Synthesis, Anticancer Activity, and In Silico Studies of 5-(3-Bromophenyl)-N-aryl-4H-1,2,4-triazol-3-amine Analogs.

In the current study, we described the synthesis of ten new 5-(3-Bromophenyl)-N-aryl-4H-1,2,4-triazol-3-amine analogs (4a-j), as well as their characterization, anticancer activity, molecular docking studies, ADME, and toxicity prediction. The title compounds (4a-j) were prepared in three steps, starting from substituted anilines in a satisfactory yield, followed by their characterization via spectroscopic techniques. The National Cancer Institute (NCI US) protocol was followed to test the compounds' (4a-j) anticancer activity against nine panels of 58 cancer cell lines at a concentration of 10-5 M, and growth percent (GP) as well as percent growth inhibition (PGI) were calculated. Some of the compounds demonstrated significant anticancer activity against a few cancer cell lines. The CNS cancer cell line SNB-75, which showed a PGI of 41.25 percent, was discovered to be the most sensitive cancer cell line to the tested compound 4e. The mean GP of compound 4i was found to be the most promising among the series of compounds. The five cancer cell lines that were found to be the most susceptible to compound 4i were SNB-75, UO-31, CCRF-CEM, EKVX, and OVCAR-5; these five cell lines showed PGIs of 38.94, 30.14, 26.92, 26.61, and 23.12 percent, respectively, at 10-5 M. The inhibition of tubulin is one of the primary molecular targets of many anticancer agents; hence, the compounds (4a-j) were further subjected to molecular docking studies looking at the tubulin-combretastatin A-4 binding site (PDB ID: 5LYJ) of tubulin. The binding affinities were found to be efficient, ranging from -6.502 to -8.341 kcal/mol, with two major electrostatic interactions observed: H-bond and halogen bond. Ligand 4i had a binding affinity of -8.149 kcal/mol with the tubulin-combretastatin A-4 binding site and displayed a H-bond interaction with the residue Asn258. The ADME and toxicity prediction studies for each compound were carried out using SwissADME and ProTox-II software. None of the compounds' ADME predictions showed that they violated Lipinski's rule of five. All of the compounds were also predicted to have LD50 values between 440 and 500 mg/kg, putting them all in class IV toxicity, according to the toxicity prediction. The current discovery could potentially open up the opportunity for further developments in cancer.

Synthesis and Anticancer Evaluation of 4-Chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol Analogues: An Insight into Experimental and Theoretical Studies.

We report herein the synthesis, docking studies and biological evaluation of a series of new 4-chloro-2-((5-aryl-1,3,4-oxadiazol-2-yl)amino)phenol analogues (6a-h). The new compounds were designed based on the oxadiazole-linked aryl core of tubulin inhibitors of IMC-038525 and IMC-094332, prepared in five steps and further characterized via spectral analyses. The anticancer activity of the compounds was assessed against several cancer cell lines belonging to nine different panels as per National Cancer Institute (NCI US) protocol. 4-Chloro-2-((5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl)amino)phenol (6h) demonstrated significant anticancer activity against SNB-19 (PGI = 65.12), NCI-H460 (PGI = 55.61), and SNB-75 (PGI = 54.68) at 10 µM. The compounds were subjected to molecular docking studies against the active site of the tubulin-combretastatin A4 complex (PDB ID: 5LYJ); they displayed efficient binding and ligand 4h (with docking score = -8.030 kcal/mol) lay within the hydrophobic cavity surrounded by important residues Leu252, Ala250, Leu248, Leu242, Cys241, Val238, Ile318, Ala317, and Ala316. Furthermore, the antibacterial activity of some of the compounds was found to be promising. 4-Chloro-2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)amino)phenol (6c) displayed the most promising antibacterial activity against both Gram-negative as well as Gram-positive bacteria with MICs of 8 µg/mL and a zone of inhibition ranging from 17.0 ± 0.40 to 17.0 ± 0.15 mm at 200 µg/mL; however, the standard drug ciprofloxacin exhibited antibacterial activity with MIC values of 4 µg/mL.

Potential of paracetamol for reproductive disruption: molecular interaction, dynamics, and MM-PBSA based in-silico assessment.

Paracetamol is generally recommended for pain and fever. However, as per experimental and epidemiological data, widespread and irrational or long-term use of paracetamol may be harmful to human endocrine homeostasis, especially during pregnancy. Some researchers suggest that prenatal exposure to paracetamol might alter fetal development and also enhance the risk of reproductive disorders. An imbalance in the levels of these hormones may play a significant role in the emergence of various diseases, including infertility. Therefore, in this study, the interaction mechanism of paracetamol with reproductive hormone receptors was investigated by molecular docking, molecular dynamics (MD) simulations, and Poisson-Boltzmann surface area (MM-PBSA) for assessing paracetamol's potency to disrupt reproductive hormones. The results indicate that paracetamol has the ability to interact with reproductive hormone receptors (estrogen 1XP9; 1QKM with binding energy of -5.61 kcal/mol; -5.77 kcal/mol; androgen 5CJ6 - 5.63 kcal/mol; and progesterone 4OAR -5.60 kcal/mol) by hydrogen bonds as well as hydrophobic and van der Waals interactions to maintain its stability. In addition, the results of the MD simulations and MM-PBSA confirm that paracetamol and reproductive receptor complexes are stable. This research provides a molecular and atomic level understanding of how paracetamols disrupt reproductive hormone synthesis. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), Radius of Gyration and hydrogen bonding exhibited that paracetamol mimic at various attribute to bisphenol and native ligand.

An Insight into the Structural Requirements and Pharmacophore Identification of Carbonic Anhydrase Inhibitors to Combat Oxidative Stress at High Altitudes: An In-Silico Approach.

Carbonic anhydrases (CA) inhibitory action could be linked to the treatment of a number of ailments, including cancer, osteoporosis, glaucoma, and several neurological problems. For the development of effective CA inhibitors, a variety of heterocyclic rings have been investigated. Furthermore, at high altitudes, oxygen pressure drops, resulting in the formation of reactive oxygen and nitrogen species, and CA inhibitors having role in combating this oxidative stress. Acetazolamide contains thiadiazole ring, which has aroused researchers' interest because of its CA inhibitory action. In the present study, we used a number of drug design tools, such as pharmacophore modeling, 3D QSAR, docking, and virtual screening on twenty-seven 1,3,4-thiadiazole derivatives that have been described as potential CA inhibitors in the literature. An atom-based 3D-QSAR analysis was carried out to determine the contribution of individual atoms to model generation, while a pharmacophore mapping investigation was carried out to find the common unique pharmacophoric properties required for biological activity. The coefficient of determination for both the training and test sets were statistically significant in the generated model. The best QSAR model was chosen based on the values of R2 (0.8757) and Q2 (0.7888). A molecular docking study was also conducted against the most potent analogue 4m, which has the highest SP docking score (-5.217) (PDB ID: 6g3v). The virtual screening revealed a number of promising compounds. The screened compound ZINC77699643 interacted with the amino acid residues, Pro201 and Thr199, in the virtual screening study (PDB ID: 6g3v). These interactions demonstrated the significance of the CA inhibitory activity of the compound. Furthermore, ADME study revealed useful information regarding compound's drug-like properties. Therefore, the findings of the present investigation could aid in the development of more potent CA inhibitors, which could benefit the treatment of oxidative stress at high altitudes.

Ultrasound promoted green synthesis, anticancer evaluation, and molecular docking studies of hydrazines: a pilot trial.

We reported herein an efficient, environmentally friendly synthesis of hydrazine carboxamides (6a-l) in a water-glycerol (6:4) solvent system using ultrasonic irradiation. Ultrasonicated reactions were found to be much faster and more productive than conventional synthesis. The prepared compounds (6a-l) were tested against nine panels of 60 cancer cell lines according to the National Cancer Institute (NCI US) protocol. N-(4-Chlorophenyl)-2-(2-oxoindolin-3-ylidene)hydrazine-1-carboxamide (6b) was discovered to be promising anticancer agents with higher sensitivity against CCRF-CEM, HOP-92, UO-31, RMPI-8226, HL-60(TB), and MDA-MB-468 with percent growth inhibitions (%GIs) of 143.44, 33.46, 33.21, 33.09, 29.81, and 29.55 respectively. Compounds (6a-l) tested showed greater anticancer activity than Imatinib, except for compound 6k. Compounds 6b and 6c were found to be lethal on the CCRF-CEM leukaemia cell line, with %GIs of 143.44 and 108.91, respectively. Furthermore, molecular docking analysis was performed to investigate ligand binding affinity at the active site of epidermal growth factor (EGFR).

Sunscreen Ingredient Octocrylene's Potency to Disrupt Vitamin D Synthesis.

Octocrylene is a widely used ingredient in sunscreen products, and it has been observed that the use of sunscreen has been increasing over the last few decades. In this paper, we investigated the way in which sunscreen's ingredient octocrylene may disrupt normal vitamin D synthesis pathway, resulting in an imbalance in vitamin D levels in the body. The key techniques used for this insilico investigation were molecular docking, molecular dynamic (MD) simulation, and MMPBSA-based assessment. Vitamin D abnormalities have become very common in human health. Unknown exposure to chemicals may be one of the important risk factors. In molecular docking analysis, octocrylene exhibited a binding energy of -11.52 kcal/mol with vitamin D binding protein (1KXP) and -11.71 for the calcitriol native ligand. Octocrylene had a binding potency of -11.152 kcal/mol with the vitamin D receptor (1DB1), and calcitriol had a binding potency of -8.73 kcal/mol. In addition, octocrylene has shown binding energy of -8.96 kcal/mol with CYP2R1, and the calcitriol binding energy was -10.36 kcal/mol. Regarding stability, the root-mean-square deviation (RMSD), the root-mean-square fluctuation (RMSF), the radius of gyration, hydrogen bonding, and the solvent-accessible surface area (SASA) exhibited that octocrylene has a stable binding pattern similar to calcitriol. These findings revealed that incessant exposure to octocrylene may disrupt normal vitamin D synthesis.

Toward the Discovery of a Novel Class of Leads for High Altitude Disorders by Virtual Screening and Molecular Dynamics Approaches Targeting Carbonic Anhydrase.

For decades, carbonic anhydrase (CA) inhibitors, most notably the acetazolamide-bearing 1,3,4-thiadiazole moiety, have been exploited at high altitudes to alleviate acute mountain sickness, a syndrome of symptomatic sensitivity to the altitude characterized by nausea, lethargy, headache, anorexia, and inadequate sleep. Therefore, inhibition of CA may be a promising therapeutic strategy for high-altitude disorders. In this study, co-crystallized inhibitors with 1,3,4-thiadiazole, 1,3-benzothiazole, and 1,2,5-oxadiazole scaffolds were employed for pharmacophore-based virtual screening of the ZINC database, followed by molecular docking and molecular dynamics simulation studies against CA to find possible ligands that may emerge as promising inhibitors. Compared to the co-crystal ligands of PDB-1YDB, 6BCC, and 6IC2, ZINC12336992, ZINC24751284, and ZINC58324738 had the highest docking scores of -9.0, -9.0, and -8.9 kcal/mol, respectively. A molecular dynamics (MD) simulation analysis of 100 ns was conducted to verify the interactions of the top-scoring molecules with CA. The system's backbone revealed minor fluctuations, indicating that the CA-ligand complex was stable during the simulation period. Simulated trajectories were used for the MM-GBSA analysis, showing free binding energies of -16.00 ± 0.19, -21.04 ± 0.17, and -19.70 ± 0.18 kcal/mol, respectively. In addition, study of the frontier molecular orbitals of these compounds by DFT-based optimization at the level of B3LYP and the 6-311G(d,p) basis set showed negative values of the HOMO and LUMO, indicating that the ligands are energetically stable, which is essential for forming a stable ligand-protein complex. These molecules may prove to be a promising therapy for high-altitude disorders, necessitating further investigations.

Green Synthesis of Oxoquinoline-1(2H)-Carboxamide as Antiproliferative and Antioxidant Agents: An Experimental and In-Silico Approach to High Altitude Related Disorders.

At high altitudes, drops in oxygen concentration result in the creation of reactive oxygen and nitrogen species (RONS), which cause a variety of health concerns. We addressed these health concerns and reported the synthesis, characterization, and biological activities of a series of 10 oxoquinolines. N-Aryl-7-hydroxy-4-methyl-2-oxoquinoline-1(2H)carboxamides (5a-j) were accessed in two steps under ultrasonicated irradiation, as per the reported method. The anticancer activity was tested at 10 µM against a total of 5 dozen cancer cell lines obtained from nine distinct panels, as per the National Cancer Institute (NCI US) protocol. The compounds 5a (TK-10 (renal cancer); %GI = 82.90) and 5j (CCRF-CEM (Leukemia); %GI = 58.61) showed the most promising anticancer activity. Compound 5a also demonstrated promising DPPH free radical scavenging activity with an IC50 value of 14.16 ± 0.42 µM. The epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), two prospective cancer inhibitor targets, were used in the molecular docking studies. Molecular docking studies of ligand 5a (docking score = -8.839) against the active site of EGFR revealed two H-bond interactions with the residues Asp855 and Thr854, whereas ligand 5a (docking = -5.337) interacted with three H-bond with the residues Gln92, Gln67, and Thr200 against the active site CA. The reported compounds exhibited significant anticancer and antioxidant activities, as well as displayed significant inhibition against cancer targets, EGFR and CA, in the molecular docking studies. The current discovery may aid in the development of novel compounds for the treatment of cancer and oxidative stress, and other high altitude-related disorders.

Simultaneous Determination of Caffeine and Paracetamol in Commercial Formulations Using Greener Normal-Phase and Reversed-Phase HPTLC Methods: A Contrast of Validation Parameters.

There has been no assessment of the greenness of the described analytical techniques for the simultaneous determination (SMD) of caffeine and paracetamol. As a result, in comparison to the greener normal-phase high-performance thin-layer chromatography (HPTLC) technique, this research was conducted to develop a rapid, sensitive, and greener reversed-phase HPTLC approach for the SMD of caffeine and paracetamol in commercial formulations. The greenness of both techniques was calculated using the AGREE method. For the SMD of caffeine and paracetamol, the greener normal-phase and reversed-phase HPTLC methods were linear in the 50-500 ng/band and 25-800 ng/band ranges, respectively. For the SMD of caffeine and paracetamol, the greener reversed-phase HPTLC approach was more sensitive, accurate, precise, and robust than the greener normal-phase HPTLC technique. For the SMD of caffeine paracetamol in commercial PANEXT and SAFEXT tablets, the greener reversed-phase HPTLC technique was superior to the greener normal-phase HPTLC approach. The AGREE scores for the greener normal-phase and reversed-phase HPTLC approaches were estimated as 0.81 and 0.83, respectively, indicated excellent greenness profiles for both analytical approaches. The greener reversed-phase HPTLC approach is judged superior to the greener normal-phase HPTLC approach based on numerous validation parameters and pharmaceutical assays.

Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study.

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a novel, promising and emerging biological target for therapeutic intervention in neurodegenerative diseases, especially in Alzheimer's disease (AD). The molMall database, comprising rare, diverse and unique compounds, was explored for molecular docking-based virtual screening against the DYRK1A protein, in order to find out potential inhibitors. Ligands exhibiting hydrogen bond interactions with key amino acid residues such as Ile165, Lys188 (catalytic), Glu239 (gk+1), Leu241 (gk+3), Ser242, Asn244, and Asp307, of the target protein, were considered potential ligands. Hydrogen bond interactions with Leu241 (gk+3) were considered key determinants for the selection. High scoring structures were also docked by Glide XP docking in the active sites of twelve DYRK1A related protein kinases, viz. DYRK1B, DYRK2, CDK5/p25, CK1, CLK1, CLK3, GSK3ß, MAPK2, MAPK10, PIM1, PKA, and PKCα, in order to find selective DYRK1A inhibitors. MM/GBSA binding free energies of selected ligand-protein complexes were also calculated in order to remove false positive hits. Physicochemical and pharmacokinetic properties of the selected six hit ligands were also computed and related with the proposed limits for orally active CNS drugs. The computational toxicity webserver ProTox-II was used to predict the toxicity profile of selected six hits (molmall IDs 9539, 11352, 15938, 19037, 21830 and 21878). The selected six docked ligand-protein systems were exposed to 100 ns molecular dynamics (MD) simulations to validate their mechanism of interactions and stability in the ATP pocket of human DYRK1A kinase. All six ligands were found to be stable in the ATP binding pocket of DYRK1A kinase.

Psychometric analysis of cognitive distortions scale-urdu on patients diagnosed with mental disorders.

OBJECTIVE: To assess the reliability and concurrent validity of Cognitive Distortions Scale-Urdu based on Beck's Cognitive Model of psychopathology on patients diagnosed with mental disorders. METHODS: The correlational study was conducted from June 15, 2019, to January 30, 2020, in Lahore, Pakistan, and comprised psychiatric patients of either gender aged 18-65 years from six government hospitals, including Mayo Hospital, Services Hospital, Punjab Institute of Mental Health, Sir Ganga Ram Hospital, Gulab Devi Hospital and the Combined Military Hospital. The participants completed the demographic information form and the Cognitive Distortions Scale-Urdu. The latter was re-administered after a gap of two weeks to determine its internal consistency and test-retest reliability. Feinstein Paranoia, Subjective Wellbeing and Siddiqui Shah Depression Scales were administered along with the Cognitive Distortions Scale-Urdu to determine its concurrent validity. Statistical analysis was done using SPSS 24. RESULTS: Of the 106 patients, 56(52.8%) were recruited for reliability analysis with an overall mean age of 32.31±10.62 years, and 50(47.2%) for concurrent validity analysis with an overall mean age of 31.30±10.52 years. Correlation analysis indicated good internal consistency (α=0.87), test retest reliability (r=0.86) and moderately high concurrent validity of the scale (range: 0.44-0.89). CONCLUSIONS: The Cognitive Distortions Scale-Urdu was found to have sound psychometric properties and was suitable for researchers to obtain quantitative estimates of the frequency and intensity of cognitive distortions in clinical samples.

Investigating Antiarthritic Potential of Nanostructured Clove Oil (Syzygium aromaticum) in FCA-Induced Arthritic Rats: Pharmaceutical Action and Delivery Strategies.

The combined application of clove oil in a lipid nanocarrier opens a promising avenue for bone and joints therapy. In this study, we successfully developed a tunable controlled-release lipid platform for the efficient delivery of clove oil (CO) for the treatment of rheumatoid arthritis (RA). The ultra-small nanostructured lipid carriers co-loaded with CO (CONCs) were developed through an aqueous titration method followed by microfluidization. The CONCs appeared to be spherical (particle size of 120 nm), stable (zeta potential of -27 mV), and entrapped efficiently (84.5%). In toluene:acetone:glacial acetic acid (90:9:1 percent v/v/v) solvent systems, high-performance thin layer chromatography (HPTLC) analysis revealed the primary components in CO as eugenol (RF = 0.58). The CONCs greatly increased the therapeutic impact of CO in both in vitro and in vivo biological tests, which was further supported by excellent antiarthritic action. The CONC had an antiarthritic activity that was slightly higher than neat CO and slightly lower than standard, according to our data. The improved formulation inhibited serum lysosomal enzymes and proinflammatory cytokines while also improving hind leg function. This study provides a proof of concept to treat RA with a new strategy utilizing essential oils via nanodelivery.

Computational Approaches for the Design of Novel Anticancer Compounds Based on Pyrazolo[3,4-d]pyrimidine Derivatives as TRAP1 Inhibitor.

In the present in-silico study, various computational techniques were applied to determine potent compounds against TRAP1 kinase. The pharmacophore hypothesis DHHRR_1 consists of important features required for activity. The 3D QSAR study showed a statistically significant model with R2 = 0.96 and Q2 = 0.57. Leave one out (LOO) cross-validation (R2 CV = 0.58) was used to validate the QSAR model. The molecular docking study showed maximum XP docking scores (-11.265, -10.532, -10.422, -10.827, -10.753 kcal/mol) for potent pyrazole analogs (42, 46, 49, 56, 43), respectively, with significant interactions with amino acid residues (ASP 594, CYS 532, PHE 583, SER 536) against TRAP1 kinase receptors (PDB ID: 5Y3N). Furthermore, the docking results were validated using the 100 ns MD simulations performed for the selected five docked complexes. The selected inhibitors showed relatively higher binding affinities than the TRAP1 inhibitor molecules present in the literature. The ZINC database was used for a virtual screening study that screened ZINC05297837, ZINC05434822, and ZINC72286418, which showed similar binding interactions to those shown by potent ligands. Absorption, distribution, metabolism, and excretion (ADME) analysis showed noticeable results. The results of the study may be helpful for the further development of potent TRAP1 inhibitors.

Upcoming diagnostic biomarkers with promising prospects in neurological disorders.

An exponential increase in the prevalence of neurological disorders requires substantial steps to be taken for their prevention and treatment. Neurodiagnostic biomarkers are gaining momentum presently in order to enhance the diagnostic accuracy of neurodegenerative disorders, to precisely assess their advancement and to monitor the efficiency of therapeutic interventions. Therefore, the primary focus of the present review is the recent development in this field of neurodiagnostic biomarkers, and the current state of biomarker exploration in the context of various neurodegenerative diseases. This review encompasses an updated and detailed account of specific (ß-Amyloid, Tau and Phospho-tau 181, Tar-DNA binding protein-43, Progranulin, a-synuclein, Clusterin, etc) and non-specific (genetic, synaptic, inflammatory and coagulation) neurodiagnostic biomarkers and the recent advances in this growing field. This comprehensive review also suggests the utilization of neurodiagnostic markers in network approaches and personalized medication that will eventually improvise the existing diagnostic and therapeutic complexities of neurodiagnostic biomarkers.

Lipid-based microemulsion gel for the topical delivery of methotrexate: an optimized, rheologically acceptable formulation with conducive dermatokinetics.

In the present study, we have formulated a methotrexate (MTX)-loaded microemulsion topical gel employing quality-by-design optimization. The optimized lipid-based microemulsion was incorporated into a 2% carbopol gel. The prepared formulation was characterized for micromeritics, surface charge, surface morphology, conductivity studies, rheology studies, texture analysis/spreadability, drug entrapment, and drug loading studies. The formulation was further evaluated for drug release and release kinetics, cytotoxicity assays, drug permeation and drug retention studies, and dermatokinetics. The developed nanosystem was not only rheologically acceptable but also offered substantial drug entrapment and loading. From drug release studies, it was observed that the nanogel showed higher drug release at pH 5.0 compared to plain MTX, plain gel, and plain microemulsion. The developed system with improved dermatokinetics, nanometric size, higher drug loading, and enhanced efficacy towards A314 squamous epithelial cells offers a huge promise in the topical delivery of methotrexate.

Design, synthesis, molecular docking and in vitro anticancer activities of 1-(4-(benzamido)phenyl)-3-arylurea derivatives.

In both premenopausal and postmenopausal women, oestrogens play a critical role in the development of breast cancer. Aromatase is an enzyme that catalyses the final step in the biosynthesis of estrogen and has emerged as a promising target for therapeutic intervention. This study aimed to design and evaluate novel 1-(4-(benzamido)phenyl)-3-arylurea derivatives as potential aromatase inhibitors. Through molecular docking, promising leads were identified and synthesized. Spectroscopic techniques confirmed their structural integrity. Cytotoxicity against various cancer cell lines was assessed using MTT assay. Docking investigations against the aromatase enzyme (3s7s) elucidated binding interactions and energies. Compound 6g, exhibiting a binding energy of -8.6 kcal mol-1 and interacting with ALA306 and THR310 residues, showed the most promising activity. It demonstrated GI50 values ranging from 14.46 µM, 13.97 µM, 11.35 µM, 11.58 µM, and 15.77 µM against A-498, NCI-H23, MDAMB-231, MCF-7, and A-549 respectively. Lastly, the physicochemical, and ADMET properties of the compound were predicted. These findings highlight the potential of 1-(4-(benzamido)phenyl)-3-arylureas as a new class of antitumor agents targeting aromatase. Their versatility and superior activity compared to standard chemotherapeutic agents, like doxorubicin, warrant further investigation for the development of broader-spectrum anticancer drugs.

Field and atom-based 3D-QSAR models of chromone (1-benzopyran-4-one) derivatives as MAO inhibitors.

Monoamine oxidases (MAOs) are flavo-enzymes that aid in the oxidative deamination of neurotransmitters like dopamine, serotonin, and epinephrine. MAO inhibitors are antidepressants that work by preventing the breakdown of brain neurotransmitters and regulating mood. MAO inhibitors that use the chromone (1-benzopyran-4-one) structure have been found to be quite effective in studies. The current study involves the creation of pharmacophore models, 3-D QSAR, virtual screening, and docking investigations, all of which are evaluated using various criteria. The investigation included 39 ligands that emerged pharmacophore AHRRR_1, as the best pharmacophore model with a survival score of 5.6485. The 3D QSAR investigation revealed a significant model with the values of R2 = 0.9064 and Q2 = 0.8239. Docking study revealed that compound 18 had the highest docking (-10.402 kcal/mol) score in the series and showed interactions with the essential amino acid TYR398 required for MAO inhibitory activity. ZINC compounds were screened using the created pharmacophore model, which was followed up with a virtual screening study. The ZINC compounds with the best XP docking scores are ZINC03113255, ZINC07777127, ZINC05166353 and ZINC09341502 (with docking scores -10.021, -9.486, -8.031 and -7.792 kcal/mol, respectively). ZINC03113255, which showed the best score, has binding interactions with amino acid residues, TYR326, TYR398 and LYS296 of monoamine oxidase B. The ADME analysis demonstrated the compound's drug-like characteristics. The findings of this study may be used in the development of chromone compounds that target the MAO inhibitor.Communicated by Ramaswamy H. Sarma.

Hexaconazole exposure disrupt acetylcholinesterase, leading to mental illness.

Hexaconazole is widely used in agricultural work, and it has been observed that it has potential to disrupt endocrine function and it has also capacity of bioaccumulation. In this study, we examined how the hexaconazole disrupts the usual balance of acetylcholinesterase. It has been already reported that heavy pesticide exposures may be a reason for several mental illnesses because these pesticides may disrupt normal balance of acetylcholinesterase. In this paper, we have done a complete molecular and dynamics analysis to understand the behavior of hexaconazole with acetylcholinesterase so that its toxicological aspect may be explored. Our findings revealed that hexaconazole has potency to interact with acetylcholinesterase in a stable manner. The binding energy of hexaconazole was found to be -7.95 kcal/mol. However, chlorpyrifos, known inhibitors of acetylcholinesterase, has binding energy of -7.17 kcal/mol. With respect to stability analysis, hexaconazole has similar stability like chlorpyrifos. Root-mean-square deviation, root-mean-square fluctuation, radius of gyration, hydrogen bonding, and solvent accessible surface area were similar to chlorpyrifos. In addition, density functional theory computations analysis reveals that hexaconazole is energetically stable like chlorpyrifos, which is necessary for establishing a stable ligand-protein complex. The result of this complete molecular analysis reveals that hexaconazole may disrupt the acetylcholinesterase balance, which leads to mental illness.

Formulation of lemongrass oil (Cymbopogon citratus)-loaded solid lipid nanoparticles: an in vitro assessment study.

Cymbopogon citratus (DC) stapf. (Gramineae) is a herb known worldwide as lemongrass. The oil obtained, i.e., lemongrass oil has emerged as one among the most relevant natural oils in the pharmaceutical industry owing to its extensive pharmacological and therapeutic benefits including antioxidant, antimicrobial, antiviral and anticancer properties. However, its usage in novel formulations is constrained because of its instability and volatility. To address these concerns, the present study aims to formulate lemongrass-loaded SLN (LGSLN) using hot water titration technique. In the Smix, Tween 80 was selected as a surfactant component, while ethanol was taken as a co-surfactant. Different ratios of Smix (1:1, 1:2, 1:3, 2:1 and 3:1) were utilized to formulate LG-loaded SLN. The results indicated the fact that the LGSLN formulation (abbreviated as LGSLN1), containing lipid phase 10% w/w (i.e., LG 3.33% and SA 6.67%), Tween 80 (20% w/w), ethanol (20% w/w) and distilled water (50% w/w), revealed suitable nanometric size (142.3 ± 5.96 nm) with a high zeta potential value (- 29.12 ± 1.7 mV) and a high entrapment efficiency (77.02 ± 8.12%). A rapid drug release (71.65 ± 5.33%) was observed for LGSLN1 in a time span of 24 h. Additionally, the highest values for steady-state flux (Jss; 0.6133 ± 0.0361 mg/cm2/h), permeability coefficient (Kp; 0.4573 ± 0.0141 (cm/h) × 102) and enhancement ratio (Er; 13.50) was also conferred by LGSLN1. Based on in vitro study results, the developed SLN appeared as a potential carrier for enhanced topical administration of lemongrass oil. The observed results also indicated the fact that the phyto-cosmeceutical prospective of the nanolipidic carrier for topical administration of lemongrass oil utilizing pharmaceutically acceptable components can be explored further for widespread clinical applicability. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03726-5.

Structural aspects of triazole derivatives as HSP90 inhibitors for the treatment of cancer: in silico studies.

HSP90, one important class of chaperons has been intensively investigated as a promising and novel class of drug target for cancer therapy from the past few decades. A series of 2-((4-resorcinolyl)-5-aryl-1, 2, 3-triazol-1-yl) acetate derivatives were taken in the present study for the generation of pharmacophore based models, predictive 3 D-QSAR models, docking and ZINC screening studies against HSP90. The investigation included 30 ligands which emerged DHRRR_1 having survival score of 5.59 was found the most effective pharmacophore model. The generated third PLS factor includes a model with significant Q2, R2, and R2 CV values as 0.62, 0.77, and 0.50, respectively. The molecular docking studies against HSP90 showed interactions with important amino acids such as GLY-97, ASN-106, THR-184, ASN-51, PHE-138 and SER-52 required for HSP90 inhibitory activity. According to the docking analysis compound 34 was the top scoring compound, had a docking score of -10.98 from the series and showed interactions with amino acids likeASP-93, GLY-97, AND ASP-102. Using pharmacophore characteristics, the virtual screening investigation was carried out and DHRRR_1 showed the potential ZINC compounds. The ZINC compounds ZINC72417069 and ZINC77522480 showed best XP docking scores (-8.205 and -7.103 consecutively) and the top-scoring compound ZINC72417069 displayed amino acid binding affinity with GLY-97, ASN-106, and THR-184 against HSP90, PDB ID: 2xjx. These ZINC compounds can be used as target for HSP90. The result of the study may further help to the scientist for the design and development of potential HSP90 inhibitors.