Search results for: Molecular modeling of 17-picolyl and 17-picolinylidene androstane derivatives with anticancer activity

Authors: Alok Shiomurti Tripathi, Ajay Kumar Timiri, Papiya Mitra Mazumder, Anil Chandewar

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The present study evaluates the possible drug interaction between glimepiride (GLIM) and sildenafil citrate (SIL) in streptozotocin (STZ) induced in diabetic nephropathic (DN) animals and also postulates the possible mechanism of interaction by molecular modeling studies. Diabetic nephropathy was induced by single dose of STZ (60 mg/kg, ip) and confirms it by assessing the blood and urine biochemical parameters on 28th day of its induction. Selected DN animals were used for the drug interaction between GLIM (0.5mg/kg, p.o.) and SIL (2.5 mg/kg, p.o.) after 29th and 70th day of protocol. Drug interaction were assessed by evaluating the plasma drug concentration using HPLC-UV and also determine the change in the biochemical parameter in blood and urine. Mechanism of the interaction was postulated by molecular modeling study using Maestro module of Schrodinger software. DN was confirmed as there was significant alteration in the blood and urine biochemical parameter in STZ treated groups. The concentration of SIL increased significantly (p<0.001) in rat plasma when co administered with GLIM after 70th day of protocol. Molecular modelling study revealed few important interactions with rat serum albumin and CYP2C9.GLIM has strong hydrophobic interaction with binding site residues of rat serum albumin compared to SIL. Whereas, for CYP2C9, GLIM has strong hydrogen bond with polar contacts and hydrophobic interactions than SIL. Present study concludes that bioavailability of SIL increases when co-administered chronically with GLIM in the management of DN animals and mechanism has been supported by molecular modeling studies.

Keywords: diabetic nephropathy, glimepiride, sildenafil citrate, pharmacokinetics, homology modeling, schrodinger

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Authors: F. Ambreen, A.Naheed

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Osteoarthritis (OA) is a degenerative disorder affecting millions of people worldwide. Nitric oxide (NO) was found to play a catabolic role in the development of osteoarthritis. It is a toxic free radical gas generated during the metabolism of L-arginine by the enzyme Nitric oxide synthase (NOS). Inducible Nitric Oxide Synthase (iNOS) is one of the isoform of NOS, and its overexpression leads to the excessive formation of NO that results in pathophysiological joint conditions. Several synthetic anti-inflammatory drugs and inhibitors are present to date, but all showed side effects and complications. Therefore, the pursuit of natural disease-modifying drugs remains a top priority. Curcumin is an active component of turmeric, and the past few decades have witnessed intense research devoted to the antioxidant and anti-inflammatory properties of curcumin. The present study focused on curcumin and its derivatives in the search for new iNOS inhibitors for the treatment of osteoarthritis. We conducted a molecular docking study on curcumin and its four derivatives; cyclocurcumin, tetrahydrocurcumin, demethoxycurcumin and curcumin monoglucoside with iNOS using CLC Drug discovery work bench 3.02. We selected two co-crystallized ligands for this study; tetrahydrobiopterin and N-omega-propyl-L-arginine present in complex with the enzyme iNOS. Results showed the best binding affinity of N-omega-propyl-L-arginine with cyclocurcumin and curcumin monoglucoside that exhibit binding energies of -65.2 kcal/mol and -68 kcal/mol respectively. Whereas with tetrahydrobiopterin, best binding scores of -64.7 kcal/mol and -62.2 kcal/mol were found with tetrahydrocurcumin and demethoxycurcumin respectively. This information could open doors of research for the designing of novel drugs using herbs such as curcumin for the treatment of inflammatory joint diseases.

Keywords: curcumin, iNOS, molecular docking, osteoarthritis

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Authors: Ozlem Temiz-Arpaci, Meryem Tasci, Fatma Sezer Senol, İlkay Erdogan Orhan

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Alzheimer’s disease (AD), a neurodegenerative disorder characterized by a progressive deterioration of memory and cognition, occurs more frequently in elderly people. Current treatment approaches in this disease with the major therapeutic strategy are based on the AChE and BChE inhibition. On the other hand, tyrosinase inhibition has become a target for the treatment of Parkinson’s disease (PD) since this enzyme may play a role in neuromelanin formation in the human brain and could be critical in the formation of dopamine neurotoxicity associated with neurodegeneration linked to PD. Also benzoxazoles are structural isosteres of natural nucleotides that can interact with biopolymers so that benzoxazoles showed a lot of different biological activities. In this study, a series of 2,5-disubstituted-benzoxazole derivatives were synthesized and were evaluated as possible inhibitors of acetylcholinesterase (AChE) / butyrylcholinesterase (BChE) and tyrosinase. The results demonstrated that the compounds exhibited a weak spectrum of AChE / BChE inhibitory activity ranging between 3.92% - 54.32% except compound 8 which showed no activity against AChE and compound 4 which showed no activity against BChE at the specified molar concentrations. Also, the compounds indicated lower than tyrosinase inhibitory activity of ranging between 8.14% - 22.90% to that of reference (kojic acid).

Keywords: AChE and BChE inhibition, Alzheimer’s disease, benzoxazoles, tyrosinase inhibition

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Authors: Imran Muhammad

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The main cause of infectious disease in the modern world is Mycobacterium Tuberculosis (MT). To combat tuberculosis, new and efficient drugs are an urgent need in the modern world. Schif bases are potent for their biological pharmacophore activity. Thus we selected different Vanillin-based Schiff bases for their binding activity against target enzymes of Mycobacterium tuberculosis that is (DprE1 (decaprenyl phosphoryl-β-D-ribose 2′-epimerase), and DNA gyrase subunit-A), using molecular docking. We evaluate the inhibition potential, interaction, and binding mode of these compounds with the target enzymes.

Keywords: schiff bases, tuberculosis, DNA gyrase, DprE1, docking

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Authors: Yasser Gaber, Mohamed Ismail, Serena Bisagni, Mohamad Takwa, Rajni Hatti-Kaul

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Enzymes are safe and selective catalysts. They skillfully catalyze chemical reactions; however, the native form is not usually suitable for industrial applications. Enzymes are therefore engineered by several techniques to meet the required catalytic task. Clopidogrel is recorded among the five best selling pharmaceutical in 2010 under the brand name Plavix. The commonly used route for production of the drug on an industrial scale is the synthesis of the racemic mixture followed by diastereomeric resolution to obtain the pure S isomer. The process consumes a lot of solvents and chemicals. We have evaluated a biocatalytic cleaner approach for asymmetric hydrolysis of racemic clopidogrel. Initial screening of a selected number of hydrolases showed only one enzyme EST to exhibit activity and selectivity towards the desired stereoisomer. As the crude EST is a mixture of several isoenzymes, a homology model of EST-1 was used in molecular dynamic simulations to study the interaction of the enzyme with R and S isomers of clopidogrel. Analysis of the geometric hindrances of the tetrahedral intermediates revealed a potential site for mutagenesis in order to improve the activity and the selectivity. Single point mutation showed dramatic increase in activity and inversion of the enantioselectivity (400 fold change in E value).

Keywords: biocatalysis, biotechnology, enzyme, protein engineering, molecular modeling

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Authors: Mohammad Kazem Mohammadi

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The use of anticancer agents forms an important part of the treatment of cancer of various types. Uranyl Complexes with DPHMP ligand have been used for the prevention and treatment of cancers. U(IV) metal complexes prepared by reaction of uranyl salt UO2 (NO3)2.6H2O with DPHMP in dry acetonitrile. Characterization of the ligand and its complexes was made by microanalyses, FT-IR, 1H NMR, 13C NMR and UV–Visible spectroscopy. These new complex showed excellent antitumor activity against two kinds of cancer cells that that are HT29:Haman colon adenocarcinoma cell line and T47D:human breast adenocarcinoma cell line.

Keywords: uranyl complexes, DPHMP ligand, antitumor activity, HT29, T47D

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Authors: Sihame Amakrane, Zineb Ouahdi, Mohammed Salah, Said Belaaouad

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\This research explores the efficacy of novel pyrimidine derivatives on bacterial strains such as Escherichia coli, Staphylococcus aureus, and Myccobacterium tuberculosis, utilizing bending energy calculations. Of the 25 compounds examined, 13 displayed potent activity against all the bacterial strains under study, exhibiting bending energy measurements between -7.4 and -10.7 kcal/mol. The -7.4 kcal/mol value corresponds to the bending energy of the SA12 and SA13 compounds with the 2xct protein (Staphylococcus aureus), whereas the -10.7 kcal/molis linked with the bending energy of SA6 and SA11 compounds with the 6GAV protein (Myccobacterium tuberculosis). Further research will involve a QSAR (Quantitative Structure-Activity Relationship) study aimed at constructing a reliable model to combat the aforementioned bacterial strains and a molecular dynamics study to evaluate the stability of ligand-protein complexes.

Keywords: docking, QSAR, bending energy, e. coli

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Authors: Said Ghalem

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Honey is primarily composed of sugars: glucose and fructose. Depending honey, it's either fructose or glucose predominates. More the fructose concentration and the less the glycemic index (GI) is high. Thus, changes in the insulin response shows a decrease of the amount of insulin secreted at an increased fructose honey. Honey is also a compound that can reduce the lipid in the blood. Several studies on animals, but which remain to be checked in humans, have shown that the honey can have interesting effects when combined with other molecules: associated with Metformin (a medicine taken by diabetics), it shows the benefits and effects of diabetes preserves the tissue; associated ginger, it increases the antioxidant activity and thus avoids neurologic complications, neuropathic. Molecular modeling techniques are widely used in chemistry, biology, and the pharmaceutical industry. Most of the currently existing drugs target enzymes. Inhibition of DPP-4 is an important approach in the treatment of type 2 diabetes. We have chosen for the inhibition of DPP-4 the following molecules: Linagliptin (BI1356), Sitagliptin (Januvia), Vildagliptin, Saxagliptin, Alogliptin, and Metformin (Glucophage), that are involved in the disease management of type 2 diabetes and added to honey. For this, we used software Molecular Operating Environment. A Wistar rat study was initiated in our laboratory with a well-studied protocol; after sacrifice, according to international standards and respect for the animal This theoretical approach predicts the mode of interaction of a ligand with its target. The honey can have interesting effects when combined with other molecules, it shows the benefits and effects of honey preserves the tissue, it increases the antioxidant activity, and thus avoids neurologic complications, neuropathic or macrovascular. The organs, especially the kidneys of Wistar, shows that the parameters to renal function let us conclude that damages caused by diabetes are slightly perceptible than those observed without the addition of a high concentration of fructose honey.

Keywords: honey, molecular modeling, DPP4 enzyme, metformin

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Authors: Mustafa Salman, Nurcan Cetinkaya, Zehra Selcuk, Bugra Genc

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The objectives of the present study were to estimate the microbial-N flow to the small intestine and to predict the digestible organic matter intake (DOMI) in grazing Karayaka sheep based on urinary excretion of purine derivatives (xanthine, hypoxanthine, uric acid, and allantoin) by the use of spot urine sampling under field conditions. In the trial, 10 Karayaka sheep from 2 to 3 years of age were used. The animals were grazed in a pasture for ten months and fed with concentrate and vetch plus oat hay for the other two months (January and February) indoors. Highly significant linear and cubic relationships (P<0.001) were found among months for purine derivatives index, purine derivatives excretion, purine derivatives absorption, microbial-N and DOMI. Through urine sampling and the determination of levels of excreted urinary PD and Purine Derivatives / Creatinine ratio (PDC index), microbial-N values were estimated and they indicated that the protein nutrition of the sheep was insufficient. In conclusion, the prediction of protein nutrition of sheep under the field conditions may be possible with the use of spot urine sampling, urinary excreted PD and PDC index. The mean purine derivative levels in spot urine samples from sheep were highest in June, July and October. Protein nutrition of pastured sheep may be affected by weather changes, including rainfall. Spot urine sampling may useful in modeling the feed consumption of pasturing sheep. However, further studies are required under different field conditions with different breeds of sheep to develop spot urine sampling as a model.

Keywords: Karayaka sheep, spot sampling, urinary purine derivatives, PDC index, microbial-N, feed intake

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Authors: Vinod Nair, C. Sadasivan

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Beta-lactam antibiotics are the most frequently prescribed medications in modern medicine. The antibiotic resistance by the production of enzyme beta-lactamase is an important mechanism seen in microorganisms. Resistance to beta-lactams mediated by beta-lactamases can be overcome successfully with the use of beta-lactamase inhibitors. New generations of the antibiotics contain mostly synthetic compounds, and many side effects have been reported for them. Combinations of beta-lactam and beta-lactamase inhibitors have become one of the most successful antimicrobial strategies in the current scenario of bacterial infections. Plant-based drugs are very cheap and having lesser adverse effect than synthetic compounds. The synergistic effect of eugenol acetate with beta-lactams restores the activity of beta-lactams, allowing their continued clinical use. It is reported here the enhanced inhibitory effect of phytochemical, eugenol acetate, isolated from the plant Syzygium aromaticum with beta-lactams on beta-lactamase. The compound was found to have synergistic effect with the antibiotic amoxicillin against antibiotic-resistant strain of S.aureus. The enzyme was purified from the organism and incubated with the compound. The assay showed that the compound could inhibit the enzymatic activity of beta-lactamase. Modeling and molecular docking studies indicated that the compound can fit into the active site of beta-lactamase and can mask the important residue for hydrolysis of beta-lactams. The synergistic effects of eugenol acetate with beta-lactam antibiotics may justify, the use of these plant compounds for the preparation of β-lactamase inhibitors against β-lactam resistant S.aureus.

Keywords: betalactamase, eugenol acetate, synergistic effect, molecular modeling

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Authors: Mohamed E. Khalifa, Adil A. Gobouri

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Potential synthesis of a series of 3-amino-4-arylazothiophene derivatives from reaction of 2-cyano-2-phenylthiocarbamoyl acetamide and the appropriate α-halogenated reagents, followed by coupling with different aryl diazonium salts (Japp-Klingemann reaction), and another series of 5-arylazo-thiazol-2-ylcarbamoyl-thiophene derivatives from base-catalyzed intramolecular condensation of 5-arylazo-2-(N-chloroacetyl)amino-thiazole with selected B-keto compounds (Thorpe-Ziegler reaction) was performed. The biological activity of the two series was studied in vitro. Their versatility for pharmaceutical purposes was reported, where they displayed remarkable activities against selected pathogenic microorganisms; Bacillus subtilize, Staphylococcus aureus (Gram positive bacteria), Escherichia coli, Pseudomonas aeruginosa (Gram negative bacteria) and Aspergillus flavus, Candida albicans (fungi) with various degrees related to their chemical structures.

Keywords: thiophene, 2-aminothiazole, compounds, antioxidant, antitumor, antimicrobial

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Authors: Muhammad Imran Din

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The aim of this study was to understand the interaction between multi-walled carbon nano tubes (MCNTs) and anticancer agents and evaluate the drug-loading ability of MCNTs. Batch adsorption experiments were carried out for adsorption of 5-Fluorouracil (5-FL) using MCNTs. The effect of various operating variables, viz., adsorbent dosage, pH, contact time and temperature for adsorption of 5-Fluorouracil (5-FL) has been studied. The Freundlich adsorption model was successfully employed to describe the adsorption process. It was found that the pseudo-second-order mechanism is predominant and the overall rate of the 5-Fluorouracil (5-FL) adsorption process appears to be controlled by the more than one-step. Thermodynamic parameters such as free energy change (ΔG°), enthalpy change (ΔH°) and entropy change (ΔS°) have been calculated respectively, revealed the spontaneous, endothermic and feasible nature of adsorption process. The results showed that carbon nano tubes were able to form supra molecular complexes with 5-Fluorouracil (5-FL) by π-π stacking and possessed favorable loading properties as drug carriers.

Keywords: drug, adsorption, anticancer, 5-Fluorouracil (5-FL)

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Authors: Eddy Neuhaus, Hanif Shirinzadeh, Cigdem Karaaslan, Elif Ince, Hande Gurer-Orhan, Sibel Suzen

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Reactive oxygen species (ROS) and oxidative stress can cause fatal damage to essential cell structures, including DNA. It is known that use of antioxidants could be advantageous in the prevention of various diseases such as cancer, cardiovascular diseases and neurodegenerative disorders. Since antioxidant properties of the indole ring-containing melatonin (MLT) has been described and evaluated, MLT-related compounds such as MLT metabolites and synthetic analogues are under investigation to determine which exhibit the highest activity with the lowest side-effects. Owing to indole and hydrazones appealing physiological properties and are mostly found in numerous biologically active compounds a series of indole-7-carbaldehyde hydrazone derivatives were synthesized, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Cytotoxicity potential of all indole-based MLT analogues was investigated both by lactate dehydrogenase leakage assay and by MTT assay. This work was supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK) Research and Development Grant 112S599.

Keywords: melatonin, antioxidant activity, indole, hydrazone, oxidative stress

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Authors: Huyen T. Pham, Nhue P. Nguyen, Tien Q. Phi, Phuong T. Dang, Hy G. Le

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Since the marine environmental conditions are extremely different from the other ones, so that marine actinomycetes might produce novel bioactive compounds. Therefore, actinomycete strains were screened from marine water and sediment samples collected from the coastal areas of Northern Vietnam. Ninety-nine actinomycete strains were obtained on starch-casein agar media by dilution technique, only seven strains, named HP112, HP12, HP411, HPN11, HP 11, HPT13 and HPX12, showed significant antibacterial activity against both gram-positive and gram-negative bacteria (Bacillus subtilis ATCC 6633, Staphylococcus epidemidis ATCC 12228, Escherichia coli ATCC 11105). Further studies were carried out with the most active HP411strain against Candida albicans ATCC 10231. This strain could grow rapidly on starch casein agar and other media with high salt containing 7-10% NaCl at 28-30oC. Spore-chain of HP411 showed an elongated and circular shape with 10 to 30 spores/chain. Identification of the strain was carried out by employing the taxonomical studies including the 16S rRNA sequence. Based on phylogenetic and phenotypic evidence it is proposed that HP411 to be belongs to species Streptomyces variabilis. The potent of the crude extract of fermentation broth of HP411that are effective against wide range of pathogens: both gram-positive, gram-negative and fungi. Further studies revealed that the crude extract HP411 could obtain the anticancer activity for cancer cell lines: Hep-G2 (liver cancer cell line); RD (cardiac and skeletal muscle letters cell line); FL (membrane of the uterus cancer cell line). However, the actinomycetes from marine ecosystem will be useful for the discovery of new drugs in the furture.

Keywords: marine actinomycetes, antibacterial, anticancer, Streptomyces variabilis

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Authors: Nail Nazarov, Alexandra Vyshtakalyuk, Vyacheslav Semenov, Irina Galyametdinova, Vladimir Zobov, Vladimir Reznik

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Among hepatic pyrimidine used as a means of stimulating protein synthesis and recovery of liver cells in her damaged toxic and infectious etiology. When an experimental toxic hepatitis hepatoprotective activity detected some pyrimidine derivatives. There are literature data on oksimetiluratcila hepatoprotective effect. For analogs of pyrimidine nucleobases - drugs Methyluracilum pentoxy and hepatoprotective effect of weakly expressed. According to the American scientists broad spectrum of biological activity, including hepatoprotective properties, have a 2,4-dioxo-5-arilidenimino uracils. Influenced Xymedon medicinal preparation (1- (beta-hydroxyethyl) -4,6-dimethyl-1,2-dihydro-2-oksopirimidin) developed as a means of stimulating the regeneration of tissue revealed increased activity of microsomal oxidases human liver. In studies on the model of toxic liver damage in rats have shown hepatoprotective effect xymedon and stimulating its impact on the recovery of the liver tissue. Hepatoprotective properties of the new compound in the series of pyrimidine derivatives L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropirimidine-2-one synthesized on the basis Xymedon preparation were firstly investigated on rats under the carbon tetrachloride action. It was shown the differences of biochemical parameters from the reference value and severity of structural-morphological liver violations decreased in comparison with control group under the influence of the compound injected before exposure carbon tetrachloride. Hepatoprotective properties of the investigated compound were more pronounced in comparison with Xymedon.

Keywords: hepatoprotectors, pyrimidine derivatives, toxic liver damage, xymedon

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Authors: Asima Shah, F. A. Masoodi, Adil Gani, Bilal Ahmad Ashwar

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The present study was designed to evaluate the effect of γ-rays on the antioxidant and antiproliferative potential of β-glucan isolated from oats. The β-glucan was irradiated with 0, 2, 6, and 10 kGy by gamma ray. The samples were characterized by FT-IR, GPC, and quantitative estimation by Megazyme β-glucan assay kit. The average molecular weight of non-irradiated β-glucan was 199 kDa that decreased to 70 kDa at 10 kGy. Both FT-IR spectrum and chemical analysis revealed that the extracted β-glucan was pure having minor impurities. Antioxidant activity was evaluated by DPPH, lipid peroxidation, reducing power, metal chelating ability and oxidative DNA damage assays. Results revealed that the antioxidant activity of β-glucan increased with the increase in irradiation dose. Irradiated β-glucan also exhibited dose dependent cancer cell growth inhibition with irradiation doses. The study revealed that low molecular weight β-glucan with enhanced antioxidant and antiproliferative activities can be produced by a simple irradiation method.

Keywords: γ-irradiation, antioxidant activity, antiproliferative activity, β-glucan, oats

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Authors: Hassan Nour, Nouh Mounadi, Oussama Abchir, Belaidi Salah, Samir Chtita

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Cholinesterase enzymes are biological catalysts essential for the transformation of acetylcholine, which is a neurotransmitter implicated in memory and learning, into acetic acid and choline, altering the neurotransmission process in Alzheimer’s disease patients. Therefore, inhibition of cholinesterase enzymes is a relevant strategy for the symptomatic treatment of Alzheimer’s disease. The current investigation aims to explore potential cholinesterase (ChE) inhibitors through a comprehensive computational approach. Forty-nine phytoconstituents extracted from Cannabis sativa L. were in-silico screened using molecular docking and pharmacokinetic and toxicological analysis to evaluate their possible inhibitory effect on the cholinesterase enzymes. Two phytoconstituents belonging to cannabinoid derivatives were revealed to be promising candidates for Alzheimer's therapy by acting as cholinesterase inhibitors. They have exhibited high binding affinities towards the cholinesterase enzymes and showed their ability to interact with key residues involved in cholinesterase enzymatic activity. In addition, they presented good ADMET profiles allowing them to be promising oral drug candidates. Furthermore, molecular dynamics (MD) simulations were executed to explore their interaction stability under mimetic biological conditions and thus support our findings. To corroborate the docking results, the binding free energy corresponding to the more stable ligand-ChE complexes was re-estimated by applying the MM-PBSA method. MD and MM-PBSA studies affirmed that the ligand-ChE recognition is a spontaneous reaction leading to stable complexes. The conducted investigations have led to great findings that would strongly guide the pharmaceutical industries toward the rational development of potent anti-Alzheimer agents.

Keywords: Alzheimer’s disease, molecular docking, Cannabis sativa L., cholinesterase inhibitors, molecular dynamics, ADMET, MM-PBSA

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Authors: Igor B. Sivaev

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Design of molecular machines is an extraordinary growing and very important area of research that it was recognized by awarding Sauvage, Stoddart and Feringa the Nobel Prize in Chemistry in 2016 'for the design and synthesis of molecular machines'. Based on the type of motion being performed, molecular machines can be divided into two main types: molecular motors and molecular switches. Molecular switches are molecules or supramolecular complexes having bistability, i.e., the ability to exist in two or more stable forms, among which may be reversible transitions under external influence (heating, lighting, changing the medium acidity, the action of chemicals, exposure to magnetic or electric field). Molecular switches are the main structural element of any molecular electronics devices. Therefore, the design and the study of molecules and supramolecular systems capable of performing mechanical movement is an important and urgent problem of modern chemistry. There is growing interest in molecular switches and other devices of molecular electronics based on transition metal complexes; therefore choice of suitable stable organometallic unit is of great importance. An example of such unit is bis(dicarbollide) complexes of transition metals [3,3’-M(1,2-C₂B₉H₁₁)₂]ⁿ⁻. The control on the ligand rotation in such complexes can be reached by introducing substituents which could provide stabilization of certain rotamers due to specific interactions between the ligands, on the one hand, and which can participate as Lewis bases in complex formation with external metals resulting in a change in the rotation angle of the ligands, on the other hand. A series of isomeric methyl sulfide derivatives of cobalt bis(dicarbollide) complexes containing methyl sulfide substituents at boron atoms in different positions of the pentagonal face of the dicarbollide ligands [8,8’-(MeS)₂-3,3’-Co(1,2-C₂B₉H₁₀)₂]⁻, rac-[4,4’-(MeS)₂-3,3’-Co(1,2-C₂B₉H₁₀)₂]⁻ and meso-[4,7’-(MeS)₂-3,3’-Co(1,2-C₂B₉H₁₀)₂]⁻ were synthesized by the reaction of CoCl₂ with the corresponding methyl sulfide carborane derivatives [10-MeS-7,8-C₂B₉H₁₁)₂]⁻ and [10-MeS-7,8-C₂B₉H₁₁)₂]⁻. In the case of asymmetrically substituted cobalt bis(dicarbollide) complexes the corresponding rac- and meso-isomers were successfully separated by column chromatography as the tetrabutylammonium salts. The compounds obtained were studied by the methods of ¹H, ¹³C, and ¹¹B NMR spectroscopy, single crystal X-ray diffraction, cyclic voltammetry, controlled potential coulometry and quantum chemical calculations. It was found that in the solid state, the transoid- and gauche-conformations of the 8,8’- and 4,4’-isomers are stabilized by four intramolecular CH···S(Me)B hydrogen bonds each one (2.683-2.712 Å and 2.709-2.752 Å, respectively), whereas gauche-conformation of the 4,7’-isomer is stabilized by two intramolecular CH···S hydrogen bonds (2.699-2.711 Å). The existence of the intramolecular CH·S(Me)B hydrogen bonding in solutions was supported by the 1H NMR spectroscopy. These data are in a good agreement with results of the quantum chemical calculations. The corresponding iron and nickel complexes were synthesized as well. The reaction of the methyl sulfide derivatives of cobalt bis(dicarbollide) with various labile transition metal complexes results in rupture of intramolecular hydrogen bonds and complexation of the methyl sulfide groups with external metal. This results in stabilization of other rotational conformation of cobalt bis(dicarbollide) and can be used in design of molecular switches. This work was supported by the Russian Science Foundation (16-13-10331).

Keywords: molecular switches, NMR spectroscopy, single crystal X-ray diffraction, transition metal bis(dicarbollide) complexes, quantum chemical calculations

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Authors: Harish K. Chandrawanshi, Mithun S. Rajput, Neelima Choure, Purnima Dey Sarkar, Shailesh Jain

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The present research study aimed to fabricate and evaluate biodegradable nanoparticles of aromatase inhibitor letrozole, intended for breast cancer therapy. Letrozole loaded poly(D,L-lactide-co-glycolide acid) nanoparticles were prepared by solvent evaporation method using dichlorometane as solvent (oil phase) and polyvinyl alcohol (PVA) as aqueous phase. Prepared nanoparticles were characterized by particle size, infrared spectra, drug loading efficiency, drug entrapment efficiency and in vitro release and also evaluated for in vivo anticancer activity. The high speed homogenizer was used to produce stable nanoparticles of mean size range 198.35 ± 0.04 nm with high entrapment efficiency (69.86 ± 2.78%). Percentage of drug and homogenization speed significantly influenced the particle size, entrapment efficiency and release (p<0.05). The nanoparticles show significant in vivo anticancer activity against Ehrlich ascites carcinoma in mice. The significant system sustained the release of letrozole drug effectively and further investigation could exhibit its potential usefulness in breast cancer therapy.

Keywords: breast cancer/therapy, letrozole, nanoparticles, PLGA

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Authors: Ravi J. Shah

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The present study deals with the synthesis of novel spiro[azetidine-2, 3’-indole]-2’, 4(1’H)-dione derivative from the reactions of 3-(phenylimino)-1,3-dihydro-2H-indol-2-one derivatives with chloracetyl chloride in presence of triethyl amine (TEA). All the compounds were characterized using IR, 1H NMR, MS and elemental analysis. They were screened for their antibacterial and antifungal activities. Results revealed that, compounds (7a), (7b), (7c), (7d) and (7e) showed very good activity with MIC value of 6.25-12.5 μg/ml against three evaluated bacterial strains and the remaining compounds showed good to moderate activity comparable to standard drugs as antibacterial agents. Compounds (7c) and (7h) displayed equipotent antifungal activity in comparison to standard drugs. Structure-activity relationship study of the compounds showed that the presence of electron withdrawing group substitution at 5’ and 7’ positions of indoline ring and on ortho or para position of phenyl ring increases both antibacterial and antifungal activity of the compound. Henceforth, our findings will have a good impact on chemists and biochemists for further investigations in search of bromine containing spiro fused antimicrobial agents.

Keywords: antibacterial activity, antifungal activity, 2-Azetidinone, indoline

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Authors: G. V. Novikov, V. S. Sivozhelezov, S. S. Kolesnikov, K. V. Shaitan

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The study reports about the influence of binding of orthosteric ligands as well as point mutations on the conformational dynamics of β-2-adrenoreceptor. Using molecular dynamics simulation we found that there was a little fraction of active states of the receptor in its apo (ligand free) ensemble corresponded to its constitutive activity. Analysis of MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion in intracellular part of its alpha-helices. Thus receptor’s constitutive activity directly results from its conformational dynamics. On the other hand the binding of a full agonist resulted in a significant shift of the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized the receptor in its inactive state. It is likely that the binding of inverse agonists might be a universal way of constitutive activity inhibition in vivo. Our results indicate that ligand binding redistribute pre-existing conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) of the receptor rather than cause induced fit in it. Therefore, the ensemble of biologically relevant receptor conformations is encoded in its spatial structure, and individual conformations from that ensemble might be used by the cell in conformity with the physiological behaviour.

Keywords: seven-transmembrane receptors, constitutive activity, activation, x-ray crystallography, principal component analysis, molecular dynamics simulation

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Authors: S. Sathiyamoorthi, P. Srinivasan, K. Suganya Devi

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Arylidene derivatives are the subclass of chalcone derivatives. Chalcone derivatives are studied widely for the past decade because of its nonlinearity. To seek new organic group of crystals which suit for fabrication of optical devices, three-member organic arylidene crystals were synthesized by using Claisen–Schmidt condensation reaction. Good quality crystals were grown by slow evaporation method. Functional groups were identified by FT-IR and FT-Raman spectrum. Optical transparency and optical band gap were determined by UV-Vis-IR studies. Thermal stability and melting point were calculated using TGA and DSC. Variation of dielectric loss and dielectric constant with frequency were calculated by dielectric measurement.

Keywords: DSC and TGA studies, nonlinear optic studies, Fourier Transform Infrared Spectroscopy, UV-vis-NIR spectra

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Authors: Amit Chaudhary, B. S. Yadav, P. K. Maurya, A. M., S. Srivastava, S. Singh, A. Mani

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Cold shock protein A (CspA) is major cold inducible protein present in Escherichia coli. The protein is involved in stabilizing secondary structure of RNA by working as chaperone during cold temperature. Two RNA binding motifs play key role in the stabilizing activity. This study aimed to investigate implications of low temperature on structure and RNA binding activity of E. coli CspA. Molecular dynamics simulations were performed to compare the stability of the protein at 37°C and 10 °C. The protein was mutated at RNA binding motifs and docked with RNA to assess the stability of both complexes. Results suggest that CspA as well as CspA-RNA complex is more stable at low temperature. It was also confirmed that RNP1 and RNP2 play key role in RNA binding.

Keywords: CspA, homology modelling, mutation, molecular dynamics simulation

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Authors: O. Antypenko, I. Vasilieva, S. Kovalenko

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Investigations for new effective and less toxic antimicrobials agents are always up-to-date. The tetrazole derivatives are quite interesting objects as for synthesis as well as for pharmacological screening. Thus, some derivatives of tetrazole demonstrated antimicrobial activity, namely 5-phenyl-tetrazolo[1,5-c]quinazoline was effective one against Staphylococcus aureus and Esherichia faecalis (MIC = 250 mg/L). Besides, investigation of the 9-bromo(chloro)-5-morpholin(piperidine)-4-yl-tetrazolo[1,5-c]quinazoline’s antimicrobial activity against Esherichia coli and Enterococcus faecalis, Pseudomonas aeruginosa and Staphylococcus aureus revealed that sensitivity of Gram-positive bacteria to the compounds was higher than that of Gram-negative bacteria. So, our previously synthesized, 31 derivatives of 1-(2-(1H-tetrazol-5-yl)-R1-phenyl)-3-R2-phenyl(ethyl)ureas were decided to test for their in vitro antibacterial activity against Gram-positive bacteria (Staphylococcus aureus ATCC 25923, Enterobacter aerogenes, Enterococcus faecalis ATCC 29212), Gram-negative bacteria (Pseudomonas aeruginosa ATCC 9027, Escherichia coli ATCC 25922, Klebsiella pneumoniae 68) and antifungal properties against Candida albicans ATCC 885653. Agar-diffusion method was used for determination of the preliminary activity compared to well-known reference antimicrobials. All the compounds were dissolved in DMSO at a concentration of 100 μg/disk, using inhibition zone diameter (IZD, mm) as a measure for the antimicrobial activity. The most active turned to be 3 structures, that inhibited several bacterial strains: 1-ethyl-3-(5-fluoro-2-(1H-tetrazol-5-yl)phenyl)urea (1), 1-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-3-(4-(trifluoromethyl)phenyl)urea (2) and 1-(4-chloro-2-(1H-tetrazol-5-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (3). IZM (mm) was 40 (Escherichia coli), 25 (Klebsiella pneumonia) for compound 1; 12 (Pseudomonas aeruginosa), 15 (Staphylococcus aureus), 10 (Enterococcus faecalis) for compound 2; 25 (Staphylococcus aureus), 15 (Enterococcus faecalis) for compound 3. The most sensitive to the activity of the substances were Gram-negative bacteria Pseudomonas aeruginosa. While none of compound effected on Candida albicans. Speaking about, reference drugs: Amikacin (30 µg/disk) showed 27 and Ceftazide (30 µg/disk) 25 against Pseudomonas aeruginosa. That is, unfortunately, higher than studied 1-(2-(1H-tetrazol-5-yl)-R1-phenyl)-3-R2-phenyl(ethyl)ureas. Obtained results will be used for further purposeful optimization of the leading compounds in the more effective antimicrobials because of the ever-mounting problem of microorganism’s resistance.

Keywords: antimicrobial, antifungal, compounds, 1-(2-(1H-tetrazol-5-yl)-R1-phenyl)-3-R2-phenyl(ethyl)ureas

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Authors: L. Mallesha, P. Mallu, B. Veeresh

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In the present study, 2, 6-diflurobenzohydrazide and 4-fluorophenylisothiocyanate were used as the starting materials to synthesize 5-phenyl-N3-(4-fluorophenyl)-4H-1, 2, 4-triazole-3, 4-diamine. Further, compound 5-phenyl-N3-(4-fluorophenyl)-4H-1, 2, 4-triazole-3,4-diamine reacted with fluoro substituted benzaldehydes to yield a series of Schiff bases. All the final compounds were characterized using IR, 1H NMR, 13C NMR, MS and elemental analyses. New compounds were evaluated for their antiproliferative effect using the MTT assay method against four human cancer cell lines (K562, COLO-205, MDA-MB231, and IMR-32) for the time period of 24 h. Among the series, few compounds showed good activity on all cell lines, whereas the other compounds in the series exhibited moderate activity.

Keywords: Schiff bases, MTT assay, antiproliferative activity, human cancer cell lines, 1, 2, 4-triazoles

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Authors: Harminder Kaur, Manpreet Kaur, Akanksha Kapila, Reenu

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Schiff base with general formula H₂L was derived from condensation of o-vanillin and 3-nitro-o-phenylenediamine. This Schiff base was used for the synthesis of organotin(IV) complexes with general formula R₂SnL [R=Phenyl or n-octyl] using equimolar quantities. Elemental analysis UV-Vis, FTIR, and multinuclear spectroscopic techniques (¹H, ¹³C, and ¹¹⁹Sn) NMR were carried out for the characterization of the synthesized complexes. These complexes were coloured and soluble in polar solvents. Computational studies have been performed to obtain the details of the geometry and electronic structures of ligand as well as complexes. Geometry of the ligands and complexes have been optimized at the level of Density Functional Theory with B3LYP/6-311G (d,p) and B3LYP/MPW1PW91 respectively followed by vibrational frequency analysis using Gaussian 09. Observed ¹¹⁹Sn NMR chemical shifts of one of the synthesized complexes showed tetrahedral geometry around Tin atom which is also confirmed by DFT. HOMO-LUMO energy distribution was calculated. FTIR, ¹HNMR and ¹³CNMR spectra were also obtained theoretically using DFT. Further IRC calculations were employed to determine the transition state for the reaction and to get the theoretical information about the reaction pathway. Moreover, molecular docking studies can be explored to ensure the anticancer activity of the newly synthesized organotin(IV) complexes.

Keywords: DFT, molecular docking, organotin(IV) complexes, o-vanillin, 3-nitro-o-phenylenediamine

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Authors: Mir Hussain Nawaz, Lyudmila Nedyalkova, Haizhong Zhu, Wael M. Rabeh

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In this study, we aim to biochemically and structurally characterize the interactions of human HK2 with the mitochondria in addition to the role of its N-terminal domain in catalysis and stability of the full-length enzyme. Here, we solved the crystal structure of human HK2 in complex with glucose and glucose-6-phosphate (PDB code: 2NZT), where it is a homodimer with catalytically active N- and C-terminal domains linked by a seven-turn α-helix. Different from the inactive N-terminal domains of isozymes 1 and 3, the N- domain of HK2 not only capable to catalyze a reaction but it is responsible for the thermodynamic stabilizes of the full-length enzyme. Deletion of first α-helix of the N-domain that binds to the mitochondria altered the stability and catalytic activity of the full-length HK2. In addition, we found the linker helix between the N- and C-terminal domains to play an important role in controlling the catalytic activity of the N-terminal domain. HK2 is a major step in the regulation of glucose metabolism in cancer making it an ideal target for the development of new anticancer therapeutics. Characterizing the structural and molecular mechanisms of human HK2 and its role in cancer metabolism will accelerate the design and development of new cancer therapeutics that are safe and cancer specific.

Keywords: cancer metabolism, enzymology, drug discovery, protein stability

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Authors: Mohammed Auwal Ibrahim, Aminu Mohammed

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Stigmasterol has previously been reported to possess antitrypanosomal activity using in vitro and in vivo models. However, the mechanism of antitrypanosomal activity is yet to be elucidated. In the present study, molecular docking was used to decipher the mode of interaction and binding affinity of stigmasterol to three known antitrypanosomal drug targets viz; adenosine kinase, ornithine decarboxylase and triose phosphate isomerase. Stigmasterol was found to bind to the selected trypanosomal enzymes with minimum binding energy of -4.2, -6.5 and -6.6 kcal/mol for adenosine kinase, ornithine decarboxylase, and triose phosphate isomerase respectively. However, hydrogen bond was not involved in the interaction of stigmasterol with all the three enzymes, but hydrophobic interaction seemed to play a vital role in the binding phenomenon which was predicted to be non-competitive like type of inhibition. It was concluded that binding to the three selected enzymes, especially triose phosphate isomerase, might be involved in the antitrypanosomal activity of stigmasterol but not mediated via a hydrogen bond interaction.

Keywords: antitrypanosomal, in silico, molecular docking, stigmasterol

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Authors: Rakhshan Hakimelahi

Abstract:

In recent years, zinc oxid nano tubes have attracted much attention. The direct use of zinc oxid nano tubes modified by SiO2 as recoverable catalysts for organic reactions is very rare. The catalysts were characterized by XRD. The average particle size of ZnO catalysts is 57 nm and there are high density defects on nano tubes surfaces. A simple and efficient method for the quinazolin derivatives synthesis from the condensation isatoic anhydride and an aromatic aldehyde with ammonium acetate in the presence of a catalytic amount zinc oxid nano tubes modified by SiO2 is described. The reason proposed for higher catalytic activity of zinc oxid nano tubes modified by SiO2 is a combination effect of the small particle size and high-density surface defects. The practical and simple method led to excellent yields of the 2,3-Di hydro quinazolin-4(1H)-one derivatives under mild conditions and within short times.

Keywords: 2, 3-Dihydroquinazolin-4(1H)-one derivatives, reusable catalyst, SiO2, zinc oxid nanotubes

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Authors: Pauline Nyssen, Ange Mouithys-Mickalad, Maryse Hoebeke

Abstract:

Inflammation is a complex physiological phenomenon involving chemical and enzymatic mechanisms. Polymorphonuclear neutrophil leukocytes (PMNs) play an important role by producing reactive oxygen species (ROS) and releasing myeloperoxidase (MPO), a pro-oxidant enzyme. Released both in the phagolysosome and the extracellular medium, MPO produces during its peroxidase and halogenation cycles oxidant species, including hypochlorous acid, involved in the destruction of pathogen agents, like bacteria or viruses. Inflammatory pathologies, like rheumatoid arthritis, atherosclerosis induce an excessive stimulation of the PMNs and, therefore, an uncontrolled release of ROS and MPO in the extracellular medium, causing severe damages to the surrounding tissues and biomolecules such as proteins, lipids, and DNA. The treatment of chronic inflammatory pathologies remains a challenge. For many years, MPO has been used as a target for the development of effective treatments. Numerous studies have been focused on the design of new drugs presenting more efficient MPO inhibitory properties. However, some designed inhibitors can be toxic. An alternative consists of assessing the potential inhibitory action of clinically-known molecules, having antioxidant activity. Propofol, 2,6-diisopropyl phenol, which is used as an intravenous anesthetic agent, meets these requirements. Besides its anesthetic action employed to induce a sedative state during surgery or in intensive care units, propofol and its injectable form Diprivan indeed present antioxidant properties and act as ROS and free radical scavengers. A study has also evidenced the ability of propofol to inhibit the formation of the neutrophil extracellular traps fibers, which are important to trap pathogen microorganisms during the inflammation process. The aim of this study was to investigate the potential inhibitory action mechanism of propofol and Diprivan on MPO activity. To go into the anti-inflammatory action of propofol in-depth, two of its oxidative derivatives, 2,6-diisopropyl-1,4-p-benzoquinone (PPFQ) and 3,5,3’,5’-tetra isopropyl-(4,4’)-diphenoquinone (PPFDQ), were studied regarding their inhibitory action. Specific immunological extraction followed by enzyme detection (SIEFED) and molecular modeling have evidenced the low anti-catalytic action of propofol. Stopped-flow absorption spectroscopy and direct MPO activity analysis have proved that propofol acts as a reversible MPO inhibitor by interacting as a reductive substrate in the peroxidase cycle and promoting the accumulation of redox compound II. Overall, Diprivan exhibited a weaker inhibitory action than the active molecule propofol. In contrast, PPFQ seemed to bind and obstruct the enzyme active site, preventing the trigger of the MPO oxidant cycles. PPFQ induced a better chlorination cycle inhibition at basic and neutral pH in comparison to propofol. PPFDQ did not show any MPO inhibition activity. The three interest molecules have also demonstrated their inhibition ability on an important step of the inflammation pathway, the PMNs superoxide anions production, thanks to EPR spectroscopy and chemiluminescence. In conclusion, propofol presents an interesting immunomodulatory activity by acting as a reductive substrate in the peroxidase cycle of MPO, slowing down its activity, whereas PPFQ acts more as an anti-catalytic substrate. Although PPFDQ has no impact on MPO, it can act on the inflammation process by inhibiting the superoxide anions production by PMNs.

Keywords: Diprivan, inhibitor, myeloperoxidase, propofol, spectroscopy

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