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The present study evaluated the antioxidant and anti-inflammatory properties of Cleome arabica (CA) fruit extract against bisphenol A (BPA)-induced ovarian injury in female Wistar rats. The antioxidant activity was estimated by the total antioxidant capacity (TAC) and superoxide radical (NBT) content. For the in vivo analyses, 24 animals were divided into the following 4 groups: the control group; the BPA group (50 mg/kg BW BPA for 30 days); the BPA + CA group (50 mg/kg BW BPA and 50 mg/kg BW CA); and the CA group (50 mg/kg BW CA). The in vitro results demonstrated that CA exhibited strong antioxidant activity and scavenged O2•− radicals.. Pharmacokinetic properties were also explored, reflecting the physiological dynamics of the five active molecules (quercetin, catechin, kaempferol, rosmarinic acid, and naringenin). The in vivo findings revealed a significant increase in body weight associated with a significant increase in plasma C-reactive protein (CRP), proinflammatory cytokines (IL-1, IL-6, and TNF-α), and testosterone levels (p < 0.01). In addition, ovarian histological disruption was observed. However, co-administration of CA extract significantly improved ovarian histological integrity and attenuated inflammatory and androgenic disturbances. Moreover, in silico investigations showed that CA compounds interacted more strongly with the active sites of IL-1β, IL-6, or TNF-α. The best binding energy was observed between catechin (five H-bonds) and IL-1β and IL-6, at −6.0 and −6.1 kcal/mol, respectively, and between rosmarinic acid (four H-bonds) and TNF-α, at −6.4 kcal/mol. The present study supports the use of Cleome arabica in the treatment of infertility for female polycystic ovary syndrome (PCOS) patients. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent cause of cancer-related deaths worldwide, and mortality rates are on the increase. This study aims to evaluate the potential of bioactive compounds from Clibadium surinamense L. leaves as inhibitors of AKT1 protein interactions, which play a crucial role in tumor growth mechanisms. Leaves of Clibadium surinamense L., obtained from Padangsidimpuan, North Sumatra, were extracted using methanol at a ratio of 1:20 for 48 h. The resulting extract was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS) to identify the bioactive compounds. Drug likeness was then assessed according to Lipinski's rules, and molecular docking analysis was performed using Autodock Vina. GC-MS results identified 11 bioactive compounds, including 2-Cyclopenten-1-one and Hexadecanoic acid, methyl ester. Of the 8 compounds evaluated, 6 met the criteria for drug candidates. Molecular docking analysis revealed significant interactions between the bioactive compounds and the AKT1 protein. These findings suggest that bioactive compounds from Clibadium surinamense L. have potential as AKT1 interaction inhibitors, which could enhance cancer treatment mechanisms. This research paves the way for further studies on the therapeutic applications of these compounds in breast cancer treatment. [ABSTRACT FROM AUTHOR]

α,β-unsaturated carbonyl compounds have extensive applications in various fields, such as organic, inorganic, analytical, and biological. In the modern era, they offer excellent pharmacological application prospects and find widespread use in the pharmaceutical industry. The current study revealed the synthesis and characterization of a novel 3-(2-bromo-5-fluorophenyl)-1-(thiophen-2-yl) prop-2-en-1-one (CY3). In vitro their antimicrobial (Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii), antifungal (Candida parapsilosis, Candida tropicalis, and Candida albicans), cytotoxicity (VERO and Hep-G2 cells), in silico, and molecular docking analysis were also performed. The in-silico analysis evaluated the drug-likeness properties of the compound CY3 using various filtering rules, including Lipinski's, Ghose filter, Veber, Egan, Muegge, and Medicinal Chemistry alerts such as Pan Assay Interference Structures (PAINS), Brenk, and Lead-likeness. Then, molecular docking studies performed using the AutoDock (AD4), Vina, and iGEMDOCK tools to determine the mechanism by which the CY3 compound interact with the bacterial strains. Here, five different receptors were selected, such as DNA gyrase, glucose 6-phosphate synthase (GlmS), dihydrofolate reductase (DHFR), dehydrosqualene synthase (DHSS), and undecaprenyl pyrophosphate synthase (UDPPS), for molecular docking analysis. The CY3 compound showed a good binding affinity with the two target proteins, DHFR and DHSS, respectively, with maximum binding energies of about − 7.07 and − 7.05 kcal/mol. The synthesized CY3 compound exhibited moderate antibacterial activity with a MIC value > 100 µg/mL against all five bacterial strains and moderate antifungal activity with a MIC value > 50 µg/mL against all three fungal strains. Drug-likeness analyses also support their favourable bioavailability. [ABSTRACT FROM AUTHOR]

Wound infection poses a significant global health threat, as it is a leading cause of morbidity and mortality among surgical patients and individuals with burn injuries, resulting in substantial healthcare burdens and devastating outcomes worldwide. Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli have frequently been implicated as major pathogens causing wound infections. This has eventually and consistently given rise to antimicrobial resistance divulging a need to mitigate infectious outbreaks. Herein, we employed a computational density functional theory (DFT) method at ωB97XD/6-311++g(d, p) level of theory to evaluate the performance of the thiophene derivative 5-(4-bromo-5-(methylthio)thiophen-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol 4, which is experimentally synthesized into five compounds (4a, 4b, 4c, 4d, and 4e). The chemical reactivity, kinetic stability, nature of interactions and functional characteristics of the thiophene derivatives were ascertained. The resistance gene PDB ID: 1K25, 2D45, 4UOT, and 7K2X were employed and docked with thiophene derivatives. Interestingly, molecular docking analysis demonstrated that ligands 4a, 4b, 4c, 4d, and 4e are more effective against proteins 1K25, 4U0T and 7K2X than amoxicillin and methicillin. Upon docking with the 2D45 protein, compounds 4c and 4e (− 5.9 kcal/mol) exhibited potential similar to that of methicillin (− 5.9 kcal/mol), while 4a and 4b showed slightly better affinities (− 6.1 kcal/mol and 6.0 kcal/mol). Using Lipinski's Rule of Five (Ghose filter, Veber rules, Muegge filter, and Egan's rule), 4d and 4e were determined to be the most promising candidates for drug development due to their compliance with all evaluated criteria, indicating favourable properties for oral bioavailability and drug likeness. This research suggested that thiophene derivatives can serve as promising antibacterial agents against wound-infected bacteria. [ABSTRACT FROM AUTHOR]

The purpose of this paper was to evaluate the phytochemical profile of Acacia cyclops trunk bark methanol extract using LC-MS/MS, as well as to assess its antioxidant and anti-tyrosinase activities. Thus, total phenolic and flavonoid contents of the studied extract were established and 19 compounds were detected and quantified. In addition of their antioxidant potential against DPPH and ABTS assays, in vitro and in silico studies were adopted to evaluate tyrosinase inhibitory property of A. cyclops extract. Methanol trunk bark extract showed significant total phenolic content, antioxidant potential in terms of free radical scavenging, as well as an interesting tyrosinase inhibitory action (IC50= 05.12 ± 0.41 μg/mL). The molecular docking analysis and the drug-likeness prediction of the major selected compounds supported the significant anti-tyrosinase activity of the studied extract. The obtained results suggest that A. cyclops extract could be a promising candidate in the treatment of skin hyperpigmentation disorders. [ABSTRACT FROM AUTHOR]

AbstractThis study investigates the drug-like properties of target molecules containing thiophene sulfonamide groups (7a–7s) using computational molecular docking techniques. The binding interactions of these derivatives were assessed using protein 2NSD (Enoyl acyl carrier protein reductase InhA, complexed with N-(4-methylbenzoyl)-4-benzylpiperidine, PDB DOI: 10.2210/pdb2NSD/pdb) as the receptor. Molecular docking results revealed notable docking scores for all compounds, ranging from −6 to −12 kcal/mol. Compounds 7e, 7i, and 7f, in particular, demonstrated impressive glide scores (>11 kcal/mol) and were selected for further analysis through molecular dynamics simulations, which provided deeper insights into their dynamic behavior and stability. The drug-like properties of these molecules were evaluated based on Lipinski’s Rule of Five and ADME (Absorption, Distribution, Metabolism, and Excretion) criteria and compared with known drugs. Additionally, we synthesized these target molecules (7a–7s) using Suzuki-Miyaura coupling with a nickel catalyst replacing palladium. The chemical structures of the synthesized compounds were confirmed through elemental analysis, LC-MS,1H-NMR, and 13C-NMR spectroscopy. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus, a notorious member of the ESKAPE pathogens, poses significant public health challenges due to its virulence and multidrug-resistant nature, particularly in methicillin-resistant S. aureus (MRSA) strains. With the increasing threat of antibiotic resistance, there is an urgent need to develop novel antibiotic agents. This study therefore aims to explore the antibacterial potential of 1,2-dibenzoylhydrazine (DBH) as a scaffold against S. aureus drug target enzymes, using integrated computational approaches. The study utilized molecular docking, lead optimization, and structure-based virtual screening techniques to evaluate the binding affinities of DBH and its derivatives against various S. aureus enzymes. Prime/MM-GBSA calculations were performed to validate the binding affinities obtained, and molecular dynamics (MD) simulations were conducted to assess the stability of the DBHs-enzyme complexes. Results indicated that, out of twenty enzymes from S. aureus examined against DBH, carotenoid dehydrosqualene synthase was predicted as a suitable target enzyme for DBH, showing a binding affinity of -8.027 kcal/mol. A lead optimization operation of the compound generated 27 DBH derivatives out of which four exhibited enhanced binding affinities compared to both DBH and a standard antibiotic, ofloxacin. The QSAR model predicted that, DBH and molecule_D_1 have higher PIC50 of 4.779 µM compared with the standard drug (ofloxacin = 4.678 µM). MD simulations confirmed the stability of the top-scoring derivatives within the enzyme's binding pocket, with RMSD and RMSF analyses supporting their potential as inhibitors of the enzyme. In conclusion, this study has predicted the effect of DBH derivatives on S. aureus based on their in silico inhibitory capacity against the carotenoid dehydrosqualene synthase from the organism. Future work will seek to experimentally validate these findings against the suggested enzyme. [ABSTRACT FROM AUTHOR]

Ajuga orientalis, a perennial herb from the Lamiaceae family, is traditionally used in Jordanian folk medicine for its therapeutic properties. This study evaluates the phytochemical profile, cytotoxicity, drug‐likeness, and molecular docking of the methanolic extract of A. orientalis to explore its potential as a source of novel therapeutic agents. GC‐MS analysis identified 21 compounds, including oleic acid methyl ester (27.1%) and palmitic acid (12.5%). The extract demonstrated significant concentration‐dependent cytotoxicity against RAW264.7 macrophage cells, with an IC50 of 91.5 µg/mL. Molecular docking studies revealed fundamental interactions of phytochemicals with cancer‐related proteins, including VEGFR2 and TLR4/MD‐2, showing strong binding affinities. Notably, 1,7‐di(2,5‐dimethylphenyl)‐2,2,4,4,6,6‐hexamethyl‐1,3,5,7‐tetraoxa‐2,4,6‐trisilaheptane and the 2TBDMS derivative of 4‐hydroxybenzeneacetic acid exhibited promising interactions, indicating potential for inhibiting angiogenesis and modulating immune responses. Drug‐likeness evaluation of 18 compounds showed that 11 meet the criteria for oral bioavailability, though some challenges for drug development remain. This research underscores the therapeutic potential of A. orientalis compounds in cancer treatment and immune modulation, suggesting further experimental validation and development of these bioactive compounds. [ABSTRACT FROM AUTHOR]

Background: The triazole ring is an attractive structural unit in medicinal chemistry, and chemical compounds containing this type of system in their structure exhibit a wide spectrum of biological activity. They are used in the development of new pharmaceuticals. One of the basic parameters considered in the initial phase of designing potential drugs is lipophilicity, which affects the bioavailability and pharmacokinetics of drugs. Methods: The study aimed to assess the lipophilicity of fifteen new triazole derivatives of aniline using reversed phase thin layer chromatography (RP-TLC) and free web servers. Based on in silico methods, the drug similarity and pharmacokinetic profile (ADMET) of synthesized molecules were assessed. Results: A relationship was observed between the structure of the title compound, including the position of substitution in the aniline ring, and the experimental values of lipophilicity parameters (logPTLC). Most of the algorithms used to determine theoretical logP values showed less sensitivity to structural differences of the tested molecules. All obtained derivatives satisfy the drug similarity rules formulated by Lipinski, Ghose and Veber. Moreover, in silico analysis of the ADME profile showed favorable values of parameters related to absorption. [ABSTRACT FROM AUTHOR]

The compounds 2-chloro-N-(3-methoxyphenyl)acetamide (m-acetamide) and 2-(3-methoxyphenylamino)-2-oxoethyl methacrylate (3MPAEMA) were synthesized in this study for the first time in the literature. FTIR, 1H, and 13C NMR spectroscopic techniques were used to characterize it. Subsequently, computational techniques were used to assess various ADME factors, such as drug-likeness properties, bioavailability score, and adherence to Lipinski's rule. Finally, molecular docking experiments were conducted with the human topoisomerase α2 (TOP2A) protein to verify and validate the reliability and stability of the docking procedure. The results of the docking scores, which quantify binding affinity, indicated that these derivatives exhibited a stronger affinity for TOP2A. [ABSTRACT FROM AUTHOR]

Lipinski's Rule of Five and Ghose filter are empirical guidelines for evaluating the drug-likeness of a compound, suggesting that orally active drugs typically fall within specific ranges for molecular descriptors such as hydrogen bond donors and acceptors, weight, and lipophilicity. We revisit these practices and offer a more analytical perspective using the Dominance-based Rough Set Approach (DRSA). By analyzing representative samples of drug and non-drug molecules and focusing on the same molecular descriptors, we derived decision rules capable of distinguishing between these two classes systematically and reproducibly. This way, we reduced human bias and enabled efficient knowledge extraction from available data. The performance of the DRSA model was rigorously validated against traditional rules and available machine learning (ML) approaches, showing a significant improvement over empirical rules while achieving comparable predictive accuracy to more complex ML methods. Our rules remain simple and interpretable while being characterized by high sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Abstract α,β-unsaturated carbonyl compounds have extensive applications in various fields, such as organic, inorganic, analytical, and biological. In the modern era, they offer excellent pharmacological application prospects and find widespread use in the pharmaceutical industry. The current study revealed the synthesis and characterization of a novel 3-(2-bromo-5-fluorophenyl)-1-(thiophen-2-yl) prop-2-en-1-one (CY3). In vitro their antimicrobial (Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii), antifungal ( Candida parapsilosis, Candida tropicalis, and Candida albicans), cytotoxicity (VERO and Hep-G2 cells), in silico, and molecular docking analysis were also performed. The in-silico analysis evaluated the drug-likeness properties of the compound CY3 using various filtering rules, including Lipinski’s, Ghose filter, Veber, Egan, Muegge, and Medicinal Chemistry alerts such as Pan Assay Interference Structures (PAINS), Brenk, and Lead-likeness. Then, molecular docking studies performed using the AutoDock (AD4), Vina, and iGEMDOCK tools to determine the mechanism by which the CY3 compound interact with the bacterial strains. Here, five different receptors were selected, such as DNA gyrase, glucose 6-phosphate synthase (GlmS), dihydrofolate reductase (DHFR), dehydrosqualene synthase (DHSS), and undecaprenyl pyrophosphate synthase (UDPPS), for molecular docking analysis. The CY3 compound showed a good binding affinity with the two target proteins, DHFR and DHSS, respectively, with maximum binding energies of about − 7.07 and − 7.05 kcal/mol. The synthesized CY3 compound exhibited moderate antibacterial activity with a MIC value > 100 µg/mL against all five bacterial strains and moderate antifungal activity with a MIC value > 50 µg/mL against all three fungal strains. Drug-likeness analyses also support their favourable bioavailability.

Emergence of COVID-19 and thereafter intensive research on bioactive natural compounds against SARS-CoV-2, identified a large number of phytochemicals (i.e., plants-derived) and mycochemicals (i.e., fungi-derived) as potential inhibitors with proven antiviral properties against SARS-CoV-2, but there are no comparative study on the reported compounds. A comparative study among the previously identified/reported main protease (Mpro) inhibitors of SARS-CoV-2 can lead to the most potent compound that eventually helps to make an effective drug lead against SARS-CoV-2. Through manual literature curation, we selected 57 potential bioactive compounds and screened them against Mpro protein of SARS-CoV-2. A series of in silico screening such as binding affinity, drug-like properties, pharmacokinetic, physicochemical, and ADMET studies identified top ten compounds as potential Mpro inhibitors. Further, docking studies prioritized the top two compounds namely Norquinadoline A and Quinadoline B, based on their predicted affinity for the target protein. Binding free energy calculations further emphasized them as top candidates for effective Mpro inhibitors that hold promise for drug development against COVID-19. In-depth molecular dynamics studies and MM/PBSA analysis culminated in the recognition of Norquinadoline A as the most potent Mpro inhibitor of SARS-CoV-2. Thus, Norquinadoline A can be used as lead compound in further drug discovery process after in vitro and in vivo experimental studies.

Background & objectives: Anopheles funestus is playing an increasingly important role in malaria transmission in sub-Saharan Africa. Trehalase, an enzyme required for trehalose breakdown, is important for mosquito flight and stress adaptation. Hence, its inhibition has emerged as a promising malaria management strategy. Methods: A collection of 1900 natural compounds from the ZINC database were screened against the 3D modeled structure of An. funestus trehalase protein using in silico tools. ADMET-AI, a web-based platform, was used to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the selected compounds. Results: We report 5 natural compounds namely, ZINC00488388, ZINC00488525, ZINC00488566, ZINC00488304, and ZINC00488456 that demonstrated strong binding affinity to the trehalase protein. These compounds interacted with critical residues of the trehalase protein and exhibited good drug-like characteristics. Interpretation & conclusion: These compounds show promise as trehalase protein inhibitors for malaria management. Nonetheless, additional experimental studies are required to optimize these compounds as potential trehalase inhibitors.

Nowadays, the physiopathological and molecular mechanisms of multiple diseases have been identified, thus helping scientists to provide a clear answer, especially to those ambiguities related to chronic illnesses. This has been accomplished in part through the contribution of a key discipline known as bioinformatics. In this study, the bioinformatics approach was applied on four compounds identified in Centaurea tougourensis, using two axes of research: an in silico study to predict the molecular characteristics, medicinal chemistry attributes as well as the possible cardiotoxicity and adverse liability profile of these compounds. In this context, four compounds were selected and named, respectively, 2,5-monoformal-l-rhamnitol (compound 1), cholest-7-en-3.beta.,5.alpha.-diol-6.alpha.-benzoate (compound 2), 7,8-epoxylanostan-11-ol, 3-acetoxy- (compound 3), and 1H-pyrrole-2,5-dione, 3-ethyl-4-methyl- (compound 4). The second part looked into molecular docking, which objective was to evaluate the possible binding affinity between these compounds and the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor. Results indicated that compounds 1 and 4 were respecting Pfizer and giant Glaxo-SmithKline rules, while compounds 2 and 3 exhibited an optimal medicinal chemistry evolution 18 score. The structural and molecular features of almost all tested compounds could be considered optimal, indicating that these phyto-compounds may possess drug-likeness capacity. However, only compounds 1 and 4 could be considered non-cardiotoxic, but with a level of confidence more pronounced for compound 1 (80%). In addition, these four biocompounds could preferentially interact with G protein-coupled receptor, ion channel, transporters, and nuclear receptors. However, the heat map was less pronounced for compound 2. Data also indicated that these four compounds could possibly interact with serotonin 5-HT2A receptor, but in an antagonistic way. This research proved once again that plants could be crucial precursors of pharmaceutical substances, which could be helpful to enrich the international pharmacopoeia.

Dendrimers are polymeric compounds which exhibit notable advantages, particularly in medicinal chemistry. The therapeutic potential of these molecular architectures can be screened through in silico method which facilitates the identification of the ones with the highest potential for further investigation. Here, we have reported the in silico investigation of a series of dendritic architecture based on para‐substituted aniline. Density functional theory (DFT) method was employed to optimize the structures and to analyze the quantum chemical parameters. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling was additionally assessed, which unveiled favorable drug‐like characteristics and moderate to good bioactivity across all compounds. Utilizing the drug‐likeness property in machine learning techniques, the potential for predicting novel drug‐like dendrimers was explored. [ABSTRACT FROM AUTHOR]

In this project, para‐carboxamidostilbene derivatives were synthesized using the Heck coupling reaction, confirmed through various analytical techniques such as FT‐IR, HRMS, and NMR analyses, and tested in vitro to evaluate their α‐amylase inhibitory activity. In silico molecular docking was employed to model the binding interactions of compounds with α‐amylase. Pharmacokinetic properties (ADME) and drug‐likeness were also examined. Structure activity relationship (SAR) analysis was conducted to establish the relationship between the chemical structure and α‐amylase inhibitory activity. The synthesized compounds exhibited significant α‐amylase inhibitory activity with IC50 values ranging from 15.0 to 37.5 µM in comparison with acarbose (IC50 = 30.2 ± 1.9 µM). Among them, compounds 6d–6f and 7c–7f demonstrated promising inhibitory activity. Furthermore, molecular docking studies revealed strong interactions between the studied molecules and the α‐amylase binding pocket. The drug‐likeness prediction results indicated that all synthesized compounds adhered to Lipinski's rule of five, suggesting their suitability as drug‐like molecules. Additionally, the assessment of ADMET properties indicated favorable absorption profiles, particularly in terms of human intestinal absorption (HIA). Overall, this study successfully identified several para‐carboxamidostilbene derivatives as potential α‐amylase inhibitors for the treatment of T2DM. [ABSTRACT FROM AUTHOR]

Pharmacokinetic and toxicity-related properties are the major causes of attrition in drug development. The emerging roles of terpenes in drug discovery require an understanding of these properties for structure modification and possible repurposing. This study evaluated the druglikeness, pharmacokinetic, and toxicity profiles of diverse phytotoxic terpenes obtained from the Toxic Plants-Phytotoxins (TPPT) database using different in silico algorithms. The database, of 1586 phytotoxins, was filtered to obtain 576 phytotoxic terpenoids (PhytoTerp). The Lipinski parameters, potential targets, pharmacokinetic profiles and toxicity on various organ endpoints were implemented using SwissADME, SwissTargetPrediction, the pkCSM and ProTox II webservers. Drug likeness prediction showed that 9.55% of the PhytoTerp obeyed Lipinski's rule of five. The toxicity profiles showed that none of the compounds inhibited hERG I, while 12.73% inhibited hERG II. In addition, 25.45% of the compounds elicited both AMES and liver toxicities; and 32.73% caused skin sensitivity. Furthermore, 72.73 and 76.36% showed high Caco-2 and skin permeability respectively. The p-glycoprotein was extruded by 29.09% and inhibited by 34.45% of PhytoTerp; 47.27% of the compounds readily crossed the blood-brain barrier, 23.64% penetrated the central nervous system, 56.36% were sensitive to cytochrome p450 isoenzymes, 36.37% inhibited cytochrome p450 isoenzymes, 49.09% were immune-toxic, 1.82% were toxic to cells, 14.55% would cause cancer, and 21.82% showed high tolerated doses in humans. All the PhytoTerp demonstrated high intestinal absorption while a significant number demonstrated moderate bioavailability. This study identified marrubiin and nine other terpenoids as drug-like, non-toxic, and highly bioavailable with potential for further optimization, and development. [ABSTRACT FROM AUTHOR]

The dopamine transporter (DAT), responsible for the regulation of dopaminergic neurotransmission, is implicated in the etiology of several neuropsychiatric disorders which, in turn, have contributed to high rates of disability and numerous deaths in recent years, significantly impacting the global health system. Although the research for new drugs for the treatment of neuropsychiatric disorders has evolved in recent years, the availability of DAT-selective drugs that do not generate the same psychostimulant effects observed in drugs of abuse remains scarce. Therefore, we performed a QSAR study based on a dataset of 36 methylamine derivatives described as DAT inhibitors. The model was obtained based only in descriptors derived from 2D structures, and it was validated and generated satisfactory results considering the metrics used for internal and external validation. Subsequently, a virtual screening step also based on 2D similarity was performed, where it was possible to identify a total of 1157 compounds. After a series of reductions of the set using toxicity filters, applicability domain evaluation, and pharmacokinetic properties in silico assessment, seven hit compounds were selected as the most promising to be used, in future studies, as new scaffolds for the development of new DAT inhibitors. [ABSTRACT FROM AUTHOR]

Mycoplasma genitalium (M. genitalium) poses a significant challenge in clinical treatment due to its increasing antimicrobial resistance. This study investigates alternative therapeutic approaches by targeting the cofactor-independent phosphoglycerate mutase (iPGM) enzyme with phytochemicals derived from ethnobotanical plants. In silico screening identified several promising inhibitors, with 2-carboxy-D-arabinitol demonstrating the highest binding affinity (− 9.77 kcal/mol), followed by gluconic acid (− 9.03 kcal/mol) and citric acid (− 8.68 kcal/mol). Further analysis through molecular dynamics (MD) simulations revealed insights into the binding mechanisms and stability of these phytochemicals within the iPGM active site. The MD simulations indicated initial fluctuations followed by stability, with intermittent spikes in RMSD values. The lowest RMSF values confirmed the stability of the ligand–protein complexes. Key residues, including Ser-61, Arg-188, Glu-62, Asp-397, and Arg-260, were found to play crucial roles in the binding and retention of inhibitors within the active pocket. These findings suggest that the identified phytochemicals could serve as novel antimicrobial agents against M. genitalium by effectively inhibiting iPGM activity. [ABSTRACT FROM AUTHOR]

Streptomyces aureofaciens widely produces the antibiotic tetracycline and many other compounds during fermentation. The compounds have yet to be known for their antibacterial potential. This work aims to determine new antibiotics or other possible antibacterial compounds produced by marine S.aureofaceiens A3 through an in silico molecular docking method. The ethyl acetate (EA) extracts from fermented marine S. aureofaciens A3 in ISP4 medium enriched with seawater components showed strong antibacterial activity. The antibacterial activity of EA extracts during 6-12 days of fermentation was carried out by the Kirby-Bauer method and the compounds of EA extracts were analyzed by GC/MS. Compounds identified by GC/MS were ligands for an in silico molecular docking study against four target proteins (DNA gyrase, topoisomerase IV, PBP 1a, and DHFR) of pathogenic bacteria. The drug-likeness of selected chemicals as antibacterial agents was assessed using Lipinski's Rule of Five. The results showed the prospective compounds as a narrow-spectrum antibacterial, including 3,5-di-tert-Butyl-4-hydroxyphenylpropionic acid against PBP 1a and Benzenepropanoic acid, and 3,5-bis (1,1-dimethyl ethyl)-4-hydroxy-, methyl esters against DHFR. Substances with broad-spectrum antibacterial activity, such as 3-Acetylphenanthrene and 3-(p-Ethoxyphenyl)-5-(O-tolyloxymethyl)-2-oxazolidone, against multitarget DNA gyrase B and DHFR, 7,9-Di-tert-butyl-1-oxaspiro (4,5) Deca-6,9-diene-2,8-dione against PBP1a and DHFR, and isobenzofuro [5,6-b] benzofuran-8-carboxylic acid, 1,3-dihydro-7,10-dimethoxy-9-methyl-1-oxo-, methyl ester against DNA gyrase B, PBP 1a, and DHFR. On the 12th day of fermentation, two compounds were identified: isobenzofuro[5,6-b] benzofuran-8-carboxylic acid, 1,3-dihydro-7,10-dimethoxy-9-methyl-1-oxo-, methyl ester, and 3-(p-Ethoxyphenyl)-5-(O-tolyl oxy methyl)-2-oxazolidone. This is the first report that these two compounds, known as potential drugs like antibiotics through in silico molecular docking, were first produced by Streptomyces species. [ABSTRACT FROM AUTHOR]

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Cosmos caudatus is a widely used traditional medicinal plant in Indonesia for cancer treatment. However, the mechanism of action of plants in treating breast neoplasms remains unclear. Thus, the active ingredients of C. caudatus and possible molecular pathways against breast neoplasms were investigated using pharmacological networks. The active compounds were screened using Lipinski and ADME parameters. Targets for the compounds were obtained using SwissTargetPrediction. Target diseases were identified using the Therapeutic Target Database, whereas disease pathways were analyzed using the Kyoto Encyclopedia of Genes and Genomes. Network pharmacology was constructed using Cytoscape. Protein-protein interactions were constructed using STRING. Gene ontology and KEGG were analyzed using DAVID. Molecular docking confirmed that the compounds and targets exhibited the best interactions. The compounds, targets, and pathways with the highest degrees in the breast neoplasm network were eriodictyol, ABCC1, and signal transduction, respectively. EGFR is the key target of PPIs. GO enrichment in BP, MF, CC, and KEGG regulated NF-KB transcription factor activity, chromatin, transcription coactivator binding, and pathways in cancer, respectively. Molecular docking with the best score on interaction 5-O-methylvisammioside-SLC2A1 (PDB ID: 6THA) (-10.3 kcal mol-1). The compound 5-O-methylvisammioside may have pharmacological activity in breast cancer through signal transduction pathways. [ABSTRACT FROM AUTHOR]

• Croton is a genus with over 1300 species that are endemic to the tropics and subtropics. • Diterpenoids make up 67.2 % of the compounds reported in this genus. • Based on predicted drug-likeness, 38 % of Croton compounds obey Lipinski's rule of five. • Croton compounds have comparable physicochemical properties to FDA-approved drugs. The genus Croton (Euphorbiaceae family) is constituted of approximately 1300 species with remarkable ethnomedicinal backgrounds supported by extensive pharmacological studies alongside over 900 compounds associated with some of the activities. However, there is no systematic review of the compounds' physicochemical features in tandem with their absorption, distribution, metabolism, extraction, and toxicity (ADMET) to corroborate both ethnomedicinal and pharmacological potential. This study focused on a virtual analysis of the physicochemical-ADMET properties of compounds from the genus Croton reported between 1990 and 2024. Various electronic databases, namely Google, Google Scholar, Scopus, ScienceDirect, Biomed Central, and Pubmed, were used to search for information related to the chemistry and pharmacology of Croton species. The physicochemical, ADMET and Scaffold information of the reported croton compounds were obtained from SWISSADME, pKCSM, and Data Warrior webservers, which were then analyzed by Origin Pro 2023 statistical software. Diterpenoids (67.2 %), alkaloids (11.1 %), sesquiterpenes (4.7 %), flavonoids (3.2 %), other terpenoids (Sesterterpenoid and triterpenoids; 2.7 %), monoterpenoids (1.7 %), megastigmane glycosides (2.2 %), proanthocyanidins (0.8 %), and other assorted compounds (6.4 %) make up the total of 900 compounds reported among the genus Croton between 1990 and 2024. Based on principal component analysis (PCA) results (PC1 and PC2, with total variances of 43.79 % and 16.50 %, respectively), most of these compounds have the same chemical space as FDA-approved medications. The biological activity that was most frequently reported was cytotoxicity (52 %) followed by anti-inflammatory actions (13 %). After the ADME screening, 38 % of the Croton compounds met the predetermined criteria for drug-likeness while toxicity analysis cleared 35.487 %, as nontoxic. The primary appropriate therapeutic candidates identified by the post- ADMET analysis were clerodanes, kauranes, labdanes and abietanes compounds, with respective ratios of 10, 10, 10, and 5 %. Alkaloids (5 %), crotofolanes at 20 %, and sesquiterpene majorly at 40 % were too determined to be appropriate therapeutic candidates. The majority of these compounds are drug-like with recommended ADME/Tox profiles. Given the promising cytotoxic potential of compounds from the genus Croton , further studies are warranted to determine their therapeutic applications and optimize their pharmaceutical development. [Display omitted] [ABSTRACT FROM AUTHOR]

The study investigated the structure, spectroscopy, and chemical reactivity of 2′,4′-dichloroacetophenone using DFT and Hartree-Fock (HF) methods. The B3LYP and LC DFT (CAM-B3LYP) methods were applied to a 6–311++G (d, p) basis set combination. The bond angles and bond lengths are appraised in depth to understand the geometrical framework. The FT-IR and FT-Raman spectra of the respective compound were analyzed within the regions of 4000–400 cm−1 respectively. The experimental spectra were compared and discussed in connection with the theoretical spectrum. The VEDA program was implemented to accomplish the vibrational assignments of all the fundamentals highlighted using the PED analysis. TD-DFT level was used to explore the essential electronic properties of LUMO and HOMO energies. To forecast reactive sites, the MEP surface was examined. NBO was computed according to the compound’s reactivity and biological requirements. The Multi-Wave Function Analyzer 3.6 was designed to examine and compare topological inquiries, specifically focusing on the LOL and ELF. The detailed investigation specifies the drug likeness and molecular docking that assisted in the prediction of the physicochemical, pharmacokinetic, and biological availability of 2′,4′-dichloroacetophenone.

Epigallocatechin gallate (EGCG) has an effect in reducing sugar levels in the blood by inhibiting α-glucosidase enzyme, which is connected explicitly by hydrogen bonds and modifies the secondary structure and micro-environment of the enzyme reversibly and non-competitive. This study looks at the activity and interaction of EGCG as α-glucosidase inhibitors in the form of binding affinity and compound bonding profiles with receptors, including toxicity predictions and drug-likeness results. The research was performed in silico with molecular docking on Autodock Vina that integrated through PyRx, then viewed the compound's binding profile with receptor using Discovery Studio 2021 Client, toxicity prediction using ProTox-II and determination of drug-likeness using SwissADME based on Lipinski's rule of five guidelines. The control drugs used were acarbose and miglitol. The molecular docking results obtained that the binding affinity of EGCG is -8.4 kcal/mol while acarbose and miglitol are -13.8 kcal/mol and -5.3 kcal/mol respectively. There are amino acid residues similar to the drug control with various interactions like electrostatic, hydrophobic, and hydrogen bonds; then it has an inactive target for each toxicity parameter and has a molecular weight of 458.37 g/mol; Log P value of 1.01; H-bond donor of 8; and H-bond acceptor of 11 in the determination of drug-likeness. Based on these results, EGCG has effectiveness as α-glucosidase inhibitors predicted to be non-toxic; however, there are violations in determining drug-likeness.

Background & objectives: Vector-borne infectious diseases contribute significantly to global mortality, with over 700,000 annual deaths, and malaria alone accounts for more than 400,000 of these fatalities. Anopheles gambiae, a prominent mosquito species, serves as a primary vector for transmitting malaria to humans. To address this issue, researchers have identified the D1-like dopamine receptor (DAR), specifically DOP2, as a promising target for developing new insecticides. Methods: The three-dimensional structure of DOP2 from A. gambiae was unavailable; in-silico approach was used to model and validate DOP2 structure. The Discovery Studio 2021 program was used to identify potential binding sites on DOP2. Virtual screening of 235 anti-parasitic compounds was performed against DOP2 using PyRx 0.8. Results: The screening demonstrated strong binding and interactions with active site residues of DOP2 for five compounds: Diclazuril, Kaempferol, Deracoxib, Clindamycin, and Diaveridine. These compounds exhibited higher binding affinity values compared to the control (Asenapine). In addition, the predicted physiochemical properties for these compounds were within acceptable ranges and there were no violations in drug-likeness properties. Interpretation & conclusion: These compounds show promise as potential new insecticides targeting A. gambiae mosquito by inhibiting the DOP2 protein. However, additional experimental validation is required to optimize their efficacy as DOP2 inhibitors.

Abstract Nowadays, infectious diseases pose an alarming global threat to human health. The genus Senna is among the most well-known taxonomic categories commonly used in folk medicine to confront these challenges. Motivated by its traditional uses, a comprehensive study was conducted on the roots extract of Senna siamea, aiming to address the in vitro antibacterial and antioxidant efficacy of phytochemicals from the dichloromethane: methanol (1:1) roots extract of the plant, along with in silico computational studies. The separation of compounds was achieved using silica gel column chromatography. Whereas, the antibacterial and antioxidant activities were examined using paper disc diffusion and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays, respectively. Silica gel column chromatography of the dichloromethane: methanol (1:1) roots extract afforded lupeol (1), β-sitosterol (2a) and stigmasterol (2b), chrysophanol (3), betulinic acid (4), and glyceryl-1-hexacosanoate (5). Although these compounds have been previously reported from the plant, proof of their medicinal applications via in vitro and in silico studies is still lacking. Notably, our findings showed remarkable inhibition zones by the extract (18.00 ± 0.00 mm and 17.17 ± 0.24 mm) against E. coli and S. aureus, respectively, at 50 mg/mL compared to ciprofloxacin (23.33 ± 0.47 mm and 22.00 ± 0.00 mm, respectively), showcasing its potential antibacterial efficiency. Considerable inhibition zones were also recorded by chrysophanol (3) against E. coli (16.33 ± 0.24 mm) and S. pyogenes (16.00 ± 0.00 mm) at 2 mg/mL, compared to ciprofloxacin which showed 23.33 ± 0.47 mm and 21.67 ± 0.47 mm, respectively, signifying its potent antibacterial activities. In addition, the crude extract and chrysophanol (3) exhibited substantial IC50 values (1.24 and 1.71 µg/mL, respectively), suggesting their significant antioxidant potential compared to that of ascorbic acid (IC50: 0.53 µg/mL). Chrysophanol (3) fulfilled Lipinski’s rule with no violation and lupeol (1), β-sitosterol (2a), stigmasterol (2b), betulinic acid (4), and glyceryl-1-hexacosanoate (5) displayed one violation each which were in favor of the drug-likeness predictions. All the compounds exhibited no cytotoxicity and except betulinic acid (4), all the compounds also showed no carcinogenicity properties which were consistent with the prediction results of ciprofloxacin. The molecular docking computations revealed that all the compound isolates displayed strong and nearly strong binding affinities against all protein targets, ranging from − 6.6 kcal/mol to -9.2 kcal/mol (lupeol (1) against E. coli DNA gyrase B and topoisomerase II α, respectively). Thus, the present findings suggest the roots of Senna siamea for potential medicinal applications against multi-drug resistant pathogens hence validating its ethno-medicinal uses.

Background & Objectives: C-Kit, a receptor tyrosine kinase involved in intracellular signaling, has a mutated form that significantly contributes to the development of certain cancers. This study aimed to evaluate a series of benzo[a]phenazin-5-ol-tethered trisubstituted methane derivatives as potential pharmacophores for inhibiting C-Kit kinase. Materials & Methods: Benzo[a]phenazine-5-ol derivatives were sketched and converted into Mol2 files using Marvin software. Their three dimensional (3D) structures were generated and saved in PDB format. Molecular docking studies with the C-Kit kinase (PDB code 1t46) were performed using AutoDock 4.2. Additionally, the derivatives' physicochemical properties, ADME characteristics, and drug-likeness parameters were assessed with the SwissADME online tool. Results: Molecular docking studies of benzo[a]phenazin-5-ol derivatives (A-L) against C-kit kinase revealed that compounds A and C exhibited greater selectivity and stronger inhibitory effects than the reference drug, Sunitinib. Ligplot analysis demonstrated that compound A formed four hydrogen bonds with Arg791(A), Ile789(A), and His790(A), while compound C formed two hydrogen bonds with Ile571(A) and Ile789(A). ADME analysis indicated that all compounds, except C, D, and I, are potential P-gp substrates. Drug-likeness analysis showed one or two violations of Lipinski's rule of five. Conclusion: In summary, molecular docking studies identified compounds A and C as promising lead candidates for inhibiting C-kit kinase, demonstrating superior binding to the active site compared to Sunitinib. ADME and drug-likeness analysis revealed that compound A is a potential P-gp substrate with one violation of Lipinski's rule of five, making it the closest pharmacological match to Sunitinib and a strong candidate for further investigation. [ABSTRACT FROM AUTHOR]

To develop new alkaline phosphatase inhibitors, a series of new azo coumarin derivatives were designed by using computer aided drug designing and virtually assessed using online platforms. At first, the compounds were screened for ADMET, physicochemical properties, drug-likeness, toxicity studies and target prediction using pKCSM, SwissADME, SwissTargetPrediction and ProTox-II tools. The predictions were supported by in silico molecular docking with alkaline phosphatase enzyme using CB-Dock2 molecular docking tool. The compounds possessed good ADMET and physicochemical properties, drug-likeness and devoid of any immunotoxicity and cytotoxicity. The evaluated binding energy values reveal that all compounds fit favorably into the alkaline phosphatase active site displaying hydrogen bonding with different amino acid residues of the target protein and could be good scaffolds for designing new alkaline phosphatase inhibitors. These results collectively framed the way for the development of new azo coumarin derivatives as possible alkaline phosphates inhibitors. [ABSTRACT FROM AUTHOR]

An efficient one-pot multi-component reaction (MCR) of 2,3-dihydro-4(1H)-quinazolinone derivative achieved by the reaction of aryl/heteroaryl aldehyde, isatoic anhydride and substituted aniline in ethanol catalyzed by novel glutamic acid (Glu) under microwave irradiation is described. In this work, derivatives 4m, 4o, 4q and 4r are novel compounds among the synthesized derivatives. For the first time, the electrochemical behavior studies for the selected derivatives were tested using cyclic voltammetry, compounds 4l, 4m, 4p, 4o, and 4q showed good reducing and oxidizing potential, due to the presence of the functional groups. Molecular docking studies of the selected compounds (4l–r) verified, among them highest docking scored 4r and 4m (− 8.572 and − 8.959 kcal/mol) molecules, respectively. Furthermore, MM/PBSA calculation identified key residues that contribute to the binding energy, activity and assessed cytotoxicity. The in vitro anticancer evaluation of the synthesized compounds was tested against human ovarian cancer PA-1 cell line tested; compounds 4r and 4m exhibited exceptionally anti-proliferative activity very close to the reference drug doxorubicin (3.66 ± 0.07) with the IC50 value 7.53 ± 0.09 and 17.93 ± 0.12, respectively. According to swissADME study, the blood–brain barrier can be crossed majority of the derivatives tested, except 4n, and have high gastrointestinal absorption. [ABSTRACT FROM AUTHOR]

The process of drug discovery is widely known to be lengthy and resource-intensive. Artificial Intelligence approaches bring hope for accelerating the identification of molecules with the necessary properties for drug development. Drug-likeness assessment is crucial for the virtual screening of candidate drugs. However, traditional methods like Quantitative Estimation of Drug-likeness (QED) struggle to distinguish between drug and non-drug molecules accurately. Additionally, some deep learning-based binary classification models heavily rely on selecting training negative sets. To address these challenges, we introduce a novel unsupervised learning framework called DrugMetric , an innovative framework for quantitatively assessing drug-likeness based on the chemical space distance. DrugMetric blends the powerful learning ability of variational autoencoders with the discriminative ability of the Gaussian Mixture Model. This synergy enables DrugMetric to identify significant differences in drug-likeness across different datasets effectively. Moreover, DrugMetric incorporates principles of ensemble learning to enhance its predictive capabilities. Upon testing over a variety of tasks and datasets, DrugMetric consistently showcases superior scoring and classification performance. It excels in quantifying drug-likeness and accurately distinguishing candidate drugs from non-drugs, surpassing traditional methods including QED. This work highlights DrugMetric as a practical tool for drug-likeness scoring, facilitating the acceleration of virtual drug screening, and has potential applications in other biochemical fields. [ABSTRACT FROM AUTHOR]

A series of new pyridine-1,2,4-triazole-tagged 1,2,3-triazole hybrid molecules were obtained. The new compounds were synthesized via click chemistry of 1,2,4-triazole-3-thiopropargyl compounds and various azides. All compounds were fully characterized through their spectroscopic analyses. Furthermore, cytotoxic activity was assessed by screening against three cancer cell lines including human colon carcinoma (HCT116), human cervix carcinoma (HeLa) and human breast adenocarcinoma (MCF7). In addition, antimicrobial assessment against one gram-positive (Staphylococcus aureus ATCC 29,213), two Gram-negative bacteria (Sarcina lutea and Escherichia coli ATCC 25,922) and one fungal (Candida albicans NRRL Y–477) microorganism‏.‏ Molecular docking studies of the synthesized compounds against DNA gyrase were used to identify their binding ability to the target enzyme. The best docked molecules unveiled binding affinities to the target ranging from −9.5 to −8.8 kcal mol−1. The adsorption, distribution, metabolic, excretion, and toxicity (ADME/Tox) and drug-likeness analyses of the best docked compounds were evaluated using in silico techniques. Based on in vitro and in silico findings, these pyridine-1,2,4-triazole-tagged 1,2,3-triazole hybrid molecules may be helpful in designing potential antimicrobial drug candidates. [ABSTRACT FROM AUTHOR]

The compound salidroside was synthesized through the glucosylation of p-tyrosol. This research prioritizes the purification of salidroside over process optimization due to insufficient product yield. High-performance centrifugal partition chromatography (HPCP) with biphasic solid-phase extraction on graphitic material is employed to achieve a final product purity of 95%. Salidroside authentication was conducted using ESIMS2 and NMR. The study integrates computational and experimental approaches, employing B3LYP with basis set 6-311++G (d, p) in density functional theory (DFT). Various characterizing instruments, including 1HNMR, IR, UV visible, and others, consistent with AIM theory (atoms in molecules) for ellipticity and experimental outcomes, are utilized. Donor–acceptor interactions are explored through NBO research. The calculated energy difference between the frontier molecular HOMO and LUMO orbitals indicates the stability of salidroside. Molecular docking studies and electrophilicity index evaluations reveal salidroside's interactions with binding proteins, ranging from 5.718 to 7.405 kcal/mol. Molecular dynamics simulations assess biomolecular stability. Drug-likeness tests suggest salidroside's antibiotic properties, exhibiting similarities with capsaicin, methylsalicylate, menthol, allantoin, lupeol, morphine, and mitragynine. This research contributes valuable scientific insights essential for innovative drug development. [ABSTRACT FROM AUTHOR]

One-pot photo induced eosin-Y catalyzed, green approach for the synthesis of 5,5-diphenylimidazolidine-2,4-dione (Phenytoin) has been developed. The reaction proceeded smoothly, for a wide range of benzil and urea/thiourea derivatives as cheap and eco friendly reagents with high reactivity and good selectivity in DMSO as green solvent at room temperature in good to excellent yields. Biological studies such as drug-likeness and molecular docking have been conducted on the synthesized compounds, some of the compounds showed appreciable activity with least binding energy. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the chronic metabolic disorders that affects more than 16 million Filipinos. Proper education, medical intervention, and a good lifestyle can help individuals control and manage this disease. Spondias pinnata is one of the underutilized crops in the Philippines that is well-known for its satisfactory flavor and medicinal properties, including its antidiabetic activity. The quest for a natural and effective drug to manage diseases is a continuous work in progress. Drug discovery and design is a tedious and expensive process. Computer-aided drug design guides the design and makes the process more efficient and less costly. Molecular docking was used to determine the potential antidiabetic compounds from the 48 reported compounds found in S. pinnata fruit. Seven compounds namely squalene (−9.1 kcal/mol), rutin (−9 kcal/mol), catechin (−8.7 kcal/mol), quercetin (−8.5 kcal/mol), tocopherol (−8.4 kcal/mol), myricetin (−8.4 kcal/mol), and ellagic acid (−8.3 kcal/mol) showed binding affinities comparable to those of pioglitazone, a standard drug, with peroxisome proliferator-activated receptor gamma (PPARγ). Tocopherol and catechin showed good ADMET properties. Among the two compounds, catechin passed the four filters for drug-likeness. Thus, catechin could be a potential compound for the development of antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five. [ABSTRACT FROM AUTHOR]

This study revealed the first synthesis of seven novel coumarins annulated with heterocycle composed of four heteroatoms, one sulfur, and three oxygen atoms in a linear pattern. This is an effort to find readily available coumarin frameworks with a broad variety of biological properties that are both adjustable and easy to get. The synthetic annulates' structural framework was confirmed by means of spectroscopic techniques, which included 1H-NMR, 13C-NMR, and FTIR. The synthesized annulates were investigated in vitro for their biomedical potential as antioxidative stress, anti-inflammatory, antidiabetic, anticancer, and antimicrobial agents. In addition, their biosafety toward nontumor cells and commensal bacterial strains was also assessed in vitro. Computer-aided programs were employed to explore the toxicity and pharmacokinetic profiles of the synthesized annulates. Based on the findings that were obtained, the authors stated the following main outcomes. There have been promising and far-reaching biological effects of the synthesized heterocyclic coumarin annulates. HC1 demonstrated strong anti-inflammatory potential through the lipoxygenase-dependent route. Moreover, HC1 exhibited significant antifungal efficacy, surpassing that of nystatin. HC2 held great promise as an antioxidative stress, anticancer, and biosafe candidate. HC3 exhibited a strong antibacterial potential against all tested aerobic bacterial strains, demonstrating a potency equivalent to that of ciprofloxacin. In addition, all of the synthesized annulates, especially HC3, exhibited a noteworthy biosafety profile against the commensal bacterial strains. The strong inhibitory capabilities of HC6 and HC7 toward glucosidase and amylase indicate that they possess great promise as antidiabetic agents. Finally, the synthesized annulates showed favorable toxicity and oral bioavailability properties. It can be inferred that these annulates have the potential to be useful frameworks for developing new drugs with a broad spectrum of bioactivity in the coming years. [ABSTRACT FROM AUTHOR]

Epigallocatechin gallate (EGCG) has an effect in reducing sugar levels in the blood by inhibiting α-glucosidase enzyme, which is connected explicitly by hydrogen bonds and modifies the secondary structure and micro-environment of the enzyme reversibly and noncompetitive. This study looks at the activity and interaction of EGCG as α-glucosidase inhibitors in the form of binding affinity and compound bonding profiles with receptors, including toxicity predictions and drug-likeness results. The research was performed in silico with molecular docking on Autodock Vina that integrated through PyRx, then viewed the compound's binding profile with receptor using Discovery Studio 2021 Client, toxicity prediction using ProTox-II and determination of drug-likeness using SwissADME based on Lipinski's rule of five guidelines. The control drugs used were acarbose and miglitol. The molecular docking results obtained that the binding affinity of EGCG is -8.4 kcal/mol while acarbose and miglitol are -13.8 kcal/mol and -5.3 kcal/mol respectively. There are amino acid residues similar to the drug control with various interactions like electrostatic, hydrophobic, and hydrogen bonds; then it has an inactive target for each toxicity parameter and has a molecular weight of 458.37 g/mol; Log P value of 1.01; H-bond donor of 8; and H-bond acceptor of 11 in the determination of drug-likeness. Based on these results, EGCG has effectiveness as α-glucosidase inhibitors predicted to be non-toxic; however, there are violations in determining drug-likeness. [ABSTRACT FROM AUTHOR]

Introduction: Drug development for Alzheimer's disease has one of the greatest failure rates of any therapeutic field and AD is still incurable. Glycogen synthase kinase-3β is a critical enzyme implicated in the pathogenesis of AD, particularly in the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles. TNF-α also plays a significant role in the pathogenesis of Alzheimer's disease by promoting neuroinflammation, contributing to the formation of amyloid plaques and neurofibrillary tangles, impairing synaptic function, and disrupting the balance of neurotrophic factors. Phytomedicine has numerous advantages over synthetic medications, acting multiple mode of action, including being less toxic and having fewer adverse effects. Flavonoids act as a promising therapeutic target for treating Alzheimer's disease. The present work investigates the anti-AD potentials of 35 flavonoids for the inhibition of GSK-3β and TNF-α. Methods: The physicochemical, pharmacokinetic parameters, toxicity profile and drug-likeliness of the selected 35 flavonoids were predicted using SwissADME & OSIRIS data Warrier property explorer web tool. All flavonoids were selected for docking studies on GSK-3β and TNF-α protein using Autodock 4.2.1. Results: The predictions of this study suggested that among the selected 35 flavonoids, Top 3 flavonoids, such as Epicatechin gallate −10.93 kcal/mol, Fisetin −9.44 kcal/mol and Eriodictyol −8.54 kcal/mol for GSK-3β targets. TNF-α Fisetin −11.52 kcal/mol, Sterubin −10.87 kcal/mol, Biochainin A −10.69 kcal/mol were compared with standard drug donepezil. Conclusion: Therefore, these flavonoids could be utilized as possible leads for the structure-based design in the advancement of new, strong Anti-Alzheimer's agents. However, more invitro and invivo analyses are required to finally confirm the outcomes of this research. [ABSTRACT FROM AUTHOR]

Lipophilicity is a physicochemical parameter well known as a decisive factor for predicting the successful development of a drug. Thus, a balance between potency and physicochemical properties during medicinal chemistry optimization is needed. In this study, the lipophilicity of isoindole-1,3(2H)-dione derivatives designed as phosphodiesterase 10A (PDE10A) inhibitors was determined by chromatographic [reversed-phase thin-layer chromatography (RP-TLC) and ultra-performance liquid chromatography/mass spectrometry (UPLC/MS)] and in silico methods. To assess the correlation between the obtained lipophilicity parameters, principal component analysis (PCA) was performed. logP values obtained by chromatographic (logPRP-TLC and logPUPLC/MS) and in silico methods were compared using the PCA method. The results of PCA revealed that logPUPLC/MS and in silico clogP provided by the ChemDraw program were highly correlated. Compounds' drug likeness was screened, and the pharmacokinetic properties were predicted. All the investigated compounds displayed drug-likeness properties, and they met the criteria of Lipinski's rule of five, which predicted the oral bioavailability of drug candidates. Analysis of the influence of physicochemical properties on the biological activity showed that the compounds with increased potency on PDE10A had significantly higher topological polar surface area (TPSA) values. The blood‒brain barrier permeability and the hemolytic activity of model compound 18 were examined. The model compound 18 displayed no toxicity effect on erythrocytes in the hemolytic assay and good parallel artificial membrane permeability. The results showed that phthalimide compounds with benzimidazole moiety are a source of compound-targeted inhibition of PDE10A with balanced physicochemical and drug-likeness properties. [ABSTRACT FROM AUTHOR]

Nowadays, infectious diseases pose an alarming global threat to human health. The genus Senna is among the most well-known taxonomic categories commonly used in folk medicine to confront these challenges. Motivated by its traditional uses, a comprehensive study was conducted on the roots extract of Senna siamea, aiming to address the in vitro antibacterial and antioxidant efficacy of phytochemicals from the dichloromethane: methanol (1:1) roots extract of the plant, along with in silico computational studies. The separation of compounds was achieved using silica gel column chromatography. Whereas, the antibacterial and antioxidant activities were examined using paper disc diffusion and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays, respectively. Silica gel column chromatography of the dichloromethane: methanol (1:1) roots extract afforded lupeol (1), β-sitosterol (2a) and stigmasterol (2b), chrysophanol (3), betulinic acid (4), and glyceryl-1-hexacosanoate (5). Although these compounds have been previously reported from the plant, proof of their medicinal applications via in vitro and in silico studies is still lacking. Notably, our findings showed remarkable inhibition zones by the extract (18.00 ± 0.00 mm and 17.17 ± 0.24 mm) against E. coli and S. aureus, respectively, at 50 mg/mL compared to ciprofloxacin (23.33 ± 0.47 mm and 22.00 ± 0.00 mm, respectively), showcasing its potential antibacterial efficiency. Considerable inhibition zones were also recorded by chrysophanol (3) against E. coli (16.33 ± 0.24 mm) and S. pyogenes (16.00 ± 0.00 mm) at 2 mg/mL, compared to ciprofloxacin which showed 23.33 ± 0.47 mm and 21.67 ± 0.47 mm, respectively, signifying its potent antibacterial activities. In addition, the crude extract and chrysophanol (3) exhibited substantial IC50 values (1.24 and 1.71 µg/mL, respectively), suggesting their significant antioxidant potential compared to that of ascorbic acid (IC50: 0.53 µg/mL). Chrysophanol (3) fulfilled Lipinski's rule with no violation and lupeol (1), β-sitosterol (2a), stigmasterol (2b), betulinic acid (4), and glyceryl-1-hexacosanoate (5) displayed one violation each which were in favor of the drug-likeness predictions. All the compounds exhibited no cytotoxicity and except betulinic acid (4), all the compounds also showed no carcinogenicity properties which were consistent with the prediction results of ciprofloxacin. The molecular docking computations revealed that all the compound isolates displayed strong and nearly strong binding affinities against all protein targets, ranging from − 6.6 kcal/mol to -9.2 kcal/mol (lupeol (1) against E. coli DNA gyrase B and topoisomerase II α, respectively). Thus, the present findings suggest the roots of Senna siamea for potential medicinal applications against multi-drug resistant pathogens hence validating its ethno-medicinal uses. [ABSTRACT FROM AUTHOR]

Extracts from Mangifera indica leaves and its main component, mangiferin, have proven antidiabetic activity. In this study, mangiferin and its natural derivatives Homomangiferin (HMF), Isomangiferin (IMF), Neomangiferin (NMF), Glucomangiferin (GMF), Mangiferin 6’-gallate (MFG), and Norathyriol (NRT) were compared regarding their action on Diabetes mellitus (DM), employing docking and molecular dynamics (MD) simulations to analyze interactions with the aldose reductase enzyme, the precursor to the conversion of glucose into sorbitol. Notably, HMF showed significant affinity to residues in the active site of the enzyme, including Trp 79, His 110, Trp 111, Phe 122, and Phe 300, with an energy of − 7.2 kcal/mol, observed in the molecular docking simulations. MD reinforced the formation of stable complexes for HMF and MFG with the aldose reductase, with interaction potential energies (IPE) in the order of − 300.812 ± 52 kJ/mol and − 304.812 ± 52 kJ/mol, respectively. The drug-likeness assessment, by multiparameter optimization (MPO), highlighted that HMF and IMF have similarities with polyphenols and glycosidic flavonoids recently patented as antidiabetics, revealing that high polarity (TPSA > 180 Å2) is a favorable property for subcutaneous administration, especially because of the gradual passive cell permeability values in biological tissues, with Papp values estimated at < 10 × 10−6 cm/s. These compounds are metabolically stable against metabolic enzymes, resulting in a low toxic incidence by metabolic activation, corroborating with a lethal dose (LD50) greater than 2000 mg/kg. In this way, HMF showed a systematic alignment between predicted pharmacokinetics and pharmacodynamics, characterizing it as the most favorable substance for inhibiting aldose reductase. [ABSTRACT FROM AUTHOR]

This study aimed to explore the phytochemical analyses and antibacterial potential of three essential oils (EOs) using both in-vitro and in-silico experiments for drug discovery. The Eos of Rosmarinus officinalis, Lavandula angustifolia , and Salvia officinalis were extracted by hydrodistillation, and GC–MS determined the chemical composition. The antibacterial activities of each EO were studied by the disc diffusion method. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of these EOs were determined by micro-dilution. In addition, the EOs were combined with ineffective antibiotics (Aztreonam et al.) against clinical bacteria (P. aeruginosa and K. pneumoniae) to determine this association's effect. The in-vitro toxicological study was based on the MTT cytotoxicity assay. Finally, in-silico methods were employed to estimate their possible antibacterial mechanisms. Molecular docking was performed to calculate the predictive binding affinities of five major volatile components to three proteins key in the bacterial cycle using the AutoDock Vina program; prediction of drug-likeness properties and Toxicity prediction were carried out respectively by SwissADME and ProToxII online server. The results showed that the three EOs possessed antibacterial activity against ATCC and clinical K. pneumoniae. We note that P. aeruginosa was resistant to lavender and sage EOs. Surprisingly, adding EOs to antibiotics ineffective against resistant bacteria showed a significant synergistic antibacterial effect. Cytotoxicity assay of essential oils showed different values ranging from 0.22 to 0.43 µL/mL. Finally, the molecular docking study revealed that both compounds (1,8-Cineol, 1-Dodecene, Linalool, cis-Thujone, and Camphor) from the three EOs have a significant potential to inhibit the protein target involved in bacteria resistance. Furthermore, the SwissADME prediction results showed that all five components satisfy the rule of five and exhibit acceptable drug-like characteristics. findings suggest that the three EOs have interesting antibacterial activity. The in-vitro and in-silico studies gave a great potentiation and may constitute a promising option to control the emergence of MDR P. aeruginosa and K. pneumoniae. [ABSTRACT FROM AUTHOR]

An efficient green method is developed as a one-pot synthesis of pyrrolo[1,2-c]imidazole-1-one derivatives under microwave conditions via two components in a substoichiometric quantity of water. The conformational and structural studies are conducted through DFT optimization and single crystal X-ray diffraction. The molecular packing is mediated through hydrogen bonding and C–H⋯π interactions. The Hirshfeld surface analysis highlights significant H–H interactions in all compounds, with compound 2a exhibiting the highest percentage. HOMO and LUMO studies reveal compound 2a as more stable and less reactive. The molecular electrostatic potential provides the charged proportionality along with the molecular surface. The drug-likeness properties suggest that compounds 2b, 2c, 2d, 2e, 2f, 2g, and 2i possess favorable properties for potential pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Computational modelling and simulation have made it possible to considerably advance in the exploration of conformational and dynamical features of the desired compound. It not only assists in the interpretation of the experimental result, but also to provide insights about the internal motions of the molecule at the atomic level. In this work, Density Functional Theory calculations are performed to replicate the experimental electronic structure of 2C4H5ClN4.C4H6O4, and its nature is discussed in detail. The B3LYP/6‐311++G(d,p) basis set applied to evaluate the optimal structure characteristics resulted in revealing the corresponding chemical, physical, and biological properties of the molecule. The energy exchange between the contributor and receiver are examined by Natural Bond Orbital analysis. Based on frontier molecular orbitals analysis, the obtained minimum energy gap (0.199 eV) value ensures the stability of the title compound. The molecular electrostatic potential mapping predicts the electrophilic and nucleophilic charge distributions on the molecule. The 3D topology of the crystal packing is analyzed and interpreted via the energy‐framework simulation studies using CystalExplorer software. Through the In‐silico‐ADME calculations, the drug‐likeness and physicochemical properties of the molecule is predicted. Furthermore, the molecular docking studies are used to determine the bioactivity and anti‐diabetic properties of the title compound. [ABSTRACT FROM AUTHOR]