Synthesis, Kinetics and Computational Explorations of 4-Phenylpiperazine Bearing N-(Aryl)-3-substituted-benzamides as Auspicious Tyrosinase Inhibitors.

In the aimed research study, a new series of N-(aryl)-3-[(4-phenyl-1-piperazinyl)methyl]benzamides was synthesized, which was envisaged as tyrosinase inhibitor. The structures of these newly designed molecules were verified by IR, 1H-NMR, 13C-NMR, EI-MS and CHN analysis data. These molecules were screened against tyrosinase and their inhibitory activity explored that these 3-substituted-benzamides exhibit good to excellent potential, comparative to the standard. The Kinetics mechanism was investigated through Lineweaver-Burk plots which depicted that molecules inhibited this enzyme in a competitive mode. Moreover, molecular docking was also performed to determine the binding interaction of all synthesized molecules (ligands) with the active site of tyrosinase enzyme and the results showed that most of the ligands exhibited efficient binding energy values. Therefore, it is anticipated that these molecules might serve as auspicious therapeutic scaffolds for treatment of the tyrosinase associated skin disorders.

Design and synthesis of thiadiazole-oxadiazole-acetamide derivatives: Elastase inhibition, cytotoxicity, kinetic mechanism, and computational studies.

Considering the biological significance of 1,3,4-thiadiazole/oxadiazole heterocyclic scaffolds, a novel series of 1,3,4-thiadiazole-1,3,4-oxadiazole-acetamide derivatives (7a-j) was designed and synthesized using molecular hybridization. The inhibitory effects of the target compounds on elastase were evaluated, and all of these molecules were found to be potent inhibitors compared to the standard reference oleanolic acid. Compound 7f exhibited the excellent inhibitory activity (IC50 = 0.06 ± 0.02 µM), which is 214-fold more active than oleanolic acid (IC50 = 12.84 ± 0.45 µM). Kinetic analysis was also performed on the most potent compound (7f) to determine the mode of binding with the target enzyme, and it was discovered that 7f inhibits the enzyme in a competitive manner. Furthermore, the MTT assay method was used to assess their toxicity on the viability of B16F10 melanoma cell lines, and all compounds did not display any toxic effect on the cells even at high concentrations. The molecular docking studies of all compounds also justified with their good docking score and among them, compound 7f had a good conformational state with hydrogen bond interactions within the receptor binding pocket, which is consistent with the experimental inhibition studies.

Synthesis, Characterization, Optical Properties, Molecular Modeling and Urease Inhibition Analysis of Organic Ligands and Their Metal Complexes.

Recently, screening of efficient urease inhibitors by employing organic small molecules metalloderivatives interests the scientific community due to their efficacy for treatment of urease triggered health complications. This study comprises the synthesis, urease inhibition activity, optical analysis and molecular modeling of hydrazinecarbothioamide and hydrazinecarboxamide metalloderivatives. Characterization of synthesized materials was done by UV-visible, fluorescence, NMR and FTIR spectroscopic analysis. Metalloderivatization of ligands induce increment in urease inhibition potential and effect was prominent for copper complexes with 10-fold enhancement, cobalt complex with 3.5 fold's enhancement and palladium with 2-fold increment in the inhibition efficacy toward urease when it was compared with reference urease inhibitor. Zinc and iron complexes cause declined urease inhibition activity of the bare ligand. The overall activity of hydrazinecarbothioamide slightly exceeds than that of hydrazinecarboxamide, possibly due to larger complexation ability of sulfur-based ligand in comparison to oxygenated derivatives i.e., hydrazinecarboxamide. The enzyme inhibition kinetics for the most active complexes represent the mixed type urease inhibition for 3a and competitive urease inhibition for 5a, as determined by Lineweaver-Burk plots. The docked scoring values for both the ligands were calculated to be 61.34, 64.72, 56.68, 62.94, 64.98 and 58.98. Three active hydrogen bonds were observed in docking complex upon computational analysis of most potent metallodrug 3a inside active region of targeted protein.

Synthesis, carbonic anhydrase inhibition, anticancer activity, and molecular docking studies of 1,3,4-oxadiazole derivatives.

In this work, we have synthesized various organic compounds possessing 1,3,4-oxadiazole as a core structure and the structure of the newly synthesized target compounds has been revealed using different analytical approaches such as FT-IR, LCMS, and NMR (proton and carbon), respectively. The in vitro carbonic anhydrase potentials of these synthesized 17 different analogues were investigated. The result suggests that compound 7g, a 3-pyridine substituted analogue with an IC50 of 0.1 µM, was found to have the most potent carbonic inhibitory activity (11-fold more active) than the positive control (acetazolamide) with an IC50 of 1.1 ± 0.1 µM. Besides, among the series 7(a-q) approved in the identification of four potent carbonic anhydrase inhibitors with the IC50 standards varies from 0.1 to 1.0 ± 0.1 µM. Additionally, the non-competitive behaviour for potent compound 7g was analysed using the Lineweaver-Burk plot from the kinetic study. Furthermore, the anticancer activity of all the synthesized compounds screened against B16F10 melanoma cells using the MTT assay method. Additionally, the molecular docking studies revealed that 7g inhibitor shows good binding energy as well as good binding interaction pattern along with enzyme.

2-Aminothiazole-Oxadiazole Bearing N-Arylated Butanamides: Convergent Synthesis, Tyrosinase Inhibition, Kinetics, Structure-Activity Relationship, and Binding Conformations.

A multi-step synthesis of novel bi-heterocyclic N-arylated butanamides was consummated through a convergent strategy and the structures of these medicinal scaffolds, 7a-h, were corroborated using spectral techniques. The in vitro analysis of these hybrid molecules revealed their potent tyrosinase inhibition as compared to the standard used. The kinetics mechanism was investigated through Lineweaver-Burk plots which exposed that, 7f, inhibited tyrosinase enzyme non-competitively by forming the enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.025 µM. Their binding conformations were ascertained by in silico computational studies whereby these molecules disclosed good binding energy values (kcal/mol). So, it was anticipated from the current research that these bi-heterocyclic butanamides might be probed as imperative therapeutic agents for melanogenesis.

Nature's Own Pharmacy: Mushroom-Based Chemical Scaffolds and Their Therapeutic Implications.

Mushrooms are new potential sources of valuable medicines, long neglected because of difficulties experienced in their cultivation. There is a large variety of medicinal mushrooms which possess significant therapeutic properties and are used as medications for various diseases because they contain several novel highly bioactive components. Medicinal mushrooms can be identified based on their morphology, size, mass, and the color of the stalk, cap and spore, and attachment to the stalk. Medicinal mushrooms possess a variety of important biological activities and are used as antioxidants, hepatoprotectors, anticancer, antidiabetic, anti-inflammatory, antiaging, antiviral, antiparasitic, and antimicrobial agents, among others. This review provides a basic overview of the chemical scaffolds present in mushrooms and their therapeutic implications in the human body.

Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies.

Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the NR0B1 gene. The functional study showed that DAX1 is a physiologically significant target for EWS/FLI1-mediated oncogenesis, particularly Ewing Sarcoma (ES). In this study, a three-dimensional DAX1 structure was modeled by employing a homology modeling approach. Furthermore, the network analysis of genes involved in Ewing Sarcoma was also carried out to evaluate the association of DAX1 and other genes with ES. Moreover, a molecular docking study was carried out to check the binding profile of screened flavonoid compounds against DAX1. Therefore, 132 flavonoids were docked in the predicted active binding pocket of DAX1. Moreover, the pharmacogenomics analysis was performed for the top ten docked compounds to evaluate the ES-related gene clusters. As a result, the five best flavonoid-docked complexes were selected and further evaluated by Molecular Dynamics (MD) simulation studies at 100 ns. The MD simulation trajectories were evaluated by generating RMSD, hydrogen bond plot analysis, and interaction energy graphs. Our results demonstrate that flavonoids showed interactive profiles in the active region of DAX1 and can be used as potential therapeutic agents against DAX1-mediated augmentation of ES after in-vitro and in-vivo evaluations.

Tyrosinase Inhibitors Naturally Present in Plants and Synthetic Modifications of These Natural Products as Anti-Melanogenic Agents: A Review.

Tyrosinase is a key enzyme target to design new chemical ligands against melanogenesis. In the current review, different chemical derivatives are explored which have been used as anti-melanogenic compounds. These are different chemical compounds naturally present in plants and semi-synthetic and synthetic compounds inspired by these natural products, such as kojic acid produced by several species of fungi; arbutin-a glycosylated hydroquinone extracted from the bearberry plant; vanillin-a phenolic aldehyde extracted from the vanilla bean, etc. After enzyme inhibition screening, various chemical compounds showed different therapeutic effects as tyrosinase inhibitors with different values of the inhibition constant and IC50. We show how appropriately designed scaffolds inspired by the structures of natural compounds are used to develop novel synthetic inhibitors. We review the results of numerous studies, which could lead to the development of effective anti-tyrosinase agents with increased efficiency and safety in the near future, with many applications in the food, pharmaceutical and cosmetics industries.

Exploration of Flavonoids as Lead Compounds against Ewing Sarcoma through Molecular Docking, Pharmacogenomics Analysis, and Molecular Dynamics Simulations.

Ewing sarcoma (ES) is a highly malignant carcinoma prevalent in children and most frequent in the second decade of life. It mostly occurs due to t(11;22) (q24;q12) translocation. This translocation encodes the oncogenic fusion protein EWS/FLI (Friend leukemia integration 1 transcription factor), which acts as an aberrant transcription factor to deregulate target genes essential for cancer. Traditionally, flavonoids from plants have been investigated against viral and cancerous diseases and have shown some promising results to combat these disorders. In the current study, representative flavonoid compounds from various subclasses are selected and used to disrupt the RNA-binding motif of EWS, which is required for EWS/FLI fusion. By blocking the RNA-binding motif of EWS, it might be possible to combat ES. Therefore, molecular docking experiments validated the binding interaction patterns and structural behaviors of screened flavonoid compounds within the active region of the Ewing sarcoma protein (EWS). Furthermore, pharmacogenomics analysis was used to investigate potential drug interactions with Ewing sarcoma-associated genes. Finally, molecular dynamics simulations were used to investigate the stability of the best selected docked complexes. Taken together, daidzein, kaempferol, and genistein exhibited a result comparable to ifosfamide in the proposed in silico study and can be further analyzed as possible candidate compounds in biological in vitro studies against ES.

Elastase inhibitory activity of quinoline Analogues: Synthesis, kinetic mechanism, cytotoxicity, chemoinformatics and molecular docking studies.

Herein, we have synthesized quinoline united various Schiff base derivatives (Q1-Q13) and systematically characterized them using diverse analytical practices such as 1H NMR, 13C NMR, FT-IR and LC-MS respectively. All of the target compounds that have been synthesized were tested for elastase inhibition, and the findings were compared to the standard drug oleanolic acid. Among the entire series, compound Q11 (IC50 = 0.897 ± 0.015 µM) exhibit most promising elastase inhibitory activity than oleanolic acid (Standard) having an IC50 value of 13.426 ± 0.015 µM. Also, the utmost effectivecompound Q11 was used for kinetic mechanism investigation based on in-vitro data, from which it has been concluded that compound Q11 inhibits elastase competitively. Furthermore, utilizing the MTT test approach, the most effective compounds were assessed for cytotoxicity on B16F10 melanoma cells. From the cytotoxicity experiment, the most potent compound did not display any hazardous response against B16F10 melanoma cells despite being treated at high concentrations. Additionally, the molecular docking study was settled to govern the binding interaction pattern among an enzyme and inhibitors.

Therapeutic Implications of microRNAs in Depressive Disorders: A Review.

MicroRNAs are hidden players in complex psychophysical phenomena such as depression and anxiety related disorders though the activation and deactivation of multiple proteins in signaling cascades. Depression is classified as a mood disorder and described as feelings of sadness, loss, or anger that interfere with a person's everyday activities. In this review, we have focused on exploration of the significant role of miRNAs in depression by affecting associated target proteins (cellular and synaptic) and their signaling pathways which can be controlled by the attachment of miRNAs at transcriptional and translational levels. Moreover, miRNAs have potential role as biomarkers and may help to cure depression through involvement and interactions with multiple pharmacological and physiological therapies. Taken together, miRNAs might be considered as promising novel therapy targets themselves and may interfere with currently available antidepressant treatments.

Ultrasonic-Assisted Synthesis of Benzofuran Appended Oxadiazole Molecules as Tyrosinase Inhibitors: Mechanistic Approach through Enzyme Inhibition, Molecular Docking, Chemoinformatics, ADMET and Drug-Likeness Studies.

Furan-oxadiazole structural hybrids belong to the most promising and biologically active classes of oxygen and nitrogen containing five member heterocycles which have expanded therapeutic scope and potential in the fields of pharmacology, medicinal chemistry and pharmaceutics. A novel series 5a-j of benzofuran-oxadiazole molecules incorporating S-alkylated amide linkage have been synthesized using ultrasonic irradiation and screened for bacterial tyrosinase inhibition activity. Most of the synthesized furan-oxadiazole structural motifs exhibited significant tyrosinase inhibition activity in the micromolar range, with one of the derivatives being more potent than the standard drug ascorbic acid. Among the tested compounds, the scaffold 5a displayed more tyrosinase inhibition efficacy IC50 (11 ± 0.25 µM) than the ascorbic acid IC50 (11.5 ± 0.1 µM). Compounds 5b, 5c and 5d efficiently inhibited bacterial tyrosinase with IC50 values in the range of 12.4 ± 0.0-15.5 ± 0.0 µM. The 2-fluorophenylacetamide containing furan-oxadiazole compound 5a may be considered as a potential lead for tyrosinase inhibition with lesser side effects as a skin whitening and malignant melanoma anticancer agent.

Hematopoietic Stem and Progenitor Cells (HSPCs) and Hematopoietic Microenvironment: Molecular and Bioinformatic Studies of the Zebrafish Models.

Hematopoietic stem cells (HSCs) reside in a specialized microenvironment in a peculiar anatomic location which regulates the maintenance of stem cells and controls its functions. Recent scientific progress in experimental technologies have enabled the specific detection of epigenetic factors responsible for the maintenance and quiescence of the hematopoietic niche, which has improved our knowledge of regulatory mechanisms. The aberrant role of RNA-binding proteins and their impact on the disruption of stem cell biology have been reported by a number of recent studies. Despite recent modernization in hematopoietic microenvironment research avenues, our comprehension of the signaling mechanisms and interactive pathways responsible for integration of the hematopoietic niche is still limited. In the past few decades, zebrafish usage with regards to exploratory studies of the hematopoietic niche has expanded our knowledge for deeper understanding of novel cellular interactions. This review provides an update on the functional roles of different genetic and epigenetic factors and molecular signaling events at different sections of the hematopoietic microenvironment. The explorations of different molecular approaches and interventions of latest web-based tools being used are also outlined. This will help us to get more mechanistic insights and develop therapeutic options for the malignancies.

Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies.

To develop new alkaline phosphatase inhibitors (ALP), a series of pyrazolo-oxothiazolidine derivatives were synthesized and biologically assessed, and the results showed that all of the synthesized compounds significantly inhibited ALP. Specifically, compound 7g displayed the strongest inhibitory activity (IC50 = 0.045 ± 0.004 µM), which is 116-fold more active than monopotassium phosphate (IC50 = 5.242 ± 0.472 µM) as a standard reference. The most potent compound among the series (7g) was checked for its mode of binding with the enzyme and shown as non-competitively binding with the target enzyme. The antioxidant activity of these compounds was examined to investigate the radical scavenging effect. Moreover, the MTT assay method was performed to evaluate their toxic effects on the viability of MG-63 human osteosarcoma cells, and all compounds have no toxic effect on the cells at 4 µM. Computational research was also conducted to examine the binding affinity of the ligands with alkaline phosphatase, and the results revealed that all compounds showed good binding energy values within the active site of the target. Therefore, these novel pyrazolo-oxothiazolidine derivatives might be employed as promising pharmacophores for potent and selective alkaline phosphatase inhibitors.

Innovations in Genomics and Big Data Analytics for Personalized Medicine and Health Care: A Review.

Big data in health care is a fast-growing field and a new paradigm that is transforming case-based studies to large-scale, data-driven research. As big data is dependent on the advancement of new data standards, technology, and relevant research, the future development of big data applications holds foreseeable promise in the modern day health care revolution. Enormously large, rapidly growing collections of biomedical omics-data (genomics, proteomics, transcriptomics, metabolomics, glycomics, etc.) and clinical data create major challenges and opportunities for their analysis and interpretation and open new computational gateways to address these issues. The design of new robust algorithms that are most suitable to properly analyze this big data by taking into account individual variability in genes has enabled the creation of precision (personalized) medicine. We reviewed and highlighted the significance of big data analytics for personalized medicine and health care by focusing mostly on machine learning perspectives on personalized medicine, genomic data models with respect to personalized medicine, the application of data mining algorithms for personalized medicine as well as the challenges we are facing right now in big data analytics.

Biological and Cheminformatics Studies of Newly Designed Triazole Based Derivatives as Potent Inhibitors against Mushroom Tyrosinase.

A series of nine novel 1,2,4-triazole based compounds were synthesized through a multistep reaction pathway and their structures were scrutinized by using spectral methods such as FTIR, LC-MS, 1H NMR, and 13C NMR. The synthesized derivatives were screened for inhibitory activity against the mushroom tyrosinase and we found that all the synthesized compounds demonstrated decent inhibitory activity against tyrosinase. However, among the series of compounds, N-(4-fluorophenyl)-2-(5-(2-fluorophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazol-3-ylthio) acetamide exhibited more prominent activity when accompanied with the standard drug kojic acid. Furthermore, the molecular docking studies identified the interaction profile of all synthesized derivatives at the active site of tyrosinase. Based on these results, N-(4-fluorophenyl)-2-(5-(2-fluorophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazol-3-ylthio) acetamide could be used as a novel scaffold to design some new drugs against melanogenesis.

A Comprehensive In Silico Exploration of Pharmacological Properties, Bioactivities, Molecular Docking, and Anticancer Potential of Vieloplain F from Xylopia vielana Targeting B-Raf Kinase.

Compounds derived from plants have several anticancer properties. In the current study, one guaiane-type sesquiterpene dimer, vieloplain F, isolated from Xylopia vielana species, was tested against B-Raf kinase protein (PDB: 3OG7), a potent target for melanoma. A comprehensive in silico analysis was conducted in this research to understand the pharmacological properties of a compound encompassing absorption, distribution, metabolism, excretion, and toxicity (ADMET), bioactivity score predictions, and molecular docking. During ADMET estimations, the FDA-approved medicine vemurafenib was hepatotoxic, cytochrome-inhibiting, and non-cardiotoxic compared to the vieloplain F. The bioactivity scores of vieloplain F were active for nuclear receptor ligand and enzyme inhibitor. During molecular docking experiments, the compound vieloplain F has displayed a higher binding potential with -11.8 kcal/mol energy than control vemurafenib -10.2 kcal/mol. It was shown that intermolecular interaction with the B-Raf complex and the enzyme's active gorge through hydrogen bonding and hydrophobic contacts was very accurate for the compound vieloplain F, which was then examined for MD simulations. In addition, simulations using MM-GBSA showed that vieloplain F had the greatest propensity to bind to active site residues. The vieloplain F has predominantly represented a more robust profile compared to control vemurafenib, and these results opened the road for vieloplain F for its utilization as a plausible anti-melanoma agent and anticancer drug in the next era.

Novel 1,3,4-oxadiazole compounds inhibit the tyrosinase and melanin level: Synthesis, in-vitro, and in-silico studies.

In this research work, we have designed and synthesized some biologically useful of 1,3,4-Oxadiazoles. The structural interpretation of the synthesized compounds has been validated by using FT-IR, LC-MS, HRMS, 1H NMR and 13C NMR techniques. Moreover, the in-vitro mushroom tyrosinase inhibitory potential of the target compounds was assessed. The in-vitro study reveals that, all compounds demonstrate an excellent tyrosinase inhibitory activity. Especially, 2-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-ylthio)-N-phenylacetamide (IC50 = 0.003 ± 0.00 µM) confirms much more significant potent inhibition activity compared with standard drug kojic acid (IC50 = 16.83 ± 1.16 µM). Subsequently, the most potent five oxadiazole compounds were screened for cytotoxicity study against B16F10 melanoma cells using an MTT assay method. The survival rate for the most potent compound was more pleasant than other compounds. Furthermore, the western blot results proved that the most potent compound considerably decreased the expression level of tyrosinase at 50 µM (P < 0.05). The molecular docking investigation exposed that the utmost potent compound displayed the significant interactions pattern within the active region of the tyrosinase enzyme and which might be responsible for the decent inhibitory activity towards the enzyme. A molecular dynamic simulation experiment was presented to recognize the residual backbone stability of protein structure.

Understanding the enzymatic inhibition of intestinal alkaline phosphatase by aminophenazone-derived aryl thioureas with aided computational molecular dynamics simulations: synthesis, characterization, SAR and kinetic profiling.

The work presented in this paper aims toward the synthesis of aryl thiourea derivatives 4a-l of pyrazole based nonsteroidal anti-inflammatory drug named 4-aminophenazone, as potential inhibitors of intestinal alkaline phosphatase enzyme. The screening of synthesized target compounds 4a-l for unraveling the anti-inflammatory potential against calf intestinal alkaline phosphatase gives rise to lead member 4c possessing IC50 value 0.420 ± 0.012 µM, many folds better than reference standard used (KH2PO4 IC50 = 2.8 ± 0.06 µM and L-phenylalanine IC50 = 100 ± 3.1 µM). SAR for unfolding the active site binding pocket interaction along with the mode of enzyme inhibition based on kinetic studies is carried out which showed non-competitive binding mode. The enzyme inhibition studies were further supplemented by molecular dynamic simulations for predicting the protein behavior against active inhibitors 4c and 4g during docking analysis. The preliminary toxicity of the synthesized compounds was determined by using brine shrimp assay. This work also includes detailed biochemical analysis along with RO5 parameters for all the newly synthesized drug derivatives 4a-l.

Novel 1,2,4-triazole analogues as mushroom tyrosinase inhibitors: synthesis, kinetic mechanism, cytotoxicity and computational studies.

We have created a novel series of mushroom tyrosinase inhibitors with 1,2,4-triazole as fundamental skeleton. The target compound 1,2,4-triazol-3-ylthio)-N-phenyl acetamide derivatives 9(a-l) were synthesized by the reaction of 4- and 5-substituted 1,2,4-triazole-3-thiol derivatives 6(a-c) with 2-chloro-N-sub/un-substituted phenyl acetamide derivatives 8(a-d) under basic condition. By using the analytical techniques for instance, FTIR, LC-MS, 1H NMR and 13C NMR, the structural verification was evaluated. The novel series of the target compounds 9(a-l) has been scanned for biological activity (mushroom tyrosinase inhibition potential) which demonstrates adequate results. Interestingly, compound 9k (IC50 = 0.0048 ± 0.0016 µM) exhibits 3500 times more activity compared with standard drug kojic acid (IC50 = 16.8320 ± 1.1600 µM) against mushroom tyrosinase inhibitor. Furthermore, the cytotoxicity experiment was carried out for the highly effective target compounds (9d, 9i, 9j and 9k) by using MTT assay method for A375 human melanoma cells to define the nontoxic performance of the most effective compounds ranging from 1 to 25 µM. Furthermore, the molecular docking study delivers the thought concerning the interface of the ligand with an enzyme. Also, the dynamic simulation was accomplished for compound 9k to govern the plausible binding model.