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Urease is an amidohydrolase enzyme that is responsible for fatal morbidities in the human body, such as catheter encrustation, encephalopathy, peptic ulcers, hepatic coma, kidney stone formation, and many others. In recent years, scientists have devoted considerable efforts to the quest for efficient urease inhibitors. In the pharmaceutical chemistry, the thiourea skeleton plays a vital role. Thus, the present work focused on the development and discovery of novel urease inhibitors and reported the synthesis of a set of 1-aroyl-3-[3-chloro-2-methylphenyl] thiourea hybrids with aliphatic and aromatic side chains 4a–j. The compounds were characterized by different analytical techniques including FT-IR, 1H-NMR, and 13C-NMR, and were evaluated for in-vitro enzyme inhibitory activity against jack bean urease (JBU), where they were found to be potent anti-urease inhibitors and the inhibitory activity IC50 was found in the range of 0.0019 ± 0.0011 to 0.0532 ± 0.9951 μM as compared to the standard thiourea (IC50 = 4.7455 ± 0.0545 μM). Other studies included density functional theory (DFT), antioxidant radical scavenging assay, physicochemical properties (ADMET properties), molecular docking and molecular dynamics simulations. All compounds were found to be more active than the standard, with compound 4i exhibiting the greatest JBU enzyme inhibition (IC50 value of 0.0019 ± 0.0011 µM). The kinetics of enzyme inhibition revealed that compound 4i exhibited non-competitive inhibition with a Ki value of 0.0003 µM. The correlation between DFT experiments with a modest HOMO-LUMO energy gap and biological data was optimal. These recently identified urease enzyme inhibitors may serve as a starting point for future research and development. [ABSTRACT FROM AUTHOR]

In the present work, we reported the synthesis of Schiff bases from 4-phenoxy-5-sulfamoylbenzoic acid motif. The reaction was carried out by substitution of different aldehyde and ketones at sulfamoyl group of sulfamoylbenzoic acid. The generated substituted pro- ducts (4a--4i) possessed potent structure activity relationship and exhibited drug like properties. The structures of synthesized compounds were characterized on the basis of FT-IR, ¹HNMR, 13C NMR and mass spectroscopic data. The effects of synthesized products were investigated on urease enzyme through anti-urease enzyme inhibition assay (Weather burn method). These compounds were further evaluated for antibacterial potential. The Rationale behind the assessment of antibacterial activity was to investigate the synthesized compound's dual mode action against urease and virulent bacterial strains in order to develop a lead candidate for the treatment of GIT diseases such as gastric and peptic ulcers, as well as hepatic encephalopathy. The synthesized derivatives have outstanding anti-urease and antibacterial action, as is evident from in vitro and in silico studies. As a result, these compounds (3-(butylamino)-4-phenoxy-5-sulfamoylbenzoic acid; 4a-4i) might be explored further as a potential lead for the development of potent inhibitors in the future. [ABSTRACT FROM AUTHOR]

• The two lead compounds (CID 5280863 and CID 9946625) exhibited strong binding affinity to EGFR kinase protein. • The two lead compounds (CID 5280863 and CID 9946625) exhibited favorable drug-able, pharmacokinetics, and toxicity properties. • Molecular dynamics simulation confirmed the binding stably of the two lead compounds (CID 5280863 and CID 9946625) to the EGFR kinase protein active pocket. • The two lead compounds (CID 5280863 and CID 9946625) could be potential drug candidates to combat non-small cell lung cancer. Non-small cell lung carcinoma (NSCLC) is one of the prominent categories of cancer worldwide. It is primarily linked to mutations in the EGFR kinase domain, leading to being effectively controlled by specific allosteric inhibitors. However, current allosteric inhibitors have limited efficacy and potential resistance, leading to a need for alternative treatments. Therefore, this study aimed to identify phytochemicals from medicinal plants that can potentially be used as therapeutic agents that can inhibit the growth of NSCLC cells harboring the mutant EGFR kinase. A total of 4565 phytochemicals were selected from medicinal plants and screened by molecular docking, DFT calculation, ADMET analysis, QSAR analysis, molecular dynamics (MD) simulations, post simulation MM-GBSA, PCA, and DCCM analysis to find the potential compound that can inhibit the spread of lung cancer. The drug Alimta (pemetrexed disodium, CID 135410875), which is on the market today to inhibit the spread of lung cancer, was used as a control. After molecular docking, two compounds (kaempferol, CID 5280863, and epoxybergamottin, CID 9946625) showed higher binding affinity (-8.523 and -8.459 kcal/mol, respectively) and safety, and were further evaluated by MD simulations to analyze their stability. The two compounds exhibited stable interactions with the EGFR kinase protein, showing acceptable RMSD, RMSF, ligand RMSD, rGyr, MolSA, and SASA values, suggesting their potential as effective inhibitors of EGFR kinase activity. In conclusion, kaempferol (CID 5280863) and epoxybergamottin (CID 9946625) are promising phytochemicals that may inhibit the spread of NSCLC by targeting EGFR kinase. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of new biphenyl benzoate embedded chalcone mesogens have been synthesized. • New mesogens exhibited polymorphism with wide range of N, SmA and SmC mesophase. • Structure-property relationship investigations revealed the significant influence of mesogenic core as well as other structural variables. • DFT simulations carried out by and FMO and MEP delve into the molecular surroundings and quantum chemical behaviour of these compounds. The construction of multifunctional molecular self-assembly is one of the fascinating areas of current research. Herein we reported a series of biphenyl benzoate derived mesogenic material EBPCH-(2 – 16), containing ester-imine and chalcone as connecting units. Compounds were substituted by decyloxy chain at one end while the other end has been systematically varied from C2-C16. By using various spectroscopic techniques, and elemental analysis, the structures of the biphenyl benzoates were determined; the results are consistent with the suggested structure. The mesomorphism of new molecules has been studied by differential scanning calorimetry and polarizing optical microscopy. Initial members of the series up to C8 exhibited enantiotropic Smectic-A (SmA) as well as nematic mesophase with good thermal stability, whereas compounds above C10 up to C16 revealed only smectogenic behaviour with enantiotropic SmA as well as SmC mesophase. Apart from these findings, additional variables like the alkyloxy groups in the molecules and the polarity and polarizability of the linking units may also have an impact on these mesogens. Further, the structure–property relationship was carried out by thorough investigations and comparison with structurally related literature on the target compounds' mesomorphism. In addition, Density functional theory simulations verify the potential conformer of biphenyl benzoates, whereas studies conducted by frontier molecular orbitals and molecular electrostatic potential delve into the molecular surroundings and quantum chemical behaviour of these compounds. [ABSTRACT FROM AUTHOR]

Across the world, nutraceuticals/dietary supplements are commonly consumed without medical supervision, and believing these products are harmless to health. However, these products may contain trace (TMs) and non-essential/heavy metals (nHMs) as contaminants at levels higher than the recommended daily allowance (RDA), which can be hazardous to human health. Consequently, it is crucial to assess the levels of these metals to ensure the safety of these products. This study aimed to analyze the concentration of TMs (Mn, Cu and Zn) and nHMs (Al, Cr, Ni, Cd and Pb) in nutraceuticals/dietary supplements. Metal analysis was conducted using inductively coupled plasma–optical emission spectrometry (ICP-OES). Multivariate and bivariate analysis including principle component analysis (PCA), hierarchical cluster analysis (HCA) and Pearson correlation coefficient (PCC) were applied to understand inter-metal association and sources of these metals. Concentration ranges for TMs were found as, Mn (0.2–4.3 mg/kg), Cu (0.11–2.54 mg/kg), and Zn (0.1–22.66 mg/kg) while the nHMs concentration ranges were: Al (0.046–3.336 mg/kg), Cr (0.11–1.63 mg/kg), Ni (0.18–0.72 mg/kg), Cd (0.04–0.92 mg/kg), and Pb (0.18–1.08 mg/kg). The levels of tolerable dietary intake (TDI) for Cr and Ni, and the provisional tolerable monthly intake (PTMI) limit for Cd, exceeded the values set by the World Health Organization (WHO) and the European Food Safety Authority (EFSA). The estimation of the target hazard quotient (THQ <1), hazard index (HI < 1) and cumulative cancer risk (CCR <1 ✕ 10−3) indicated no significant non-carcinogenic and carcinogenic health risks associated with consuming these products. Therefore, the primary recommendation from this study is to use the nutraceuticals/dietary supplements should be under the supervision of dietitian. • Estimation of Al, Cr, Mn, Ni, Cu, Zn, Cd, and Pb in nutraceuticals/dietary supplements. • Risk evaluation was done using DI, EDI, the non-carcinogenic THQ and CR and CCR. • Few samples exhibited higher TDI values for Ni, Cd and BMDL10 for Pb established by EFSA. • THQ, HI, and CCR were below than respective allowed threshold. • Low exposure risk to metals indicated by THQ, HI, and CCR through consumption of supplements. [ABSTRACT FROM AUTHOR]

• Terminal methylene biphenyl-coumarin Schiff base-esters have been prepared and studied for liquid crystalline behaviour. • New compounds showed nematic as well as interdigitated smectic A mesophase. • The presence of mesophase has been verified using VT-XRD analysis. • Correlation of mesophase behaviour and geometrical parameters has been done using DFT calculations. • A comparative study with structurally analogous molecules has been carried out. In the present investigation new unsymmetrical coumarin-methylene biphenyl MBPCE-(2–16) mesogens were designed and synthesized. Methylene biphenyl end group at one end of molecules have been linked to the 7-alkyloxy substituted coumarin core through imine and ester mesogenic connecting units. The structures of new hybrids have been elucidated employing different analytical techniques including FT-IR, 1H NMR, 13C NMR, Mass & CHN elemental analysis. New molecules have been investigated for their mesomorphic behaviour using DSC (Measurement of transition temperature and enthalpy associated) and POM (Texture study) techniques and the existence of mesophase was established by VT-XRD analysis. Compounds with n = 2 (-OC 2 H 5) to n = 7 (-OC 7 H 15) chain length exhibited enantiotropic nematic mesophase with good thermal stability. As the chain length increases, compounds from n = 8 (-OC 8 H 17) and n = 10 (-OC 10 H 21) displayed enantiotropic nematic as well as smectic-A mesophase whereas compound with n = 12 (-OC 12 H 25) showed only interdigitated SmA phase. Next two members of the series failed to show any mesomorphism. The commencement of SmA phase and disappearance of nematic could be attributed to more layer arrangement with increased van der waals interactions. The density functional theory (DFT) calculations were employed to complement the experimental results concerning the mesomorphic behaviour. Development of smectic phase could be due to the augmentation in the area of the intermolecular interaction which increases the degree of molecular packing. Conversely, it was discovered that higher polarizability leads to lower nematic thermal stability because it strengthens parallel intermolecular interactions, which promotes a higher degree of molecular order while reducing the development of lower-order nematic mesophase. [Display omitted] [ABSTRACT FROM AUTHOR]

Serum albumin is the major transporter protein present in systemic circulation and the ability to transport ligands can be influenced in presence of other ligands. This interaction can influence the pharmacodynamic and pharmacokinetic property of certain ligands. Spectroscopic and molecular docking studies were conducted to understand the poziotinib binding interaction to bovine serum albumin (BSA). Further, influence of different flavonoids (quercetin, rutin, naringenin and sinapic acid) on displacing poziotinib from BSA binding sites was also studied. The BSA and poziotinib followed a static quenching mechanism as the Stern–Volmer constant showed decrease (7.6 × 104–6.0 × 104) when the temperature increased from 298 K to 310 K. The BSA and poziotinib interaction was spontaneous and enthalpy driven. Involvement of Van der Waals forces and hydrogen bonding in the binding interaction was suggested on the basis of thermodynamic study results. Conformational changes were suggested in the BSA on its interaction with poziotinib based on fluorescence experimental data. The binding constant for BSA-poziotinib showed a maximum decrease in presence of quercetin followed by naringenin, rutin and sinapic acid respectively. Site displacement studies suggested binding of poziotinib site I of BSA. Unlabelled Image • The investigational drug poziotinib is a suitable anticancer drug candidate for EGFR TKI–resistant lung cancer cells • Plasma protein binding has a major role in drug therapy specifically the pharmacokinetics and pharmacodynamics. • The interaction between poziotinib and BSA has been investigated by using spectroscopic methods. • Effect of 4 different flavonoids was investigated on poziotinib-BSA interaction. • The experimental results will be helpful in preclinical drug development of poziotinib [ABSTRACT FROM AUTHOR]

Arsenic compounds exist in inorganic and organic forms with inorganic form confirmed as a potent carcinogen. Toxogenomics and multi-omics analysis were used to explore the molecular mechanisms of carcinogenecity induced by arsenicals. Comparative toxogenomics revealed sodium arsenite and arsenate as the most toxic arsenicals to humans, interacting with various genes and altering gene expression through mRNA binding proteins. Both metalloids were classified as Class II toxins by the ProTox II prediction tool, with a lethal dose (LD50) of 149 mg/kg body weight. The most frequently interacting genes were HMOX1, CAT, NFE2L2, CASP3, MAPK1, CXCL8, PARP1, TNF, and PYGM. Analysis of TCGA pan-cancer data revealed that 46 % of hepatocellular carcinoma patients exhibited alterations in the genes HMOX1, CAT, NFE2L2, CASP3, MAPK1, CXCL8, PARP1, TNF, and PYGM, suggesting their significant role in the development of this disease. The alteration in the gene list decreased the overall patient survival but insignificantly in the Kaplan-Meier curves revealing insignificant role in survival. GSEA suggested significant enrichment of the gene list in pathways involved in the G2M checkpoint, apoptosis, hypoxia, TNFA signaling via NFKB, PI3K AKTMTOR signaling, P53, IFN gamma and inflammatory response pathways revealing the involvement of these pathways. Ten microRNAs (miRNAs) regulated the expressions of the genes involved in the above-mentioned pathways with the significant enrichment in miR-21-3p, miR-206 and mir486a-5p. The relevant pathway and graphical representation of the network of miRNA-target interactions identified by the enrichment analysis along with disease ontologies were predicted. This study will be helpful insight into setting of laboratory experiments., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Seema zargar reports financial support was provided by King Saud University., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Cancer remains a significant global health challenge, prompting exploration into alternative treatments such as those derived from natural compounds found in traditional medicine. Recent research has underscored the role of proteins like Focal Adhesion Kinase (FAK), Vascular Endothelial Growth Factor (VEGF), and Metastasis-Associated Protein 1 (MTA1) in driving cancer cell proliferation and survival. Here, we investigated the potential of a single molecule to modulate these key proteins involved in metastasis, offering a promising avenue for cancer therapy. Terminalia elliptica, commonly known as Asna, possesses a diverse range of medicinal properties, including antimicrobial, anti-inflammatory, anticancer, antidiabetic, antiaging, hepatoprotective, antioxidant, and neuroprotective activities. Our study aimed to explore the anticancer potential of Terminalia elliptica by identifying bioactive compounds capable of targeting FAK, VEGF, and MTA1 to impede cancer metastasis. Through in silico analysis, we conducted network analysis using Cytoscape to assess the significance of these bioactive compounds in the inhibition of signaling pathways driving metastasis. The utilization of these bioactives as potential candidates for targeted therapy of VEGF, FAK, and MTA1 regulated pathways was preliminarily assessed by Molecular Docking and MD Simulation. Our findings revealed that phytobioactives namely, Chebulinic Acid of Terminalia elliptica , exhibited notable binding affinity and interaction with FAK, and Chebulagic Acid with VEGF, and MTA1. This discovery holds promise as a novel therapeutic approach for combating cancer, offering potential benefits in cancer treatment and management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shreevatsa, Hegde, Narayan, Dharmashekar, Jain, Wani, Prabhuswamimath, Kollur and Shivamallu.)

Background: The use of protein supplements by athletes has risen due to their effectiveness in meeting dietary needs. However, there is a growing concern about the presence of potentially toxic metals (PTMs. Al, Cr, Mn, Ni, Cu, Zn, Cd, and Pb) in these supplements. Consequently, it is crucial to evaluate the levels of these PTMs to ensure the safety of the supplements., Methods: The objective of the current study was to assess the PTMs concentrations in protein supplements and examine any possible health hazards. Twenty-five samples of protein supplements were purchased from different pharmacies to screen them for metals. Inductively coupled plasma-optical emission spectrometry (ICP-OES) was utilized to analyze metal content. Additionally, chemometric methods such as Pearson's correlation coefficient (PCC), principal component analysis (PCA), and hierarchical cluster analysis (HCA) were employed to identify possible sources of PTMs contamination in protein supplements., Results: Concentration ranges for PTMs were found as, Al (0.03-3.05 mg/kg), Cr (0.11-0.89 mg/kg), Mn (1.13-8.40 mg/kg), Ni (0.06-0.71 mg/kg), Cu (1.05-5.51 mg/kg), Zn (2.14-27.10 mg/kg), Cd (0.01-0.78 mg/kg), and Pb (0.06-0.57 mg/kg). The weekly intake of Cd exceeded the level of tolerable weekly intake (TWI) set by the European Food Safety Authority (EFSA)., Conclusion: Athletes, bodybuilders, fitness enthusiasts, dieters, young adults and adolescents, and health-conscious individuals should be conscious of Cd concentration as it does not compliance the TWI set by EFSA. Target hazard quotient (THQ < 1), hazard index (HI < 1), margin of exposure (MOE ≥ 1), percentile permitted daily exposure (% PDE < 100), and cumulative cancer risk (CCR < 1 × 10 -3 ) analyses revealed that there are no appreciable non-carcinogenic and carcinogenic health risks associated with the use of these products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Elevated levels of trace metals (TMs) and heavy/non-essential metals (HnMs) in commonly consumed beverages concern the public and regulatory agencies. Thus, frequent monitoring of these metals is critically important. The present study intended to assess TMs and HnMs concentrations and associated health risks in beverages. Ten metals, such as Mn, Co, Cr, Cu, and Zn (TMs) and Ni, Cd, Pb, Al, and As (HnMs), were quantified in different beverage brands categorized into two groups such as non-carbonated and carbonated beverages. Chemometric analysis such as hierarchical cluster analysis (HCA), Pearson's correlation coefficient (PCC), and principal component analysis (PCA) were also performed to demonstrate the possible natural and anthropogenic sources of metal contamination. Among the TMs, the mean concentration of Zn (233.3 ± 3.3-291.7 ± 3.2 µg/L) followed by Mn (119.0 ± 2.3-146.4 ± 2.2 µg/L) was found highest in both carbonated and non-carbonated beverage samples. In the case of HnMs, the lowest mean concentration of Cd (7.4 ± 0.9-18.6 ± 1.2 µg/L) followed by Pb (4.1 ± 0.4-4.5 ± 0.4 µg/L) was observed in both types of beverage samples. The tolerable dietary intake (TDI) value for Ni and provisional tolerable monthly intake (PTMI) value for Cd were higher than the value established by the WHO and EFSA. The computed values of the hazard index (HI < 1) and the cumulative cancer risk (CCR) indicated a low risk of exposure., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A theoretical thermodynamic study was conducted to investigate the antioxidant activity and mechanism of 1,3,4-oxadiazol-2-ylthieno[2,3-d]pyrimidin-4-amine derivatives (OTP) using a Density Functional Theory (DFT) approach. The study assessed how solvent environments influence the antioxidant properties of these derivatives. With the increasing prevalence of diseases linked to oxidative stress, such as cancer and cardiovascular diseases, antioxidants are crucial in mitigating the damage caused by free radicals. Previous research has demonstrated the remarkable scavenging abilities of 1,3,4-oxadiazole derivatives, prompting this investigation into their potential using computational methods. DFT calculations were employed to analyze key parameters, including bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), and electron transfer enthalpy (ETE), to delineate the antioxidant mechanisms of these compounds. Our findings indicate that specific electron-donating groups such as amine on the phenyl rings significantly enhance the antioxidant activities of these derivatives. The study also integrates global and local reactivity descriptors, such as Fukui functions and HOMO-LUMO energies, to predict the stability and reactivity of these molecules, providing insights into their potential as effective synthetic antioxidants in pharmaceutical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bakheit, Wani, Al-Majed, Alkahtani, Alanazi, Alqahtani and Zargar.)

Background: The perennial evergreen tea (Camellia sinensis) plant is one of the most popular nonalcoholic drinks in the world. Fertilizers and industrial, agricultural, and municipal activities are the usual drivers of soil contamination, contaminating tea plants with potentially toxic elements (PTEs). These elements might potentially accumulate to larger amounts in the leaves of plants after being taken up from the soil. Thus, frequent monitoring of these elements is critically important., Methods: The present study intended to determine PTEs (Al, Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd, and Pb) in both tea leaves and infusions using ICP-OES. Various multivariate data analysis methods such as principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to elucidate the potential sources of PTEs contamination, whether from anthropogenic activities or natural origins. Additionally, Pearson's correlation coefficient (PCC) was calculated to assess the relationships between the variables under study., Results: The mean contents (mg/L) of all studied elements in tea infusions decreased in order Mn (150.59 ± 1.66) > Fe (11.39 ± 0.99) > Zn (6.62 ± 0.89) > Cu (5.86 ± 0.62) > Co (3.25 ± 0.64) > Ni (1.69 ± 0.23) > Pb (1.08 ± 0.16) > Cr (0.57 ± 0.09) > Cd (0.46 ± 0.09) > Al (0.05 ± 0.008), indicating that Mn exhibits the highest abundance. The mean concentration trend in tea leaf samples mirrored that of infusions, albeit with higher concentrations of PTEs in the former. The tolerable dietary intake (TDI) value for Ni and provisional tolerable monthly intake (PTMI) value for Cd surpassed the standards set by the WHO and EFSA. Calculated hazard index (HI < 1) and cumulative cancer risk (CCR) values suggest negligible exposure risk., Conclusion: Elevated levels of PTEs in commonly consumed tea products concern the public and regulatory agencies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

In humans, FOXP gene family is involved in embryonic development and cancer progression. The FOXP4 (Forkhead box protein P4) gene belongs to this FOXP gene family. FOXP4 gene plays a crucial role in oncogenesis. Single nucleotide polymorphisms are biological markers and common determinants of human diseases. Mutations can largely affect the function of the corresponding protein. Therefore, the molecular mechanism of nsSNPs in the FOXP4 gene needs to be elucidated. Initially, the SNPs of the FOXP4 gene were extracted from the dbSNP database and a total of 23124 SNPs was found, where 555 nonsynonymous, 20525 intronic, 1114 noncoding transcript, 334 synonymous were obtained and the rest were unspecified. Then, a series of bioinformatics tools (SIFT, PolyPhen2, SNAP2, PhD SNP, PANTHER, I-Mutant2.0, MUpro, GOR IV, ConSurf, NetSurfP 2.0, HOPE, DynaMut2, GeneMANIA, STRING and Schrodinger) were used to explore the effect of nsSNPs on FOXP4 protein function and structural stability. First, 555 nsSNPs were analyzed using SIFT, of which 57 were found as deleterious. Following, PolyPhen2, SNAP2, PhD SNP and PANTHER analyses, 10 nsSNPs (rs372762294, rs141899153, rs142575732, rs376938850, rs367607523, rs112517943, rs140387832, rs373949416, rs373949416 and rs376160648) were common and observed as deleterious, damaging and diseases associated. Following that, using I-Mutant2.0 and MUpro servers, 7 nsSNPs were found to be the most unstable. GOR IV predicted that these seven nsSNPs affect protein structure by altering the protein contents of alpha helixes, extended strands, and random coils. Following DynaMut2, 5 nsSNPs showed a decrease in the ΔΔG value compared with the wild-type and were found to be responsible for destabilizing the corresponding protein. GeneMANIA and STRING network revealed interaction of FOXP4 with other genes. Finally, molecular dynamics simulation analysis revealed consistent fluctuation in RMSD and RMSF values, Rg and hydrogen bonds in the mutant proteins compared with WT, which might alter the functional and structural stability of the corresponding protein. As a result, the aforementioned integrated comprehensive bioinformatic analyses provide insight into how various nsSNPs of the FOXP4 gene change the structural and functional properties of the corresponding protein, potentially proceeding with the pathophysiology of human diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Limeum indicum has been widely utilized in traditional medicine but no experimental work has been done on this herb. The primary objective of this study was to conduct a phytochemical analysis and assess the multifunctional capabilities of aforementioned plant in dual therapy for Alzheimer's disease (AD) and Type 2 diabetes (T2D). The phytochemical screening of ethanol, methanol extract, and their derived fractions of Limeum indicum was conducted using GC-MS, HPLC, UV-analysis and FTIR. The antioxidant capacity was evaluated by DPPH method. The inhibitory potential of the extracts/fractions against α-, β-glucosidase acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoaminine oxidases (MAO-A & B) was evaluated. Results revealed that acetonitrile fraction has highest inhibitory potential against α-glucosidase (IC 50 =68.47±0.05 μg/mL), methanol extract against β-glucosidase (IC 50 =91.12±0.07 μg/mL), ethyl acetate fraction against AChE (IC 50 =59.0±0.02 μg/mL), ethanol extract against BChE (28.41±0.01 μg/mL), n-hexane fraction against MAO-A (IC 50 =150.5±0.31 μg/mL) and methanol extract for MAO-B (IC 50 =75.95±0.13 μg/mL). The docking analysis of extracts\fractions suggested the best binding scores within the active pocket of the respective enzymes. During the in-vivo investigation, ethanol extract produced hypoglycemic effect (134.52±2.79 and 119.38±1.40 mg/dl) after 21 days treatment at dose level of 250 and 500 mg/Kg. Histopathological findings further supported the in-vivo studies., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background and Objectives : TAA is potent hepatic/renal toxicant. Conversely, WGO is a potent dietary supplement with impressive antioxidant properties. Olmutinib is an apoptotic chemotherapy drug that does not harm the liver or kidney. This study investigated the impact of olmutinib and wheat germ oil (WGO) on Thioacetamide (TAA)-induced gene alterations in mice liver and kidney tissues. Materials and Methods : Adult male C57BL/6 mice were exposed to 0.3% TAA in drinking water for 14 days, followed by the oral administration of olmutinib (30 mg/kg) and WGO (1400 mg/kg) for 5 consecutive days. Treatment groups included the following: groups I (control), II (TAA-exposed), III (TAA + olmutinib), IV (TAA + WGO), and V (TAA + olmutinib + WGO). Results : The findings revealed that TAA exposure increased MKi67 and CDKN3 gene expression in liver and kidney tissues. Olmutinib treatment effectively reversed these TAA-induced effects, significantly restoring MKi67 and CDKN3 gene expression. WGO also reversed MKi67 effects in the liver but exhibited limited efficacy in reversing CDKN3 gene alterations induced by TAA exposures in both the liver and kidney. TAA exposure showed the tissue-specific expression of TP53, with decreased expression in the liver and increased expression in the kidney. Olmutinib effectively reversed these tissue-specific alterations in TP53 expression. While WGO treatment alone could not reverse the gene alterations induced by TAA exposure, the co-administration of olmutinib and WGO exhibited a remarkable potentiation of therapeutic effects in both the liver and kidney. The gene interaction analysis revealed 77.4% of physical interactions and co-localization between MKi67, CDKN3, and TP53 expressions. Protein-protein interaction networks also demonstrated physical interactions between MKi67, TP53, and CDKN3, forming complexes or signaling cascades. Conclusions : It was predicted that the increased expression of the MKi67 gene by TAA leads to the increase in TP53, which negatively regulates the cell cycle via increased CDKN3 expression in kidneys and the restoration of TP53 levels in the liver. These findings contribute to our understanding of the effects of olmutinib and WGO on TAA-induced gene expression changes and highlight their contrasting effects based on cell cycle alterations.

The genus Cassia is a rich source of physiologically active secondary metabolites, including a novel compound named 21-methylene-24-ethylidene lophenol, alongside 15 known compounds. These compounds were characterized using different spectroscopic techniques. They exhibited promising antimicrobial activity, particularly against bacteria causing gastrointestinal infections. Compound 1 showed strong anti-bacterial activity against H. pylori and S. aur with MIC values of 0.28 and 0.12 μg mL -1 respectively. The study investigated their impact on H. pylori , a contributor to ulcer development, by inhibiting the urease enzyme. Inhibiting urease can reduce H. pylori 's pathogenic potential, evident from the fact that the compounds evaluated toward urease enzyme showed higher inhibitory activity (1.024 ± 0.43 50 > 6.678±0.11 μM) compared to standard thiourea (IC 50 = 18.61 ± 0.11 μM). Molecular docking studies confirmed their inhibitory action, with compound 7 notably outperforming thiourea in inhibiting urease (-6.95 kcal mol -1 vs. -3.13 kcal mol -1 ). Additionally, these compounds showed positive effects on liver functioning, which H. pylori can impair. Compound 9 shows the best response against human HepG2 liver cancer cell lines i.e. , % viability is 14.47% ± 0.69 and IC 50 is 7.8 μM ± 0.21. These compounds hold potential as lead compounds for addressing gastrointestinal and liver disorders caused by H. pylori ., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

The Epidermal Growth Factor Receptor (EGFR) is an important therapeutic target for the treatment of a variety of epithelial malignancies, including breast cancer, in which EGFR is aberrantly expressed.The fluorocyclopentenyl-purine-pyrimidines derivatives, which have previously been described as powerful compounds against breast cancer, were selected to investigate their potential against EGFR using computational tools in an effort to obtain potent inhibitors with fewer adverse effects. The molecule's chemical reactivity and stability were assessed by determining the HOMO-LUMO energy gap using density functional theory (DFT) calculations. Among all the selected compounds, PU4 displayed a HOMO-LUMO gap of 0.191 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of PU4 within the active pocket of EGFR-TK. The compound PU4 showed potent interactions with EGFR exhibiting -32.3 kJ/mol binding energy which was found best as compared to gefitinib i. e., -27.4 kJ/mol which was further validated by molecular dynamics simulations and ADMET analysis. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective EGFR inhibitor. Therefore, it is recommended to further investigate the inhibitory potential of these identified compounds using in vitro and in vivo approaches., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

The search for novel drug scaffolds that can improve effectiveness and safety through drug conjugates is a promising approach. Consequently, drug conjugates constitute a dynamic field of study and advancement within medicinal chemistry. This research demonstrates the conjugation of diclofenac and mefenamic acid with sulfa drugs and their screening for urease inhibition. These conjugates' structural confirmation was performed using elemental analysis and spectroscopic methods, including IR, 1 H NMR, and 13 C NMR. Diclofenac conjugated with sulfanilamide (4), sulfacetamide (10), and mefenamic acid conjugated with sulfanilamide (12), and sulfamethoxazole (17) was found potent and demonstrated urease inhibition competitively, with IC 50 (μM) values 3.59 ± 0.07, 5.49 ± 0.34, 7.92 ± 0.27, and 8.35 ± 0.26, respectively. Diclofenac conjugated with sulfathiazole (6), sulfamerazine (8), and sulfaguanidine (11), while mefenamic acid conjugated with sulfisoxazole (13), sulfathiazole (14), and sulfadiazine (15) exhibited a mixed mode of urease inhibition. The IC 50 (μM) values were 16.19 ± 0.21, 9.50 ± 0.28, 4.35 ± 0.23, 15.86 ± 0.25, 14.80 ± 0.27, and 7.92 ± 0.27, respectively. Furthermore, molecular docking studies were employed to predict the binding pose of competitive inhibitors at the urease active site. These conjugates generated stable complexes with the urease protein observed through molecular dynamics (MD) simulations, where no conformational changes occurred throughout the simulations. These results highlight the potential for approved therapeutic molecule conjugates to give rise to new categories of pharmacological agents for urease inhibition. The structural similarity of sulfonamides with urea allows them to compete with urea for binding to the active site of the urease enzyme. Sulfonamides and nonsteroidal anti-inflammatory drugs (NSAIDs) can interact hydrophobically with the active site of the urease enzyme, which may disturb its structure and catalytic activity. Therefore, these conjugates may be helpful in the development of novel pharmacological agents for the treatment of a variety of illnesses in which the urease enzyme is involved., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Solid lipid nanoparticles (SLNs) have the advantages of a cell-specific delivery and sustained release of hydrophobic drugs that can be exploited against infectious diseases. The topical delivery of hydrophobic drugs needs pharmaceutical strategies to enhance drug permeation, which is a challenge faced by conventional formulations containing a drug suspended in gel, creams or ointments. We report the fabrication and optimization of SLNs with sulconazole (SCZ) as a model hydrophobic drug and then a formulation of an SLN-based topical gel against fungal infections. The SLNs were optimized through excipients of glyceryl monostearate and Phospholipon ® 90 H as lipids and tween 20 as a surfactant for its size, drug entrapment and sustained release and resistance against aggregation. The SCZ-SLNs were physically characterized for their particle size (89.81 ± 2.64), polydispersity index (0.311 ± 0.07), zeta potential (-26.98 ± 1.19) and encapsulation efficiency (86.52 ± 0.53). The SCZ-SLNs showed sustained release of 85.29% drug at the 12 h timepoint. The TEM results demonstrated spherical morphology, while DSC, XRD and FTIR showed the compatibility of the drug inside SLNs. SCZ-SLNs were incorporated into a gel using carbopol and were further optimized for their rheological behavior, pH, homogeneity and spreadability on the skin. The antifungal activity against Candida albicans and Trichophyton rubrum was increased in comparison to a SCZ carbopol-based gel. In vivo antifungal activity in rabbits presented faster healing of skin fungal infections. The histopathological examination of the treated skin from rabbits presented restoration of the dermal architecture. In summary, the approach of formulating SLNs into a topical gel presented an advantageous drug delivery system against mycosis.

Background and objectives : Non-small cell lung cancer (NSCLC) is often caused by EGFR mutations, leading to overactive cell growth pathways. Drug resistance is a significant challenge in lung cancer treatment, affecting therapy effectiveness and patient survival. However, combining drugs in research shows promise in addressing or delaying resistance, offering a more effective approach to cancer treatment. In this study, we investigated the potential alterations in the apoptotic pathway in A549 cells induced by a combined targeted therapy using tyrosine kinase inhibitors (TKIs) olmutinib and poziotinib, focusing on cell proliferation, differential gene expression, and in silico analysis of apoptotic markers. Methods: A combined targeted therapy involving olmutinib and poziotinib was investigated for its impact on the apoptotic pathway in A549 cells. Cell proliferation, quantitative differential gene expression, and in silico analysis of apoptotic markers were examined. A549 cells were treated with varying concentrations (1, 2.5, and 5 μM) of poziotinib, olmutinib, and their combination. Results: Treatment with poziotinib, olmutinib, and their combination significantly reduced cell proliferation, with the most pronounced effect at 2.5 μM ( p < 0.005). A synergistic antiproliferative effect was observed with the combination of poziotinib and olmutinib ( p < 0.0005). Quantitative differential gene expression showed synergistic action of the drug combination, impacting key apoptotic genes including STK-11, Bcl-2, Bax, and the Bax/Bcl-2 ratio. In silico analysis revealed direct interactions between EGFR and ERBB2 genes, accounting for 77.64% of their interactions, and 8% co-expression with downstream apoptotic genes. Molecular docking indicated strong binding of poziotinib and olmutinib to extrinsic and intrinsic apoptotic pathway markers, with binding energies of -9.4 kcal/mol and -8.5 kcal/mol, respectively, on interacting with STK-11. Conclusions : Combining poziotinib and olmutinib therapies may significantly improve drug tolerance and conquer drug resistance more effectively than using them individually in lung cancer patients, as suggested by this study's mechanisms.

Itraconazole (ITZ) is a broad-spectrum antifungal for superficial subcutaneous and systemic fungal infections. This study aimed to enhance the antifungal activity of ITZ using surfactin A (SA), a cyclic lipopeptide produced by the SA-producing Bacillus strain NH-100, possessing strong antifungal activity. SA was extracted, and ITZ-loaded SA micelles formulations were prepared via a single-pot rinsing method and characterized by particle size, zeta potential, and infrared spectroscopy. In vitro dissolution at pH 1.2, as well as hemolysis studies, was also carried out. The fabricated formulations were stable and non-spherical in shape, with an average size of about 179 nm, and FTIR spectra depicted no chemical interaction among formulation components. ITZ-loaded micelles showed decreased hemolysis activity in comparison to pure ITZ. The drug released followed the Korsmeyer-Peppas model, having R 2 0.98 with the diffusion release mechanism. In an acidic buffer, drug release of all prepared formulations was in the range of 73-89% in 2 h. The molecular simulation showed the outstanding binding and stability profile of the ITZ-SA complex. The aromatic ring of the ITZ mediates a π-alkyl contact with a side chain in the SA. It can be concluded that ITZ-loaded micelles, owing to significant enhanced antifungal activity up to 6-fold due to the synergistic effect of SA, can be a promising drug delivery platform for delivery of poorly soluble ITZ.

Cassia occidentalis L. is widely used in indigenous and traditional medicine, but its impact on multi-drug resistant (MDR) bacterial infections mostly remains unknown. Therefore, this study aimed to evaluate the in vitro antibacterial efficiency of methanol and ethyl acetate extracts of C. occidentalis L. leaves (MECOL and EAECOL) against multi-drug resistant Pseudomonas aeruginosa and to identify potential antibacterial agents through computational studies targeting the LasR protein. Initially, 82 compounds were identified using GC-MS analysis, and the functional groups were determined through FT-IR analysis. Both extracts of the plant exhibited dose-dependent antibacterial activity, with MICs of 104.16 ± 36.08 μg mL -1 for MECOL and 83.33 ± 36.08 μg mL -1 for EAECOL, and an MBC of 125 μg mL -1 . Among the 82 compounds, 12 potential compounds were identified based on binding scores using molecular docking with the LasR protein and MM-GBSA analysis. Furthermore, screening for ADME properties, including physicochemical features, water solubility, lipophilicity, RO5 compliance, and toxicity, identified the top three compounds: methyl dihydrojasmonate, methyl benzoate, and 4a-methyl-4,4a,5,6,7,8-hexahydro-2(3 H )-naphthalenone, which also demonstrated binding affinity with the active site residues of the LpxC protein of the bacteria. Additionally, molecular dynamics (MD) simulations confirmed the binding reliability of these three phytochemicals to LasR's active pocket, comparable to the protein native inhibitory ligands (C12-HSL). The study offers scientific support for the traditional use of C. occidentalis in treating bacterial infections, highlighting the potential of the three compounds as leads for developing LasR inhibitors to combat multi-drug resistant P. aeruginosa ., Competing Interests: The authors affirm that they have no known competing financial interests or personal relationships that could have influenced the work presented in this paper., (This journal is © The Royal Society of Chemistry.)

COVID-19 has infected millions and significantly affected the global economy and healthcare systems. Despite continuous lockdowns, symptomatic management with currently available medications, and numerous vaccination drives, it is still far more difficult to control. Against COVID-19 infection, the pressure to develop vaccines and drugs has led to using some currently available medications like remdesivir, azithromycin, hydroxychloroquine and ritonavir. Understanding the importance and potential of harmless molecules to tackle SARS-COV-2, we designed the present study to identify potential natural phytocompounds. In the present study, we docked natural compounds and standard drugs against SARS-COV-2 proteins: papain-like protease, main protease and helicase. ADME/T and ProTox-II analyses were used to determine the toxicity of phytocompounds and drugs. The docking analysis revealed that podophyllotoxin gave the highest binding affinity scores of -8.1, -7.1 and -7.4 kcal/mol against PLpro, Mpro and helicase, respectively. Among the control drugs, doxycycline hydrochloride showed the highest binding affinity of -10.5, -8.4 and -8.8 kcal/mol against PLpro, Mpro and helicase. The results of this study revealed that podophyllotoxin and doxycycline hydrochloride could be promising inhibitors against SARS-Cov-2. Molecular dynamic simulations were executed for the best docked (PLpro-podophyllotoxin) complex, and the results displayed stable conformation and convergence. Energy plot results predicted a global minima average energy of -95 kcal/mol and indicated podophyllotoxin's role in stabilizing protein and making it compact and complex. FarPPI server used MM/GBSA approach to determine free binding affinity, and helicase-gallic acid complex showed the highest affinity, respectively. Therefore, it can be concluded that there is still a need for in vitro and in vivo studies to support further and validate these findings and validate these findings.Communicated by Ramaswamy H. Sarma.

Tioconazole (TCZ) is a broad-spectrum fungicidal BCS class II drug with reported activity against Candida albicans , dermatophytes , and certain Staphylococci bacteria. We report the use of TCZ-loaded transethosomes (TEs) to overcome the skin's barrier function. TCZ-loaded TEs were fabricated by using a cold method with slight modification. Box-Behnken composite design was utilized to investigate the effect of independent variables. The fabricated TEs were assessed with various physicochemical characterizations. The optimized formulation of TCZ-loaded TEs was incorporated into gel and evaluated for pH, conductivity, drug content, spreadability, rheology, in vitro permeation, ex vivo permeation, and in vitro and in vivo antifungal activity. The fabricated TCZ-loaded TEs had a % EE of 60.56 to 86.13, with particle sizes ranging from 219.1 to 757.1 nm. The SEM images showed spherically shaped vesicles. The % drug permeation was between 77.01 and 92.03. The kinetic analysis of all release profiles followed Higuchi's diffusion model. The FTIR, DSC, and XRD analysis showed no significant chemical interactions between the drug and excipients. A significantly higher antifungal activity was observed for TCZ-loaded transethosomal gel in comparison to the control. The in vivo antifungal study on albino rats indicated that TCZ-loaded transethosomal gel showed a comparable therapeutic effect in comparison to the market brand Canesten ® . Molecular docking demonstrated that the TCZ in the TE composition was surrounded by hydrophobic excipients with increased overall hydrophobicity and better permeation. Therefore, TCZ in the form of transethosomal gel can serve as an effective drug delivery system, having the ability to penetrate the skin and overcome the stratum corneum barrier with improved efficacy.

Energetic heterocycles, including pyridines, triazoles, and tetrazoles, exhibit greater density, heats of formation, and oxygen balance compared to their carbocyclic counterparts, making them a promising approach for synthesizing novel bis-tetrazole acetamides. Synthesized compounds A-F, some of which feature a chlorine atom attached to the phenyl ring, serve as valuable synthons for aryl coupling reactions. Analysis via 1 H-NMR and 13 C-NMR spectroscopy, as well as density functional considerations through B3LYP functional correlation with 6-311 +  + G(d) and 6-31G(d) basis set, revealed the observed LUMO/HOMO energies and charge transfer within the molecule. Additionally, the dipole moment, chemical hardness, softness, ionization potential, local reactivity potential via Fukui indices and thermodynamic properties (entropy, enthalpy, and Gibbs free energy) of the molecule were calculated through density functional theory studies. In addition, Molecular Docking studies were conducted to investigate the anti-cancer potential of synthesized heterocyclic compounds against caspase 3, NF-KAPPA-B and P53 protein. Molecular docking analysis demonstrated a potent interaction between 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2,4-dinitrophenyl) acetamides (6d) and TP53 and NF-KAPPA-B with binding energies of - 11.8 kJ/mol and - 10.9 kJ/mol for TP53 and NF-KAPPA-B, respectively. Similarly, 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2-chlorophenyl) acetamides (6f) exhibited a strong interaction with caspase-3 with binding energy of -10.0 kJ/mol, indicating their potential as therapeutic agents against these proteins. Furthermore, the findings of current study was further strengthen by 100 ns molecular dynamics (MD) simulations. Finally, theoretical studies of oxygen balance and nitrogen percentage suggest that these molecules can be utilized as energetic materials., (© 2023. Springer Nature Switzerland AG.)

Derivative synthesis has been a crucial method for altering the effects of already-approved medications, especially to lessen adverse effects and enhance results. Making use of this multi-target approach, a series of naproxen-sulfa drug conjugates was designed and synthesized. The newly designed conjugates were confirmed by spectroscopic techniques like IR, 1 HNMR, 13 CNMR, and elemental analysis. The conjugates were screened for anti-inflammatory, urease, and cyclooxygenase-2 (COX-2) inhibition. Naproxen conjugated with sulfanilamide, sulfathiazole, and sulfaguanidine was found potent and showed a competitive mode of urease inhibition, with IC 50 (µM) values 6.69 ± 0.11, 5.82 ± 0.28, 5.06 ± 0.29, respectively. When compared to other screened conjugates, the naproxen-sulfamethoxazole conjugation showed better anti-inflammatory action by inhibiting induced edema by 82.8%, which is comparable to the medication indomethacin (86.8% inhibition). Whereas it exhibited 75.4% inhibition of COX-2 at 10 µM concentration which is comparable with the reference drug (celecoxib, 77.1% inhibition). Moreover, the binding modes of competitive inhibitors with the urease and COX-2 receptor were predicted through molecular docking studies and their stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and there were no conformational changes that occurred during simulation. The obtained results showed that the conjugates of approved therapeutic molecules may lead to the development of novel types of pharmacological agents in the treatment of several pathological disorders where urease and COX-2 enzymes are involved., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ahmad, Abdul Qadir, Ahmed, Imran, Yousaf, Wani, Zargar, Ali and Muddassar.)

One of medicinal chemistry's top priorities is the discovery of new molecules with anticancer potential. Compounds that interact with DNA are an intriguing family of chemotherapeutic medications used to treat cancer. Studies in this area have uncovered a plethora of potential anticancer medicines, such as groove binding, alkylating, and intercalator compounds. The anticancer activity of DNA intercalators (molecules that intercalate between DNA base pairs) has drawn special interest. The current study investigated the promising anticancer drug 1,3,5-Tris(4-carboxyphenyl)benzene (H3BTB) against breast and cervical cancer cell lines. In addition, 1,3,5-Tris(4-carboxyphenyl)benzene binds to DNA by groove binding. The binding of H3BTB to DNA was found to be significant which unwinds the DNA helix. Considerable electrostatic and non-electrostatic contributions were present in the binding's free energy. The cytotoxic potential of H3BTB is effectively demonstrated by the computational study outcomes, which include molecular docking and molecular dynamics (MD) simulations. The minor groove binding for the H3BTB-DNA complex is supported by molecular docking research. This study will promote empirical investigation into the synthesis of metallic and non-metallic H3BTB derivatives and their potential use as bioactive molecules for the treatment of cancer.

The mycotoxin citrinin, which can contaminate food, is a major global concern. Citrinin is regarded as an inevitable pollutant in foods and feed since fungi are widely present in the environment. To identify contentious toxicity and lessen its severity by understanding the targets of citrinin in the human body and the impacted biosynthetic pathways, we analyzed the production of citrinin from Aspergillus flavus and Penicillium notatum and used a thorough bioinformatics analysis to characterize the toxicity and predict genes and protein targets for it. The predicted median fatal dosage (LD 50 ) for citrinin was 105 mg/kg weight, and it belonged to toxicity class 3 (toxic if swallowed). Citrinin was found to be well absorbed by human intestinal epithelium and was a Pgp nonsubstrate (permeability glycoprotein), which means that once it is absorbed, it cannot be pumped out, hence leading to bioconcentration or biomagnification in the human body. The main targets of toxicity were casp3, TNF, IL10, IL1B, BAG3, CCNB1, CCNE1, and CDC25A, and the biological pathways implicated were signal transduction involved in DNA damage checkpoints, cellular and chemical responses to oxidative stress, DNA damage response signal transduction by P53, stress-activated protein kinase signaling cascade, netrin-UNC5B signaling, PTEN gene regulation, and immune response. Citrinin was linked to neutrophilia, squamous cell carcinoma, Fanconi anemia, leukemia, hepatoblastoma, and fatty liver diseases. The transcription factors E2F1, HSF1, SIRT1, RELA, NFKB, JUN, and MYC were found to be responsible. When data mining was performed on citrinin targets, the top five functional descriptions were a cell's response to an organic cyclic compound, the netrin-UNC5B signaling pathway, lipids and atherosclerosis, thyroid cancer, and controlling the transcription of the PTEN gene.

The presence of the p-aryl/cyclohexyl ring in the N -(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazine carbothioamide derivative (2C) is reported to enhance the antifungal properties when compared to those of itraconazole. Serum albumins present in plasma bind and transport ligands, including pharmaceuticals. This study explored 2C interactions with BSA using spectroscopic methods such as fluorescence and UV-visible spectroscopy. In order to acquire a deeper comprehension of how BSA interacts with binding pockets, a molecular docking study was carried out. The fluorescence of BSA was quenched by 2C via a static quenching mechanism since a decrease in quenching constants was observed from 1.27 × 10 5 to 1.14 × 10 5 . Thermodynamic parameters indicated hydrogen and van der Waals forces responsible for the BSA-2C complex formation with binding constants ranging between 2.91 × 10 5 and 1.29 × 10 5 , which suggest a strong binding interaction. Site marker studies displayed that 2C binds to BSA's subdomains IIA and IIIA. Molecular docking studies were conducted to further comprehend the molecular mechanism of the BSA-2C interaction. The toxicity of 2C was predicted by Derek Nexus software. Human and mammalian carcinogenicity and skin sensitivity predictions were associated with a reasoning level of equivocal, inferring 2C to be a potential drug candidate.

Wheat germ oil (WGO) is the richest source of unexplored antioxidants and anti-inflammatory compounds. In this study, we identified the constituents of WGO by gas chromatography-mass spectrometry (GC-MS). The physicochemical and pharmacokinetic behaviors were evaluated for the top 12 constituents with the common target FABP4. Three fatty acids with significant anti-inflammatory activity were evaluated for their interaction with FABP4 by molecular docking. The molecular mechanisms involved in anti-inflammatory responses were analyzed by various in-silico analytical tools and multidimensional data analysis. WGO showed anti-inflammatory activities via FABP4 interacting physically with target genes (77.84%) and by co-expressing with 8.01% genes. Primary targets for inflammatory pathways were PPARα, PPARγ, LPL, LEP, and ADIPOQ, as depicted by gene network enrichment analysis. The key pathways implicated were the metabolism of lipids, PPAR signaling, cellular response to alcohol, oxygen and nitrogen pathway, inflammatory response pathway, and regulation of the inflammatory pathway. The common transcription factors implicated were HNF1, AP2α, CEBP, FOX, STATS, MYC, Zic, etc. In this study, we found that WGO possesses anti-inflammatory potential via FABP4 binding to PPARα, PPARγ, LPL, LEP, and ADIPOQ gene expression by regulatory transcription factors HNF, AP2α, and CEPB., Competing Interests: The authors declare no conflict of interest.

Carbonic anhydrases (CA), having Zn 2+ metal atoms, are responsible for the catalysis of CO 2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR ( 1 H, 13 C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC 50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a , 6e , and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of -6.12, -6.99, and -6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

The crystal structure of N -((4-acetylphenyl)carbamothioyl)pivalamide (3) was synthesized by inert refluxing pivaloyl isothiocyanate (2) and 4-aminoacetophenone in dry acetone. The spectroscopic characterization ( 1 H-NMR, 13 CNMR, FT-IR) and single crystal assays determined the structure of synthesized compound (3). Systematic experimental and theoretical studies were conducted to determine the molecular characteristics of the synthesized crystal. The biological examination of (3) was conducted against a variety of enzymes i.e., acetyl cholinesterase (AChE), butyl cholinesterase (BChE), alpha amylase, and urease enzyme were evaluated. The crystal exhibited approximately 85% enzyme inhibition activity against BChE and AChE, but only 73.8 % and 57.9% inhibition activity against urease and alpha amylase was observed respectively. The theoretical calculations were conducted using density functional theory studies (DFTs) with the 6-31G (d, p) basis set and B3LYP functional correlation. The Frontier molecular orbital analysis revealed that the HOMO/LUMO energy gap was smaller, which corresponds to the molecule's reactivity. In terms of reactivity, the chemical softness value was found to be in good agreement with experimental values. In Crystal structure analysis, the intramolecular N-H•••O hydrogen bond generates a S 6) ring motif and N-H•••O interactions exist in crystal structure between the centroids of neighboring parallel aromatic (C4-C9) rings with a centroid to centroid distance of 3.9766 (7)Å. These intermolecular interactions were useful in structural stabilization. The Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis of the crystal structure the most substantial contributions to the crystal packing are from H ••• O and H ••• N/N ••• H interactions. Molecular docking studies were conducted to evaluate the binding orientation of synthesized crystal with multiple targets. The compound exhibited stronger interactions with AChE and BChE with binding energies of -7.5 and -7.6 kcal/mol, respectively. On the basis of in-vitro and in-silico findings, it is deduced that N -((4-acetylphenyl)carbamothioyl)pivalamide 3) possesses reactive and potent multiple target inhibitory properties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saeed, Ejaz, Khalid, Channar, Aziz, Wani, Zargar, Hassan, Ismail, Khalid, Hashmi, Hökelek and Aborode.)

Betaxolol is a relatively cardioselective β-adrenoceptor blocking drug, with no partial agonist (intrinsic sympathomimetic) activity and weak membrane-stabilizing (local anesthetic) activity. Betaxolol selectively and competitively binds to and blocks beta-1 (β1) adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. When applied topically in the eye, this agent reduces aqueous humor secretion and lowers the intraocular pressure (IOP). In addition, betaxolol prevents the release of renin, a hormone secreted by the kidneys that causes constriction of blood vessels. Betaxolol (S)-(-)-enantiomer shows higher pharmacological activity. This chapter provides a complete review of nomenclature, physiochemical properties, methods of preparation, identification techniques and various qualitative and quantitative analytical techniques as well as pharmacology of betaxolol. In addition, the chapter also includes review of several methods for enantiomeric separation betaxolol using chromatographic techniques., (© 2021 Elsevier Inc. All rights reserved.)

Topiramate, 2,3:4,5-di-O-isopropylidene-β-d-fructopyranose sulfamate, is a potent antiepileptic drug with a broad spectrum of activity. It is effective in both partial and generalized seizures. Topiramate was also found to have significant efficacy in migraine prevention with considerable reductions in the frequency of migraine headaches. The most common adverse events, which may accompany the use of topiramate, are paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease and taste perversion. The weight loss observed with the use of topiramate in obese, epileptic patients, afforded the approval of this drug as an anti-obesity medication. This action is thought to be based on the selective inhibition of mitochondrial carbonic anhydrase isoforms. This profile is prepared to discuss and explain physical characteristics, proprietary and nonproprietary names of topiramate. It also includes methods of preparation, thermal and spectral behavior and methods of analysis. Pharmacokinetics, metabolism, excretion and pharmacology together with its uses and applications are also discussed., (© 2019 Elsevier Inc. All rights reserved.)