Investigation of H-Bonding and pH on the Fluorescence Spectral Behavior of Valsartan.

The photophysical properties of valsartan (VAL), a potent phenyl tetrazole derivative sartan, were investigated. Valsartan has absorption bands at 230 nm and 255 nm and a fluorescence band at about [Formula: see text] = 346 nm in butanol which is red shifted depending on the H-bonding capability of the solvent. The role of H-bonding in the excited state was approved through the linear correlation of the emission energy of VAL with Camlet-Taft acidity and basicity parameters, α and ß, of polar protic solvents. The position and intensity of fluorescence emission bands of VAL are found to be pH dependent, shifting from 425 nm at pH 2 to 375 nm at pH 4 with enhancement of intermolecular H-bonding and fluorescence intensity depletion beyond pH 5 with formation of tetrazole anion. The results were supported by time-resolved fluorescence measurements which indicated the presence of different species with different lifetimes in the excited state depending on solution pH value. Computational results based on time dependent density functional methods (TDDFT) show that the tetrazole moiety is involved in the [Formula: see text] absorption transitions, while natural bond analysis (NBO) shows that VAL adopts a dimer conformation in water because of effective intermolecular H-bonding.

Design and biological evaluation of 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2-TK inhibitors.

The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1H,3H)-dione 2a-g, in addition to the preparation of some new derivatives namely, 3 and 4a-j. Three compounds namely, 2c, 4b, and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC50 range 0.052-0.084 µM). Both compounds 4b, 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1H,3H)-dione derivatives are promising antiproliferative candidates that require further optimisation.HighlightsNew 3-substituted quinazoline-2,4(1H,3H)-dione derivatives were synthesised and characterised.Compounds 4b and 4e showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines.Both compounds 4b and 4e showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line.Compound 4b was superior to cabozantinib in VEGFR-2 inhibition while compound 2c was equipotent to cabozantinib.Compounds 4b and 4e showed remarkable c-Met inhibitory activity.Compounds 4b and 4e arrested cell cycle and induced significant levels of apoptosis.In silico ADME prediction revealed high oral bioavailability and enhanced water solubility of target compounds as compared to cabozantinib.Target compounds interacted with both c-Met and VEGFR-2 active site in similar way to cabozantinib.

Antimicrobial Potency and E. coli ß-Carbonic Anhydrase Inhibition Efficacy of Phenazone-Based Molecules.

In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative 3. The as-prepared carbodithioate derivative 3 is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (4-9) through its reaction with the appropriate hydrazonoyl halides. Furthermore, a typical Biginelli three-component cyclocondensation reaction involving ethyl acetoacetate, 4-antipyrinecarboxaldhyde, and thiourea under the standard conditions is carried out in the presence of sulfuric acid to afford the corresponding antipyrine-pyrimidine hybrid molecule (10). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative (11) which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (12). The structure of the newly synthesized compounds was affirmed by their spectral and microanalytical data. We also screened for their antimicrobial potential (ZOI and MIC) and conducted a kinetic study. Additionally, the mechanism of biological action was assessed by a membrane leakage assay and SEM imaging technique. Moreover, the biological activities and the binding modes of these compounds were further supplemented by an in silico docking study against E. coli ß-carbonic anhydrase. The amount of cellular protein released by E. coli is directly correlated to the concentration of compound 9, which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound 9. This finding supports compound 9's antibacterial properties and explains how the formation of holes in the E. coli cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against E. coli ß-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound (9) declared a greater activity than the other synthesized compounds.

Solvent-Free Synthesis, In Vitro and In Silico Studies of Novel Potential 1,3,4-Thiadiazole-Based Molecules against Microbial Pathogens.

A new series of 1,3,4-thiadiazoles was synthesized by the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate (2) with selected derivatives of hydrazonoyl halide by grinding method at room temperature. The chemical structures of the newly synthesized derivatives were resolved from correct spectral and microanalytical data. Moreover, all synthesized compounds were screened for their antimicrobial activities using Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Bacillus subtilis, Staphylococcus aureus, and Candida albicans. However, compounds 3 and 5 showed significant antimicrobial activity against all tested microorganisms. The other prepared compounds exhibited either only antimicrobial activity against Gram-positive bacteria like compounds 4 and 6, or only antifungal activity like compound 7. A molecular docking study of the compounds was performed against two important microbial enzymes: tyrosyl-tRNA synthetase (TyrRS) and N-myristoyl transferase (Nmt). The tested compounds showed variety in binding poses and interactions. However, compound 3 showed the best interactions in terms of number of hydrogen bonds, and the lowest affinity binding energy (-8.4 and -9.1 kcal/mol, respectively). From the in vitro and in silico studies, compound 3 is a good candidate for the next steps of the drug development process as an antimicrobial drug.

Novel Thiadiazole-Based Molecules as Promising Inhibitors of Black Fungi and Pathogenic Bacteria: In Vitro Antimicrobial Evaluation and Molecular Docking Studies.

Novel 1,3,4-thiadiazole derivatives were synthesized through the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate and the appropriate hydrazonoyl halides in the presence of a few drops of diisopropylethylamine. The chemical structure of the newly fabricated compounds was inferred from their microanalytical and spectral data. With the increase in microbial diseases, fungi remain a devastating threat to human health because of the resistance of microorganisms to antifungal drugs. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) have higher mortality rates in many populations. The present study aimed to find new antifungal agents using the disc diffusion method, and minimal inhibitory concentration (MIC) values were estimated by the microdilution assay. An in vitro experiment of six synthesized chemical compounds exhibited antifungal activity against Rhizopus oryzae; compounds with an imidazole moiety, such as the compound 7, were documented to have energetic antibacterial, antifungal properties. As a result of these findings, this research suggests that the synthesized compounds could be an excellent choice for controlling black fungus diseases. Furthermore, a molecular docking study was achieved on the synthesized compounds, of which compounds 2, 6, and 7 showed the best interactions with the selected protein targets.

Computational insights into binding mechanism of drugs as potential inhibitors against SARS-CoV-2 targets.

Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (Mpro), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein-drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-021-01843-0.

Antibacterial Activities and Molecular Docking of Novel Sulfone Biscompound Containing Bioactive 1,2,3-Triazole Moiety.

In this study, a new synthetic 1,2,3-triazole-containing disulfone compound was derived from dapsone. Its chemical structure was confirmed using microchemical and analytical data, and it was tested for its in vitro antibacterial potential. Six different pathogenic bacteria were selected. MICs values and ATP levels were determined. Further, toxicity performance was measured using MicroTox Analyzer. In addition, a molecular docking study was performed against two vital enzymes: DNA gyrase and Dihydropteroate synthase. The results of antibacterial abilities showed that the studied synthetic compound had a strong bactericidal effect against all tested bacterial strains, as Gram-negative species were more susceptible to the compound than Gram-positive species. Toxicity results showed that the compound is biocompatible and safe without toxic impact. The molecular docking of the compound showed interactions within the pocket of two enzymes, which are able to stabilize the compound and reveal its antimicrobial activity. Hence, from these results, this study recommends that the established compound could be an outstanding candidate for fighting a broad spectrum of pathogenic bacterial strains, and it might therefore be used for biomedical and pharmaceutical applications.

Physicochemical stability study of protein-benzoic acid complexes using molecular dynamics simulations.

Carboxyl-modified substrates are the most common chemical moieties that are frequently used as protein defibrillators. We studied the stability of protein-benzoic acid complexes with bovine serum albumin (BSA), zein and lysozyme proteins using various computational methods. Structural model for zein was built using homology modelling technique and molecular docking was used to prepare complex structures of all three proteins with benzoic acid. Molecular dynamics calculations performed on these complex structures provided a strong support for the stability of protein-benzoic acid complexes. The results from various analyses including root-mean-square deviation (RMSD) and radius of gyration showed the stability and compactness of all proteins-benzoic acid complexes. Moreover, exploration of structural fluctuations in proteins revealed the stability of active site residues. Two potential binding modes of benzoic acid with all three proteins were identified via cluster analysis. The binding mode which was retrieved from top cluster containing 86-91% of total conformations displayed very strong binding interactions for zein, BSA and lysozyme proteins. In addition, the results of binding mode showed that various interactions, including hydrogen binding, hydrophobic and electrostatic interactions were important for the optimal binding of benzoic acid with the active sites of proteins. Exploration of solvent accessible surface area showed that lysozyme-binding cavity was more exposed to the surface as compared to the other two proteins. Free energy analysis of all protein systems showed the stability of protein-benzoic acid complexes with lysozyme and BSA relatively more stable than zein system. The results of our study provided important insights to the dynamic and structural information about protein-benzoic acid interactions with BSA, zein and lysozyme proteins. This work is important in enhancing the stability of therapeutic protein drugs loaded on carboxyl substrates.

Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures.

Nitrogen and oxygen medium rings, in particular nine-membered rings, epitomize a unique area of chemical space that occurs in many natural products and biologically appealing compounds. The scarcity of 8- to 12-membered rings among clinically approved drugs is indicative of the difficulties associated with their synthesis, principally owing to the unfavorable entropy and transannular strain. We report here a scandium triflate-catalyzed reaction that allows for a modular access to a diverse collection of nine-membered ring heterocycles in a one-pot cascade and with complete diastereocontrol. This cascade features an intramolecular addition of an acyl group-derived enol to a α,ß-unsaturated carbonyl moiety, leading to N- and O-derived medium-ring systems. Computational studies using the density functional theory support the proposed mechanism. Additionally, a one-pot cascade leading to hexacyclic chromeno[3',4':2,3]indolizino[8,7-b]indole architectures, with six fused rings and four contiguous chiral centers, is reported. This novel cascade features many concerted events, including the formation of two azomethine ylides, [3 + 2]-cycloaddition, 1,3-sigmatropic rearrangement, Michael addition, and Pictet-Spengler reaction among others. Phenotypic screening of the resulting oxazonine collection identified chemical probes that regulate mitochondrial membrane potential, adenosine 5'-triphosphate contents, and reactive oxygen species levels in hepatoma cells (Hepa1-6), a promising approach for targeting cancer and metabolic disorders.

Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates.

BACKGROUND: Imidazo[2,1-b]thiazole scaffolds were reported to possess various pharmaceutical activities. RESULTS: The novel compound named methyl-2-(1-(3-methyl-6-(p-tolyl)imidazo[2,1-b]thiazol-2-yl)ethylidene)hydrazine-1-carbodithioate 3 acted as a predecessor molecule for the synthesis of new thiadiazole derivatives incorporating imidazo[2,1-b]thiazole moiety. The reaction of 3 with the appropriate hydrazonoyl halide derivatives 4a-j and 7-9 had produced the respective 1,3,4-thiadiazole derivatives 6a-j and 10-12. The chemical composition of all the newly synthesized derivatives were confirmed by their microanalytical and spectral data (FT-IR, mass spectrometry, 1H-NMR and 13C-NMR). All the produced novel compounds were screened for their anti-proliferative efficacy on hepatic cancer cell lines (HepG2). In addition, a computational molecular docking study was carried out to determine the ability of the synthesized thiadiazole molecules to interact with active site of the target Glypican-3 protein (GPC-3). Moreover, the physiochemical properties of the synthesized compounds were derived to determine the viability of the compounds as drug candidates for hepatic cancer. CONCLUSION: All the tested compounds had exhibited good anti-proliferative efficacy against hepatic cancer cell lines. In addition, the molecular docking results showed strong binding interactions of the synthesized compounds with the target GPC-3 protein with lower energy scores. Thus, such novel compounds may act as promising candidates as drugs against hepatocellular carcinoma.

Synthesis, Characterization and Biological Evaluation of Metal Adamantyl 2-Pyridylhydrazone Complexes.

Four new complexes derived from adamantly containing hydrazone (APH) ligand with Cu(II) (1), Co(II) (2), Ni(II) (3) and Zn(II) (4), have been synthesized and characterized using different physicochemical methods. The structure of the ligand APH and its copper complex 1 have been established by single-crystal X-ray diffraction direct methods, which reveal that complex 1 has distorted square-pyramidal geometry. Complexes 1-4 are screened against seven human cancer cell lines namely, breast cancer cell lines (MCF7, T47D, MDA-MB-231), prostate cancer cell lines (PC3, DU145) and the colorectal cancer cell line Coco-2, for their antiproliferative activities. Complex 1 has shown a promising anticancer activity compared to the other ones. The structural and spectroscopic analysis of APH and its complexes are confirmed by DFT calculations.

Old leaves accumulate more heavy metals than other parts of the desert shrub Calotropis procera at a traffic-polluted site as assessed by two analytical techniques.

Calotropis procera is a perennial big shrub that has the potential to accumulate high concentrations of heavy metals. Metal sequestration in old organs has been considered as a mechanism for plant survival in polluted soils. The aim of the present study was to assess the role of the old leaves as a sink for HMs accumulation in C. procera. Two instruments were used: atomic absorption spectroscopy (AAS) and X-ray fluorescence (XRF) microscopy. Soil and plant samples were collected from around one of the worst congested traffic areas in the United Arab Emirates (UAE). Samples from roots, stem, and green and old leaves were prepared and analyzed by both instruments. Calotropis procera was able to concentrate Fe, Mn, Sr, and Zn in the roots, but their translocation to stem and green leaves was low. Old leaves had greater ability to accumulate significantly higher concentrations of different metals, especially Fe and Sr, than other parts of the plants, indicating that C. procera uses these metabolically less-active leaves as sinks for heavy metals. Fe and Sr attained higher bioconcentration and accumulation values, compared to Zn and Mn. There were significant positive correlations between XRF and AAS for all elements in the different organs.

New 1,3-diphenyl-1H-pyrazol-5-ols as anti-methicillin resistant Staphylococcus aureus agents: Synthesis, antimicrobial evaluation and in silico studies.

In the present work, two hybrid series of pyrazole-clubbed pyrimidine and pyrazole-clubbed thiazole compounds 3-21 from 4-acetyl-1,3-diphenyl-1H-pyrazole-5(4H)-ole 1 were synthesized as novel antimicrobial agents. Their chemical structures were thoroughly elucidated in terms of spectral analyses such as IR, 1H NMR, 13C NMR and mass spectra. The compounds were in vitro evaluated for their antimicrobial efficiency against various standard pathogen strains, gram -ive bacteria (Pseudomonas aeruginosa, Klebsiella pneumonia), gram + ive bacteria (MRSA, Bacillus subtilis), and Unicellular fungi (Candida albicans) microorganisms. The ZOI results exhibited that most of the tested molecules exhibited inhibition potency from moderate to high. Where compounds 7, 8, 12, 13 and 19 represented the highest inhibition potency against most of the tested pathogenic microbes comparing with the standard drugs. In addition, the MIC results showed that the most potent molecules 7, 8, 12, 13 and 19 showed inhibition effect against most of the tested microbes at low concentration. Moreover, the docking approach of the newly synthesized compounds against DNA gyrase enzyme was performed to go deeper into their molecular mechanism of antimicrobial efficacy. Further, computational investigations to calculate the pharmacokinetics parameters of the compounds were performed. Among them 7, 8, 12, 13 and 19 are the most potent compounds revealed the highest inhibition efficacy against most of the tested pathogenic microbes comparing with the standard drugs.

ß-Cyclodextrin-Functionalized Fe3O4-Supported Pd-Nanocatalyst for the Reduction of Nitroarenes in Water at Mild Conditions.

In this study, a novel heterogeneous catalyst (Fe3O4@ß-CD@Pd) has been developed by the deposition of palladium nanoparticles on the ß-cyclodextrin-functionalized surface of magnetic Fe3O4. The catalyst was prepared by a simple chemical co-precipitation method and characterized extensively by using Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma-optical emission spectrometry (ICP-OES) analyses. Herein, the applicability of the prepared material was evaluated for the catalytic reduction of environmentally toxic nitroarenes to the corresponding anilines. The catalyst Fe3O4@ß-CD@Pd showed excellent efficiency for the reduction of nitroarenes in water under mild conditions. A low catalyst loading of 0.3 mol % Pd is found to be efficient for reducing nitroarenes in excellent to good (99-95%) yields along with high TON values (up to 330). Nevertheless, the catalyst was recycled and reused up to the 5th cycle of reduction of nitroarene without any loss of significant catalytic activity.

Design, synthesis and antimicrobial assessments of aminoacetylenic-piperazine nitroimidazole hybrid compounds.

A new series of aminoacetylenic nitroimidazole piperazine hybrid compounds were prepared via three-component reaction. Mannich-type reaction was utilized to couple the nitroimidazole containing propargylic moiety with secondary amines and formaldehyde in the presence of Cu (I) catalyst. The newly synthesized molecules 10a-10w, were characterized an ambiguously through NMR and mass spectrometry. The prepared compounds were assessed in vitro for their antibacterial activity against selected gram-positive and gram-negative bacteria. All of the compounds had shown insignificant activities toward gram-negative bacteria. While compounds 10m, 10q, 10s and 10t had shown moderate activities against the gram-positive bacteria Staphylococcus aureus, Bacillus subtilis and against fungi Escherichia coli and Proteus vulgaris.

Modified Graphite Pencil Electrode Based on Graphene Oxide-Modified Fe3O4 for Ferrocene-Mediated Electrochemical Detection of Hemoglobin.

This study describes the synthesis of graphene oxide-modified magnetite (rGO/Fe3O4) and its use as an electrochemical sensor for the quantitative detection of hemoglobin (Hb). rGO is characterized by a 2θ peak at 10.03° in its X-ray diffraction, 1353 and 1586 cm-1 vibrations in Raman spectroscopy, while scanning electron microscopy coupled with energy-dispersive spectroscopy of rGO and rGO/Fe3O4 revealed the presence of microplate structures in both materials and high presence of iron in rGO/Fe3O4 with 50 wt %. The modified graphite pencil electrode, GPE/rGO/Fe3O4, is characterized using cyclic voltammetry. Higher electrochemical surface area is obtained when the GPE is modified with rGO/Fe3O4. Linear scan voltammetry is used to quantify Hb at the surface of the sensor using ferrocene (FC) as an electrochemical amplifier. Linear response for Hb is obtained in the 0.1-1.8 µM range with a regression coefficient of 0.995, a lower limit of detection of 0.090 µM, and a limit of quantitation of 0.28 µM. The sensor was free from interferents and successfully used to sense Hb in human urine. Due to the above-stated qualities, the GPE/rGO/Fe3O4 electrode could be a potential competitive sensor for trace quantities of Hb in physiological media.

Newly Synthesized Pyrazolinone Chalcones as Anticancer Agents via Inhibiting the PI3K/Akt/ERK1/2 Signaling Pathway.

A series of novel pyrazolinone chalcones 3-9 have been synthesized through the condensation of azo pyrazolinone derivatives with various aromatic aldehydes. Spectroscopic techniques and elemental analysis have both corroborated this. Furthermore, all compounds were screened in silico for their ability to inhibit cancer proliferation and metastasis by targeting the PI3K/Akt signaling pathway. This inhibitory pathway might be an efficient approach for the death of cancer cells, angiogenesis, and metastasis prevention. Our results indicated that only compound 6b was the top-ranked. It demonstrated the highest binding energies of -11.1 and -10.7 kcal/mol against the target proteins PI3K and Akt, respectively; thus, it was chosen for in vitro studies. Compound 6b exhibited the most effective cytotoxic impact against the Caco cell line with IC50 of 23.34 ± 0.14 µM. Furthermore, it showed significant inhibition of PI3K/Akt proteins and oxidative stress, leading to elevated Bax and p53 expression, reduced Bcl-2 expression, and triggered cell cycle arrest at the sub-G0/G1 phase. Additionally, it showed significant downregulation of the Raf-1 gene, leading to ERK1/2 protein inhibition. These findings demonstrate that compound 6b obeyed Lipinski's rule of five and might be used as a favored scaffold for cancer treatment by inhibiting proliferation and metastasis via inhibition of the PI3K/Akt and Raf-1/ERK1/2 signaling pathways.

Synthesis, Anticancer Evaluation, Computer-Aided Docking Studies, and ADMET Prediction of 1,2,3-Triazolyl-Pyridine Hybrids as Human Aurora B Kinase Inhibitors.

A novel series of 1,2,3-triazolyl-pyridine hybrids were prepared through the reaction of the triazole derivative (1) with the appropriate aldehyde (2a-g) and malononitrile or ethyl cyanoacetate in the presence of ammonium acetate in refluxed acetic acid. The chemical composition of the products was established on the basis of spectral and elemental analyses. Aurora B kinase is a protein with diverse biological actions in controlling tumorigenesis by inhibiting apoptosis and promoting proliferation and metastasis, making it an emerging target for diseases such as hepatocellular carcinoma (HCC). Alteration in the target protein expression causes unequal distribution of genetic information, causing HCC. The new compounds were tested for their antihepatic cancer activity, and some of them had strong efficacy against human hepatoblastoma (HepG2) cell lines.

Lysozyme and Human Serum Albumin Proteins as Potential Nitric Oxide Cardiovascular Drug Carriers: Theoretical and Experimental Investigation.

Nitric oxide-containing drugs present a critical remedy for cardiovascular diseases. Nitroglycerin (NG, O-NO) and S-nitrosoglutathione (SNG, S-NO) are the most common nitric oxide drugs for cardiovascular diseases. Insights regarding the binding affinity of NO drugs with lysozyme and human serum albumin (HSA) proteins and their dissociation mechanism will provide inquisitive information regarding the potential of the proteins as drug carriers. For the first time, the binding interactions and affinities are investigated using molecular docking, conventional molecular dynamics, steered molecular dynamics, and umbrella sampling to explore the ability of both proteins to act as nitric oxide drug carriers. The molecular dynamics simulation results showed higher stability of lysozyme-drug complexes compared to HSA. For lysozyme, cardiovascular drugs were bound in the protein cavity mainly by the electrostatic and hydrogen bond interactions with residues ASP53, GLN58, ILE59, ARG62, TRP64, ASP102, and TRP109. For HSA, key binding residues were ARG410, TYR411, LYS414, ARG485, GLU450, ARG486, and SER489. The free energy profiles produced from umbrella sampling also suggest that lysozyme-drug complexes had better binding affinity than HSA-drug. Binding characteristics of nitric oxide-containing drugs NG and SNG to lysozyme and HSA proteins were studied using fluorescence and UV-vis absorption spectroscopy. The relative change in the fluorescence intensity as a function of drug concentrations was analyzed using Stern-Volmer calculations. This was also confirmed by the change in the UV-vis spectra. Fluorescence quenching results of both proteins with the drugs, based on the binding constant values, demonstrated significantly weak binding affinity to NG and strong binding affinity to SNG. Both computational and experimental studies provided important data for understanding protein-drug interactions and will aid in developing potential drug carrier systems in cardiovascular diseases.

Synthesis, Molecular Docking Analysis and in Vitro Biological Evaluation of Some New Heterocyclic Scaffolds-Based Indole Moiety as Possible Antimicrobial Agents.

In the present study, a general approach for the synthesis of 1-(1H-indol-3-yl)-3,3-dimercaptoprop-2-en-1-one (1) and 5-(1H-indol-3-yl)-3H-1,2-dithiole-3-thione (2) was performed. They are currently used as efficient precursors for the synthesis of some new compounds bearing five- and/or six-membered heterocyclic moieties, e.g., chromenol (3, 4), 3,4-dihydroquinoline (7, 8) and thiopyran (10, 12)-based indole core. In addition, molecular docking studies were achieved, which showed that all the newly synthesized compounds are interacting with the active site region of the target enzymes, the targets UDP-N-acetylmuramatel-alanine ligase (MurC), and human lanosterol14α-demethylase, through hydrogen bonds and pi-stacked interactions. Among these docked ligand molecules, the compound (9) was found to have the minimum binding energy (-11.5 and -8.5 Kcal/mol) as compared to the standard drug ampicillin (-8.0 and -8.1 Kcal/mol) against the target enzymes UDP-N-acetylmuramatel-alanine ligase (MurC), and Human lanosterol14α-demethylase, respectively. Subsequently, all new synthesized analogues were screened for their antibacterial activities against Gram-positive (Bacillus subtilis), and Gram-negative bacteria (Escherichia coli), as well as for antifungal activities against Candida albicans and Aspergillus flavus. The obtained data suggest that the compounds exhibited good to excellent activity against bacterial and fungi strains. The compound (E)-2-(6-(1H-indole-3-carbonyl)-5-thioxotetrahydrothieno [3,2-b]furan-2(3H)-ylidene)-3-(1H-indol-3-yl)-3-oxopropanedithioic acid (9) showed a high binding affinity as well as an excellent biological activity. Therefore, it could serve as the lead for further optimization and to arrive at potential antimicrobial agent.