Monoamine oxidase (MAO) inhibitors are widely used to treat neurological disorders, including Parkinson's disease and depression, by increasing and prolonging dopamine activity. In this study, fourteen isatin-based derivatives from phenyl substituted thiosemicarbazone (IT) and semicarbazone (ISZ) sub-series were synthesized and evaluated for MAO inhibition. Most compounds showed higher MAO-B selectivity, with ISZ9 being the most potent MAO-B inhibitor (IC50 = 0.016 mu M), surpassing safinamide (IC50 =0.021 mu M) and pargyline (IC50 =0.14 mu M). In the IT series, IT20 (IC50 = 0.162 mu M) also exhibited strong MAO-B inhibition. For MAO-A, ISZ12 (IC50 = 0.17 mu M) was the most potent inhibitor. ISZ8 had the highest selectivity index (SI = 962.33). Kinetic studies confirmed competitive and reversible inhibition, with ISZ9 and IT20 targeting MAO-B, while ISZ12 inhibited MAO-A. ISZ9 showed blood-brain barrier permeability, was non-toxic, and improved behavioral parameters and dopamine levels in rotenone-treated Drosophila. Docking and molecular dynamics studies revealed that ISZ9 stably binds MAO-B via hydrogen bonds (Tyr326, Ile198) and it-it stacking (Phe343), supporting its potential for neuroprotective therapy.

Neurodegenerative disorders such as Parkinson's disease are closely associated with dysregulated activity of monoamine oxidase-B (MAO-B), which leads to dopamine depletion and oxidative stress. Despite the availability of numerous monoamine oxidase (MAO) inhibitors on the market, their irreversibility and associated side effects necessitate the development of more effective and reversible MAO-B inhibitors. In this study, a series of twenty-one indole-based derivatives (PSH1-PSH21), collectively designated as PSH, was synthesised and evaluated for inhibitory activity against MAO isoforms. Most synthesised compounds showed higher inhibitory activity toward MAO-B than MAO-A, indicating selectivity for MAO-B. Among the PSH derivatives, PSH18 exhibited the most potent MAO-B inhibitory activity (IC50 = 0.95 ± 0.02 µM), followed by PSH6 (IC50 = 1.79 ± 0.40 µM) and PSH2 (IC50 = 1.96 ± 0.08 µM). Compound PSH18 showed the highest selectivity index value of 42.11, followed by PSH6 (22.35) and PSH2 (20.41). Additionally, PSH18 was confirmed to be a competitive and reversible inhibitor of MAO-B with an inhibition constant value of 0.89 ± 0.035 µM. Notably, PSH18 exhibited good permeability across the blood-brain barrier in parallel artificial membrane permeability assay experiments, along with acceptable absorption, distribution, metabolism, excretion, and toxicity parameters predicted through in silico modelling, suggesting its potential as a central nervous system-targeted molecule. Molecular docking and a 200 ns molecular dynamics simulation demonstrated stable binding of the ligand to the MAO-B active-site pocket, driven by hydrophobic and π-π stacking interactions with key amino acid residues lining the aromatic cage. Moreover, the calculated binding energy indicated strong ligand-protein interactions. Overall, these results indicate that the PSH scaffold could serve as a promising lead structure for the development of potent and selective MAO-B inhibitors. These compounds may have therapeutic potential for the treatment of neurodegenerative diseases.

Multi-target drug design (MTDD) represents the paradigm shift in pharmaceutical research, moving beyond the conventional one-drug-one-target approach to address the complexity of multifactorial diseases. This strategy aims to develop single therapeutic candidates that can simultaneously modulate multiple biological targets, offering more comprehensive disease management and reducing the likelihood of drug resistance. In this article, we highlighted the design, synthesis, and structure-activity relationships (SARs) of various dual acting inhibitors involved in treatment of neurodegenerative diseases. Dual acting inhibitors targeting carbonic anhydrases (CAs), monoamine oxidases (MAOs), and cholinesterases (ChEs) have emerged as promising therapeutic agents due to their potential in treating complex neurodegenerative and psychiatric disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). By integrating CA inhibitors with MAO and ChE inhibition, researchers aim to address both the neuroprotective and symptomatic aspects of these disorders. The review also discusses key SAR studies that have guided the optimization of dual inhibitors, focusing on achieving selectivity and potency while minimizing off-target effects. From a medicinal chemistry perspective, the dual inhibition approach offers advantages such as improved efficacy, reduced polypharmacy, and better management of disease progression. However, challenges remain, including maintaining selectivity for target isoforms and overcoming pharmacokinetic limitations. Overall, the development of dual-acting CA-MAO-ChE inhibitors represents a compelling avenue in drug discovery, with the potential to significantly impact the treatment of neurodegenerative diseases.

Background: The low solubility and poor skin permeability of sulfasalazine (SLZ) present significant challenges for its effective topical delivery. The objective of the current investigation is to formulate a hydrogel-based SLZ-loaded cyclodextrin nanosponge for topical therapy in psoriasis. Methods: SLZ-loaded nanosponges were prepared by the melt polymerization method and evaluated for physiochemical characteristics, drug release, and cytocompatibility. The selected nanosponges (SLZ-NS4) were transformed to hydrogel and further evaluated for rheology, texture, safety, skin permeability, and in vivo for anti-psoriatic effect in mouse tail and imiquimod-induced psoriasis-like inflammation models in mice. Results: Physiochemical data confirms nanoscale architecture, drug inclusion in nanosponges, crystalline structure, and formulation stability. The release profile of SLZ-NS4 revealed sustained release behavior (22.98 ± 2.24% in 3 h). Cytotoxicity assays indicated negligible toxicity against THP1 cells, resulting in higher viability of cells than pure SLZ (p < 0.05). The HET-CAM assay confirmed the safety, while confocal laser scanning microscopy demonstrated deeper skin permeation of SLZ. In the mouse tail model, a remarkable decline in relative epidermal thickness, potential improvement in percent orthokeratosis, and drug activity with respect to control was observed in animals treated with SLZ-NS4 hydrogel. The efficiency of the developed SLZ-NS4-loaded hydrogel in treating psoriasis was confirmed by the decline in PASI score (81.68 ± 3.61 and 84.86 ± 5.74 with 1 and 2% w/v of SLZ-NS-HG). Histopathological analysis and assessment of oxidative stress markers revealed the profound anti-psoriatic potential of the fabricated SLZ-NS4 hydrogel. Conclusions: These findings highlight the profound potential of the developed delivery system as an effective topical therapy for psoriasis.

The present work aimed to prepare and evaluate novel capsaicin (CAP) loaded nanosponges (NS) embedded Carbopol hydrogel (CAPNS-HG) with rosemary oil (RO) for arthritis management. CAP loaded NS were formulated using melt technique employing diphenylcarbonate and β-cyclodextrin. To facilitate their dermal application, CAPNS were integrated with Carbopol 934 hydrogel using RO as a permeation enhancer. Nanogel samples so formed were analyzed for physicochemical and rheological properties, followed by their in vitro, ex vivo, and in vivo evaluations. Based on the findings herein, CAPNS-HG was found to exhibit favorable rheological characteristics (610.56 cP), effective skin permeation (31.410 ± 1.145 µg/cm2), and delayed-release (61.91

Monoamine oxidases are the enzymes involved in the management of brain homeostasis through oxidative deamination of monoamines such as neurotransmitters, tyramine etc. The excessive production of monoamine oxidase-B specifically results in numerous neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Inhibitors of monoamine oxidase-B are applied in the management of these disorders. Here in this article we have developed robust hybrid descriptor based QSAR models related to 123 monoamine oxidase-B inhibitors through CORAL software by means of Monte Carlo optimization method. Three target functions were applied to prepare QSAR models and three splits were made for each target function. The most reliable, robust and better predictive QSAR models were developed with TF3 (correlation intensity index -index of ideality of correlation). Correlation intensity index showed positive effect on QSAR models. The structural features obtained from the QSAR modeling were incorporated in newly designed molecules and exhibited positive effect on their endpoint. Significant binding interactions were represented by these molecules in docking studies. Molecule B5 displayed prominent pIC50 (8.3) and binding affinity (-11.5 kcal mol-1) towards monoamine oxidase-B.

At different times in life, people have different views on aging. As a process, aging not only affects the medical and economic levels at the individual level but also at the social and national levels. Aging is a natural process, but its standard definition in the healthcare field is unclear. Delaying the Aging process and maintaining a high quality of life until old age are the two most important goals. Various healthcare methods are being considered and tested to best regard aging as a disease. Nutritious food is a value-added dietary supplement product which has great potential to change the key structure and function of aging. Nutritional health products can be the key to changing the physiological and metabolic system abnormalities caused by aging. Nutraceuticals for Aging and anti-aging: Basic understanding and clinical evidence are based on 10 main challenges to address aging and anti-aging nutritional drugs, such as cognitive health, malnutrition, drug abuse, bladder control, and oral health. It explores how to supplement these challenges with nutritious foods and connects the application to the traditional 2wisdom of the aging process. The purpose of this chapter is to elucidate the significance of anti-aging dietary components and go over current views on ageing. Additionally, it discusses the function of anti-aging nutrients, how dietary requirements change as people age, issues with diet quality among the ageing population, and senior people's eating habits.

Psoriasis is a chronic immune-mediated skin disorder, induced by aberrant activation of dendritic cells, followed by modifications in the immune cells (skin) and keratinocytes (epidermis). Previously, to enhance the poor aqueous solubility and photostability, and to enhance preclinical antipsoriatic performance, clobetasol propionate–loaded cyclodextrin nanosponges (CPNS) were fabricated and, subsequently, embedded in Carbopol hydrogel. Pharmacotechnological evaluation, cytocompatibility studies, and in vivo antipsoriatic assay in mouse tail model advocated the significance of the fabricated delivery system for psoriasis. The current study is an extension work to assess the targeting potential of CPNS hydrogel via confocal laser scanning microscopy (CLSM) to skin strata. Further, to validate the safety of this novel formulation, in vitro skin irritation was performed using the HET-CAM (hen’s egg-chorioallantoic membrane) assay. The results of this study indicated no change in skin barrier function and no sign of erythema or irritation, suggesting the safety of prepared hydrogel for topical application. In vivo antipsoriatic studies were carried out using an imiquimod-induced mouse model to further validate the previous findings. Altogether, the results of phenotypic, histopathological, and biochemical estimations of the current investigation substantiated the profound antipsoriatic potential and safety of CP-loaded nanosponge hydrogel.

A new series of benzenesulfonamide derivatives, namely N-(1-(2-chloropyrimidin-4-yl)-1[Formula: see text]-indazol-5-yl) compounds (4a-i) and N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1[Formula: see text]-indazol-5-yl) derivatives (5a-i), were synthesized. This was achieved by reducing 1-(2-halopyrimidin-4-yl)-5-nitro-1[Formula: see text]-indazole (3) with SnCl 2 , followed by reacting with various aryl sulphonyl chlorides in pyridine. Structural confirmation was carried out through IR, 1H-NMR, [Formula: see text]C-NMR and mass spectral methods. Anticancer activity evaluation of compounds 4a-i and 5a-i revealed that N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1H-indazol-5-yl)-2-nitrobenzenesulfonamide (5b) displayed exceptional efficacy. Molecular dynamics simulations were employed to rigorously assess the stability of ligand–protein complexes, highlighting a consistent and robust binding of the most potent compound within the binding sites of target proteins. The results unequivocally affirmed the remarkable anticancer activity, supported by comprehensive molecular docking analyses uncovering intricate interactions involving hydrogen bonds, electrostatic forces and hydrophobic contacts. These findings collectively offer invaluable insights into the complex molecular structure and dynamics of receptor target sites, establishing a robust foundation for the development of novel and potent anticancer agents with promising pharmaceutical implications.

Many scientists and researchers have published their work on the analysis of pesticides in biological as well as, non-biological matrices and their toxicokinetics using different separation techniques and detection procedures but no study gives a direct indication towards any “one” method or technique to carry out the procedure more effectively and efficiently. This review provides comprehensive information regarding variant bioanalytical techniques, their sensitivity, precision, and accuracy to determine the most efficient bioanalysis method for multiple pyrethroids. Since, these insecticides are extensively used in various sectors that lead to an extravagant exposure to humans, animals, and aquatic life, necessarily be showing some toxicities. These toxicities raise the need to monitor their toxicokinetics and assess the risks caused by cumulative as well as single pyrethroidal exposure. After carrying out the comparative study of the above mentioned parameters, it is evident that solid phase extraction procedure gives high percent recovery with minimum matrix interferences when analysed with LC-MS/MS for few pyrethroids residing in brain, whereas liquid-liquid extraction with GC-MS-NCI technique is reported to be most sensitive to quantitate a wide range of pyrethroids accumulating in blood and serum. This study can aid a reader or an analyst to understand different analytical procedures and to develop and optimize better determination techniques for pyrethroids to monitor their exposure and resulting effects.

Natural plants and their products continue to be the major source of phytoconstituents in food and therapeutics. Scientific studies have evidenced the benefits of sesame oil and its bioactives in various health conditions. Various bioactives present in it include sesamin, sasamolin, sesaminol, and sesamol; among these, sesamol represents a major constituent. This bioactive is responsible for preventing various diseases including cancer, hepatic disorders, cardiac ailments, and neurological diseases. In the last decade, the application of sesamol in the management of various disorders has attracted the increasing interest of the research community. Owing to its prominent pharmacological activities, such as antioxidant, antiinflammatory, antineoplastic, and antimicrobial, sesamol has been explored for the above-mentioned disorders. However, despite the above-mentioned therapeutic potential, its clinical utility is mainly hindered owing to low solubility, stability, bioavailability, and rapid clearance issues. In this regard, numerous strategies have been explored to surpass these restrictions with the formulation of novel carrier platforms. This review aims to describe the various reports and summarize the different pharmacological activities of sesamol. Furthermore, one part of this review is devoted to formulating strategies to improve sesamol’s challenges. To resolve the issues such as the stability, low bioavailability, and high systemic clearance of sesamol, novel carrier systems have been developed to open a new avenue to utilize this bioactive as an efficient first-line treatment for various diseases.

The Health and environmental hazards of benzene and nitrobenzene (NB) derivatives have remained a topic of interest of researchers. In silico methods for prediction of toxicity of chemicals have proved their worth in accurate forecast of environmental as well as health toxicity and are strongly recommended by regulatory authorities. Two quantitative structure-toxicity relationship (QSTR) models explaining Scenedesmus obliquus toxicity trends among 39 benzene derivatives and Tetrahymena pyriformis toxicity of 103 NB and 392 benzene derivatives are developed using semiempirical quantum chemical parameters. The best constructed QSTR models have good fitting ability (R2 = 0.8053, 0.7591, and 0.8283) and robustness (Q2LOO = 0.7507, 0.7227, and 0.8194; Q2LMO = 0.7338, 0.7153, and 0.8172). The external predictivity of all the models are quite good (R2EXT = 0.8256, 0.9349, and 0.8698). Electronegativity, Cosmo volume, total energy, and molecular weight are responsible for the increase and decrease of toxicity of benzene derivatives against S. obliquus while electronegativity, electrophilicity index, the heat of formation, total energy, hydrophobicity, and cosmo volume are responsible for modulation of toxicity of NB and benzene derivatives toward T. pyriformis. These models fulfill the requirements of all the five OECD principles.

A new series of N-(1-(2-chloropyrimidin-4-yl)-1H-indazol-5-yl) benzenesulfonamide derivatives (4 a-i) and N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1H-indazol-5-yl) benzenesulfonamide derivatives (5 a-i) was synthesized via reduction of 1-(2-halopyrimidin-4-yl)-5-nitro-1H-indazole (3) with SnCl2 followed by reaction with various aryl sulphonyl chlorides in pyridine. The structures were confirmed using IR, 1H-NMR, 13C-NMR, and mass spectral methods. Compounds 4 a-i and 5 a-i were evaluated for antifungal and antibacterial activities against Gram-negative and Gram-positive bacteria. They also exhibited antioxidant potential in DPPH (IC50=0.094-0.467 mu mol/ml) and ABTS assays (IC50=0.101-0.496 mu mol/ml). Remarkably, N-(1-(2-chloropyrimidin-4-yl)-1H-indazol-5-yl)-2-nitrobenzenesulfonamide displayed the highest antibacterial activity, while N-(1-(2-chloropyrimidin-4-yl)-1H-indazol-5-yl)-4-methoxybenzenesulfonamide showed excellent antifungal potential. Compound N-(1-(2-chloropyrimidin-4-yl)-1H-indazol-5-yl)-2-nitrobenzenesulfonamide exhibited the most significant antioxidant activity. In this study, molecular dynamics simulations were utilized to rigorously examine the stability of ligand-protein complexes, demonstrating a consistent and robust binding of the most potent compound within the target proteins ' binding sites. Computational assessments were further employed to predict the drug-likeness and ADMET properties of the synthesized compounds. The results unequivocally confirmed the remarkable antioxidant and antimicrobial potential of all derivatives, a finding substantiated by comprehensive molecular docking analyses that revealed intricate interactions involving hydrogen bonds, electrostatic forces, and hydrophobic contacts. These findings collectively provide invaluable insights into the complex molecular structure and receptor target site dynamics, laying a strong foundation for the development of novel active antioxidant and antimicrobial agents with promising pharmaceutical implications. Discovering the remarkable antioxidant and antimicrobial potential of N-(1-(2-chloropyrimidin-4-yl)-1H-indazol-5-yl) benzenesulfonamide derivatives. Compound 4 b showcases potent antioxidant effects and multi-pronged antimicrobial interactions, paving the way for innovative therapies.image

N-Heterocycles stand out in medicinal chemistry as significant pharmacophores because of their wide biological potential and structural diversity. In this perspective, we have synthesized a new series of isatin-semicarbazone linked acetamide triazole hybrids via CuAAC reaction with an aim of obtaining a series with tractable SAR and antimicrobial potencies better than the existing antimicrobial agents. All derivatives were structurally charac-terized using FT-IR, 1H NMR, 13C NMR, HRMS and tested their antimicrobial efficacy against various microbial species. Among the synthesized series compound 7d exhibited highest potency against E. coli with MIC of 0.0108 mu mol/mL, while 6b displayed highest efficacy towards A. niger with MIC of 0.0072 mu mol/mL. Further, in order to find out the interactions of synthesized triazoles within the active sites of 1KZN and 5TZ1, molecular docking was performed. Results of the molecular docking were found in agreement with the in vitro antimicrobial study results.

In the present study, a series of 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were synthesized, characterized and evaluated for theirin vitroactivity, i. e., antimicrobial, antioxidant and anti-inflammatory. The target compounds were synthesized by condensation reaction of 3-hydroxy-2-naphthoic acid hydrazide with substituted benzaldehydes which were subjected to cyclization reaction with thioglycolic acid and ZnCl2 to get target compounds. The synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were examined for their antimicrobial activity and 3-hydroxy-N-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-yl)-2-naphthamide (S20) exhibited the highest antimicrobial potential. The N '-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide (S5) displayed good antifungal potential against Rhizopus oryzae, whereas N '-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide (S20) showed the highest antioxidant potential and N-(2-(2,6-dichlorophenyl)-4-oxothiazolidin-3-yl)-3-hydroxy-2-naphthamide (S16) displayed the highest anti-inflammatory activity. The results of molecular docking studies revealed that existence of hydrogen bonding and hydrophobic interactions with their respective proteins. In silico ADMET studies were carried out by Molinspiration, Pre-ADMET and OSIRIS property explorer to predict the pharmacokinetic behaviour of synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives.

Background Dithranol, a standard drug for psoriasis, has lured keen attention by virtue of its antioxidant, anti-proliferative and anti-inflammatory activities. However, its poor stability and solubility critically impair the formulation design, evaluation and administration. To improve these issues, dithranol was encased in β-cyclodextrin nanosponges using solvent evaporation technique. Previously, nanosponges containing dithranol were developed in our laboratory using melt technique. Herein, a comparison of nanosponges prepared by both techniques was also included. Results Different nanosponge batches were engineered using diphenyl carbonate as cross-linker with β-cyclodextrin as polymer employing solvent evaporation technique. Dithranol was loaded in nanosponges via lyophilization. Fourier transform infrared spectroscopy, differential scanning colorimeter and powdered X-ray diffraction studies confirmed successful encapsulation and complexation of this drug in β-cyclodextrin nanosponges. The effect of a variable amount of cross-linker on the solubility, encapsulation efficiency, zeta potential, particle size and polydispersity index was evaluated in fabricated nanocarriers. Further, β-cyclodextrin nanosponge batches were subjected to solubility studies, photostability examination and antioxidant activity analysis and compared with previously prepared dithranol-loaded nanosponges. From the present studies results, it was concluded that dithranol-loaded nanosponges using solvent evaporation technique not only improved solubility and photostability but also preserved the antioxidant efficacy of the chosen drug. Conclusion The overall results emphasized moral guidance concerning encapsulation, evaluation and characterization and accredited dithranol solubilization, photostability and antioxidant potential. However, solvent evaporation and melt method are easy and promising methods to fabricate nanosponges for dithranol. This comparative study demonstrated the parameters which were affected by chosen techniques. Further, from the results of present studies, it was concluded that the formulation scientists should select the preparation technique based on the objective of their research work and requirement of desired features. Graphical abstract

The rising possibilities of quantum dots in biological fields have raised significant concerns about their toxicological influence, and there is a requirement of methods for prediction of toxic quantum dots. In the current research work, quantitative feature toxicity relationship models for HEK cells cytotoxicity of forty one CdSe/CdTe/CdZnS core quantum dots as a function of their size, surface ligand, ligand chemical, charge, surface modification, assay type and quantum dot concentration have been developed. The models are constructed by using quasiSMILES representation symbolizing the experimental conditions and molecular architecture of the quantum dots. The index of ideality of correlation helps in the building of eight statistically significant, robust and predictive models using Monte Carlo optimization. The results are used successfully for extraction of features causing an increase and decrease of cytotoxicity of quantum dots.