate pharmacological effects and optimize chemical design. These trials will improve lead optimization, target selection, and ADMET property prediction in drug development. In silico benzimidazole derivative studies will be assessed for gaps and future research. Prospective studies might include empirical verification, pharmacodynamic analysis, and computational methodology improvement. OBJECTIVES: This review discusses benzimidazole derivative in silico research to understand their specific pharmacological effects. This will help scientists design new drugs and guide future research. METHODS: Latest, authentic and published reports on various benzimidazole derivatives and their activities are being thoroughly studied and analyzed. RESULT: The overview of benzimidazole derivatives is more comprehensive, highlighting their structural diversity, synthetic strategies, mechanisms of action, and the computational tools used to study them. CONCLUSION: In silico studies help understand benzimidazole derivative SAR. By meticulously altering substituents, ring modifications, and linker groups, this study identified the structural factors that affect the pharmacological activity of benzimidazole derivatives, enabling the rational design and optimization of more potent and selective compounds.

Quinoline Derivatives as Promising Scaffolds for Antitubercular Activity: A Comprehensive Review.

BACKGROUND: Heterocyclic compounds and their derivatives play a significant role in the design and development of novel quinoline drugs. Among the various pharmacologically active heterocyclic compounds, quinolines stand out as the most significant rings due to their broad pharmacological roles, specifically antitubercular activity, and their presence in plant-based compounds. Quinoline is also known as benzpyridine, benzopyridine, and 1-azanaphthalene. It has a benzene ring fused with a pyridine ring, and both rings share two carbon atoms. The importance of quinoline lies in its incorporation as a key component in various natural compounds found in medicinal plant families like Fumariaceae, Berberidaceae, Rutaceae, Papavaraceae, and others. OBJECTIVE: This article is expected to have a significant impact on the advancement of effective antitubercular drugs. Through harnessing the potent activity of quinoline derivatives, the research aims to make valuable contributions to combating tuberculosis more efficiently and ultimately reducing the global burden of this infectious disease. METHODS: Numerous nitrogen-containing heterocyclic compounds exhibit significant potential as antitubercular agents. These chemicals have fused aromatic nitrogen-heterocyclic nuclei that can change the number of electrons they have, which can change their chemical, physical, and biological properties. This versatility comes from their ability to bind with the receptors in multiple modes, a critical aspect of drug pharmacological screening. Among these compounds, quinoline stands out as it incorporates a stable fusion of a benzene ring with a pyridine nucleus. Quinolines have demonstrated a diverse range of pharmacological activities, including but not limited to anti-tubercular, anti-tumor, anticoagulant, anti-inflammatory, antioxidant, antiviral, antimalarial, anti-HIV, and antimicrobial effects. RESULTS: Some molecules, such as lone-paired nitrogen species, include pyrrole, pyrazole, and quinoline. These molecules contain nitrogen and take part in metabolic reactions with other molecules inside the cell. However, an excessive accumulation of reactive nitrogen species can lead to cytotoxicity, resulting in damage to essential biological macromolecules. Among these compounds, quinoline stands out as the oldest and most effective one, exhibiting a wide range of significant properties such as antitubercular, antimicrobial, anti-inflammatory, antioxidant, analgesic, and anticonvulsant activities. Notably, naturally occurring quinoline compounds, such as quinine, have proven to be potent antimalarial drugs. CONCLUSION: This review highlights quinoline derivatives' antitubercular potential, emphasizing recent research advancements. Utilizing IC50 values, the study emphasizes the efficacy of various quinoline substitutions, hybrids, and electron-withdrawing groups against MTB H37Rv. Continued research is essential for developing potent, low-toxicity quinoline derivatives to combat tuberculosis.

Anti-inflammatory and antimicrobial activity of 4,5-dihydropyrimidine-5-carbonitrile derivatives: their synthesis and spectral elucidation.

Thirteen new 6-(1-H-indole-2-yl)-4-oxo-2-[2-(substituted-benzylidene)-hydrazinyl]-4,5-dihydropy-rimidine-5-carbonitrile derivatives were synthesized. The title compounds, hydrazones, were synthesized by reaction of hydrazine group of 2-hydrazinyl-4-(1-H-indole-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2) with different substituted aromatic aldehydes using a mixture (2:8, v/v) of glacial acetic acid and alcohol. The required intermediate compound 2 was synthesized from 2-mercapto-4-(1-H-indole-2-yl)-6-oxo-1,6-dihy-dropyrimidine-5-carbonitrile 1 upon nucleophilic attack by the hydrazine hydrate. Compound 1 was synthesized by modified Biginelli condensation method using indole-3-carbaldehyde, ethyl cyanoacetate and thiourea. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and antimicrobial actions. Among the newer derivatives, one compound i.e., 6-(1-H-indole-2-yl)-4-oxo-2-[2-(2,6-dichlorobenzylidene)-hydrazinyl]-4,5-dihydropyrimidine-5-carbonitrile (7) emerged as lead compound having 71.14% inhibition of edema and 12.5 microg/mL MIC against both bacterial and fungal strains.

Therapeutic Journey and Recent Advances in the Synthesis of Coumarin Derivatives.

BACKGROUND: Coumarin is an oxygen-containing compound in medicinal chemistry. Coumarin plays an important role in both natural systems like plants and synthetic medicinal applications as drug molecules. Many structurally different coumarin compounds have been found to possess a wide range of similarities with the vital molecular targets in terms of their pharmacological action and small modifications in their structures, resulting in significant changes in their biological activities. OBJECTIVE: This review provides detailed information regarding the studies focused on the recent advances in various pharmacological aspects of coumarins. METHODS: Various oxygen-containing heterocyclic compounds represent remarkable biological significance. The fused aromatic oxygen-heterocyclic nucleus can change its electron density, thus altering the chemical, physical and biological properties, respectively, due to its multiple binding modes with the receptors, which play a crucial role in the pharmacological screening of drugs. Several heterocyclic compounds have been synthesized which have their nuclei derived from various plants and animals. In coumarins, the benzene ring is fused with a pyrone nucleus which provides stability to the nucleus. Coumarins have shown a wide range of pharmacological activities, such as anti-tumor, anticoagulant, anti-inflammatory, anti-oxidant, antiviral, antimalarial, anti-HIV, antimicrobial, etc. Results: Reactive oxygen species, like superoxide anion, hydroxyl radical, and hydrogen peroxide, are a type of unstable molecule containing oxygen, which reacts with other molecules in the cell during metabolism; however, when the number of reactive oxygen species increases, it may lead to cytotoxicity, thereby damaging the biological macromolecules. Hydroxyl Radical (OH) is a strong oxidizing agent and it is responsible for the cytotoxicity caused by oxygen in different plants, animals, and other microbes. Coumarin is the oldest and effective compound having antimicrobial, anti-inflammatory, antioxidant, antidepressant, analgesic, anticonvulsant activities, etc. Naturally existing coumarin compounds act against SARS-CoV-2 by preventing viral replication and targeting the active site against the Mpro target protein. CONCLUSION: This review highlights the different biological activities of coumarin derivatives. In this review, we provide an updated summary of the researches which are related to recent advances in biological activities of coumarins analogs and their most recent activities against COVID -19. Natural compounds act as a rich resource for novel drug development against various SARS-CoV-2 viral strains and viruses, like herpes simplex virus, influenza virus, human immunodeficiency virus, hepatitis B and C viruses, middle east respiratory syndrome, and severe acute respiratory syndrome.

Biological and medicinal application of Cucumis sativus Linn. - review of current status with future possibilities.

OBJECTIVES: The increasing demand for herbal drugs for the human application is causing a growing demand for the cultivation of Medicinal Plants. This demand has developed because of cost-effective, plant-derived products rather than commercially available synthetic drugs. Cucumis sativus Linn. (Ver. Kheera) is a vegetable climber, species belongs to family Cucurbitaceae This species has a wide range of medicinal and biological applications thanks to its richness in carbohydrate, proteins, minerals (calcium, iron, magnesium, phosphorus, potassium, zinc) and secondary metabolites like alkaloids, tannins, flavonoids, saponins, and phenolic compounds These phytoconstituents may be responsible for allied therapeutic application. So, C. sativus possess wider applications for preventing certain ailments. CONTENT: The literature in various national and international journals and reports pertaining to the medicinal and nutritional uses were reviewed. The result revealed the current therapeutic applications of C. sativus whole plants other than the nutritional value. C. sativus pharmacological action includes antioxidant, anti-diabetic, UV protectant, hepatoprotective, gastroprotective, anti-helminthic, wound healing, antimicrobial, and anticancer. So, it could be useful for both preventive and additive therapy along with modern medicine for the better management of certain disorders. SUMMARY AND OUTLOOK: This review furnishes updated information about the phytoconstituents and their medicinal applications so that it can pose a path for the young researchers to do future findings.

2(3H)-furanones and 2(3H)-pyrrolones: synthesis and antimycobacterial evaluation.

A series of 3-arylidene-5-(substituted phenyl)-2(3H)-furanones (3-10) and their nitrogen analogues, 3-arylidene-5-(substituted phenyl)-1-benzyl-2(3H)-pyrrolone (11-14), and 3-arylidene-5-(substituted phenyl)-2(3H)-pyrrolones (15-21) were synthesized. All the compounds were screened for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv (ATCC 27294) in BACTEC medium using the Microplate Alamar Blue Assay (MABA). Among the synthesized compounds, compound 19, 3-(4-chlorobenzylidene)-5-(4-methylphenyl)-2(3H)-pyrrolone, emerged as a lead compound having the highest activity against Mycobacterium tuberculosis. The antimycobacterial activity was found to improve upon replacement of oxygen of furanone ring with nitrogen atom (pyrrolones), however, substitution with benzylamine moiety (1-benzylpyrrolones) markedly decreases the activity.

Dibenzepinones, dibenzoxepines and benzosuberones based p38α MAP kinase inhibitors: Their pharmacophore modelling, 3D-QSAR and docking studies.

In the present study, a series of dibenzepinones, dibenzoxepines, and benzosuberones targeting p38α MAP kinase were subjected to pharmacophore modelling, 3D-QSAR and molecular docking studies. The IC50 values for these 67 compounds ranged between 0.003 and 6.80 µM. A five-point model (DDHHR.8) was generated using these compounds. This model was found to be statistically significant and was found to have high correlation (R2 = 0.98), cross-validation coefficient (Q2 = 0.95) and F (330) values at six component PLS factor. Tests were performed to ascertain the efficacy of the generated model. These tests included external validation, Tropsha's test for predictive ability, Y-randomisation test and domain of applicability (APD). In order to check the restrictivity of the model, enrichment studies were performed with inactive compounds by using decoy set molecules. To evaluate the effectiveness of the docking protocol, the co-crystallised ligand was extracted from the ligand-binding domain of the protein and was re-docked into the same position. Both the conformers were then superimposed, suggesting satisfactory docking parameters with an RMSD value of less than 1.0 Š(0.853 Å). A 10 ns molecular dynamics simulation confirmed the docking results of the 3UVP-ligand complex and the presumed active conformation. The outcome of the present study provides insight into the molecular features that promote bioactivity and can be exploited for the prediction of novel potent p38α MAP kinase inhibitors before carrying out their synthesis and anticancer evaluation.

Revealing quinquennial anticancer journey of morpholine: A SAR based review.

Morpholine, a six-membered heterocycle containing one nitrogen and one oxygen atom, is a moiety of great significance. It forms an important intermediate in many industrial and organic syntheses. Morpholine containing drugs are of high therapeutic value. Its wide array of pharmacological activity includes anti-diabetic, anti-emetic, growth stimulant, anti-depressant, bronchodilator and anticancer. Multi-drug resistance in cancer cases have emerged in the last few years and have led to the failure of many chemotherapeutic drugs. Newer treatment methods and drugs are being developed to overcome this problem. Target based drug discovery is an effective method to develop novel anticancer drugs. To develop newer drugs, previously reported work needs to be studied. Keeping this in mind, last five year's literature on morpholine used as anticancer agents has been reviewed and summarized in the paper herein.