Publications by authors named "Homa Azizian"

20 Publications

  • Page 1 of 1

Phenothiazine as novel human superoxide dismutase modulators: discovery, optimization, and biological evaluation.

J Biomol Struct Dyn 2021 Mar 4:1-14. Epub 2021 Mar 4.

Faculty of Pharmacy, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran, Iran.

Superoxide dismutases (SODs) are regarded as important antioxidants for protecting cells against damage arising from oxidative stress. Much research is focused on finding new chemicals with an ability to boost human SOD activity. In the research described herein a structure-based approach was used to identify new human Cu-Zn superoxide dismutase (SOD1) modulators based on previously reported plasmodium falciparum iron SOD inhibitors using induced fit docking and molecular dynamic (MD) protocols. The compound with the highest docking binding energy was selected for further structure simplification followed by structural similarity and MD in order to find a new activator/inhibitor scaffold of the SOD1 enzyme. According to the docking survey of the mentioned series, 1,4-bis(3-(1,4,8-trichloro-10Hphenothiazin-10-yl) propyl) piperazine (DS88) was the top scoring compound interacting with the SOD1 active site channel. Following structure simplification and similarity search, the most promising scaffold which is closely related to the phenothiazine antipsychotic class, was identified. Compared with the normal blood SOD1 activity, the percent of O production increased with trifluoperazine, while it decreased with the chlorpromazine. The molecular dynamic investigation shows that trifluoperazine exerts its SOD1 activating effect by stabilizing electrostatic loop while chlorpromazine employs SOD1 inhibition activity through repositioning of the electrostatic loop and increasing its distance from the catalytic metal site which diminished substrate specificity and catalytic activity of the SOD1 enzyme. The results identified the preferred region, orientation, and types of interaction for each activator or inhibitor compound.
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http://dx.doi.org/10.1080/07391102.2021.1893819DOI Listing
March 2021

Quinazolinone-dihydropyrano[3,2-b]pyran hybrids as new α-glucosidase inhibitors: Design, synthesis, enzymatic inhibition, docking study and prediction of pharmacokinetic.

Bioorg Chem 2021 Apr 8;109:104703. Epub 2021 Feb 8.

Nano Alvand Company, Avicenna Tech Park, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A series of new quinazolinone-dihydropyrano[3,2-b]pyran derivatives 10A-L were synthesized by simple chemical reactions and were investigated for inhibitory activities against α-glucosidase and α-amylase. New synthesized compounds showed high α-glucosidase inhibition effects in comparison to the standard drug acarbose and were inactive against α-amylase. Among them, the most potent compound was compound 10L (IC value = 40.1 ± 0.6 µM) with inhibitory activity around 18.75-fold more than acarboase (IC value = 750.0 ± 12.5 µM). This compound was a competitive inhibitor into α-glucosidase. Our obtained experimental results were confirmed by docking studies. Furthermore, the cytotoxicity of the most potent compounds 10L, 10G, and 10N against normal fibroblast cells and in silico druglikeness, ADME, and toxicity prediction of these compounds were also evaluated.
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http://dx.doi.org/10.1016/j.bioorg.2021.104703DOI Listing
April 2021

Design, synthesis, and preliminary pharmacological evaluation of novel thiazolidinone derivatives as potential benzodiazepine agonists.

Mol Divers 2021 Jan 23. Epub 2021 Jan 23.

Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No.2660, Vali-E-Asr., 1991953381, Tehran, Iran.

Thiazolidinones are well-known heterocycles that demonstrate promising biological effects such as anticonvulsant activity. Hybridization of these chemicals with scaffold, which has necessary pharmacophores for binding to the benzodiazepine receptors, can prompt a novel structure possessing extensive anticonvulsant effects. In this study, novel derivatives of thiazolidinone as new benzodiazepine agonists were designed, synthesized, and biologically evaluated. Compound 5h, 4-chloro-2-(2-fluorophenoxy)-N-(4-oxo-2-(p-tolyl)thiazolidin-3-yl)benzamide, exhibited considerable anticonvulsant activity, proper sedative-hypnotic effect, no memory impairment, and no muscle relaxant effect. The pharmacological effects of the designed compounds were antagonized by flumazenil, which confirmed the benzodiazepine receptors' involvement in their biological effects. Based on in silico calculations of ADME properties of our novel compounds, they could be active oral agents potentially. In this study, we designed novel structures by the hybridization of thiazolidinone moiety with scaffold which has necessary pharmacophores for binding to the benzodiazepine receptors. The results are very promising for developing new lead compounds as benzodiazepine agonists possess anticonvulsant effects.
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http://dx.doi.org/10.1007/s11030-021-10182-xDOI Listing
January 2021

Design and synthesis of novel pyrazole-phenyl semicarbazone derivatives as potential α-glucosidase inhibitor: Kinetics and molecular dynamics simulation study.

Int J Biol Macromol 2021 Jan 4;166:1082-1095. Epub 2020 Nov 4.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the α-glucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast α-glucosidase inhibition (IC values in the range of 65.1-695.0 μM) even much more potent than standard drug acarbose (IC = 750.0 μM). Among them, compounds 8o displayed the most potent α-glucosidase inhibitory activity (IC = 65.1 ± 0.3 μM). Kinetic study of compound 8o revealed that it inhibited α-glucosidase in a competitive mode (Ki = 87.0 μM). Limited SAR suggested that electronic properties of substitutions have little effect on inhibitory potential of compounds. Cytotoxic studies demonstrated that the active compounds (8o, 8k, 8p, 8l, 8i, and 8a) compounds are also non-cytotoxic. The binding modes of the most potent compounds 8o, 8k, 8p, 8l and 8i was studied through in silico docking studies. Molecular dynamic simulations have been performed in order to explain the dynamic behavior and structural changes of the systems by the calculation of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF).
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http://dx.doi.org/10.1016/j.ijbiomac.2020.10.263DOI Listing
January 2021

New 1,2,3-triazole-(thio)barbituric acid hybrids as urease inhibitors: Design, synthesis, in vitro urease inhibition, docking study, and molecular dynamic simulation.

Arch Pharm (Weinheim) 2020 Sep 28;353(9):e2000023. Epub 2020 Jun 28.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

A new series of 1,2,3-triazole-(thio)barbituric acid hybrids 8a-n was designed and synthesized on the basis of potent pharmacophores with urease inhibitory activity. Therefore, these compounds were evaluated against Helicobacter pylori urease. The obtained result demonstrated that all the synthesized compounds, 8a-n, were more potent than the standard urease inhibitor, hydroxyurea. Moreover, among them, compounds 8a, 8c-e, 8g,h, and 8k,l exhibited higher urease inhibitory activities than the other standard inhibitor used: thiourea. Docking studies were performed with the synthesized compounds. Furthermore, molecular dynamic simulation of the most potent compounds, 8e and 8l, showed that these compounds interacted with the conserved residues Cys592 and His593, which belong to the active site flap and are essential for enzymatic activity. These interactions have two consequences: (a) blocking the movement of a flap at the entrance of the active site channel and (b) stabilizing the closed active site flap conformation, which significantly reduces the catalytic activity of urease. Calculation of the physicochemical and topological properties of the synthesized compounds 8a-n predicted that all these compounds can be orally active. The ADME prediction of compounds 8a-n was also performed.
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http://dx.doi.org/10.1002/ardp.202000023DOI Listing
September 2020

Synthesis, Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4-Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate.

Chem Biodivers 2020 May 21;17(5):e1900710. Epub 2020 Apr 21.

Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box, 15875-4416, Tehran, Iran.

A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2-(2-hydroxyphenyl)-4H-benzo[e][1,3]oxazin-4-one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC values of 1.268 and 3.254 μm, respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors.
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http://dx.doi.org/10.1002/cbdv.201900710DOI Listing
May 2020

Design, Synthesis, Molecular Docking, and Cholinesterase Inhibitory Potential of Phthalimide-Dithiocarbamate Hybrids as New Agents for Treatment of Alzheimer's Disease.

Chem Biodivers 2019 Nov 7;16(11):e1900370. Epub 2019 Oct 7.

Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, 1417653761, Iran.

A novel series of phthalimide-dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti-cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti-AChE and anti-BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h, respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug-like properties and were able to cross the BBB.
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http://dx.doi.org/10.1002/cbdv.201900370DOI Listing
November 2019

Anticancer properties of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives; kinase inhibitors.

Bioorg Chem 2019 09 10;90:103055. Epub 2019 Jun 10.

Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran, Iran. Electronic address:

Structure activity correlation revealed that the quinoxaline ring is a satisfactory backbone for anticancer activity and a specific functional group at position 1 and 2 can improve the activity. In this basis, besides quinoxaline, imidazoles as potential anticancer agents were used as a supplementary agents for cancer treatment. In this paper, a new series of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives were synthesized in a simple and efficient step. The products are fully characterized by 1H NMR, C NMR, FT-IR, HRMS, and CHN elemental analysis. Several starting materials with different functionalities have been used for the synthesis of the final products with high isolated yields. The biological activities of the synthesized compounds were evaluated in kinase inhibition and cytotoxic activity in several cancerous cell lines. All compounds (6) were evaluated for inhibition of the cell proliferation using 4 cancerous cell lines. Five of the more active compounds were studied for determination of IC50 Compounds 6(32-34) showed good activity on some of cancerous cell lines. The results showed that compound 6-32 has the highest biological activity (IC% 9.77 for K562 cell line). An IC% value of 15.84 µM was observed for 6-34. Furthermore 6-34 exhibited inhibition of ABL1 and c-Src kinases with an IC50% value of 5.25 µM and 3.94 µM respectively. Docking simulation was performed to position active synthesized compounds 6-32, 6-33, and 6-34 over the ABL1 active site in two different wild-type (DFG-in and DFG-out motif conformer) and T315I mutant to determine the probable binding orientation, conformation and mode of interaction. According to docking study, the docked location in wild type forms is similar and can be found near the P-loop region while in the case of T315I mutant form, the compounds have a distinct docked location which is close to the αC helix and activation loop. Also, it concluded the role of R substituent on phenyl ring produced higher interaction energy. Additionally, the detailed inter-molecular energy and types of non-bonding interaction of these compounds over the wild-type and mutant form of ABL1.
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http://dx.doi.org/10.1016/j.bioorg.2019.103055DOI Listing
September 2019

Two DNA binding modes of a zinc-metronidazole and biological evaluation as a potent anti-cancer agent.

Nucleosides Nucleotides Nucleic Acids 2019 28;38(7):449-480. Epub 2019 Jan 28.

c Department of Medicinal Chemistry Faculty of Pharmacy-International Campus , Iran University of Medical Sciences , Tehran , Iran.

A complex of metronidazole (MTZ) with zinc ion was synthesized and characterized by UV-Vis, Fourier transform infrared (FT-IR), H-NMR, X-ray crystallography and thermal gravimetric-differential thermal analysis (TG-DTA). The cytotoxicity effect of the synthesized complex investigated over SKNMC, A549, MCF-7, and MCDK cell lines and the results have shown that it has high cytotoxic potential over cancer cell lines. In order to clarify the mechanism of cell cytotoxicity, the oxidative stress and binding of the complex to the calf thymus-DNA studied by evaluating the intrinsic binding constant and defining thermodynamic parameters of complex over the DNA accompanying with in silico molecular modeling method. For this purpose, the complex optimized at the B3LYP/LANL2DZ level and docked over the DNA structure. The results revealed that the metronidazole-zinc complex interacted with DNA via hydrogen binding and electrostatic interaction to the minor groove region and phosphate backbone of DNA, respectively.
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http://dx.doi.org/10.1080/15257770.2018.1562073DOI Listing
July 2019

Synthesis, CYP 450 evaluation, and docking simulation of novel 4-aminopyridine and coumarin derivatives.

Arch Pharm (Weinheim) 2019 Mar 14;352(3):e1800247. Epub 2019 Jan 14.

Pharmidex Pharmaceutical Service, Limited, London, United Kingdom.

Four series of novel compounds based on 4-aminopyridine, glatiramer acetate, pyrone, and coumarin backbones were sufficiently synthesized and identified by spectroscopic methods. CYP enzyme inhibition assays of five predominate human P450 isozymes indicate that all compounds, except for 4-hydrazide pyridine 1c, seem to be less toxic than 4-aminopyridine. Further investigation of the compounds using molecular docking experiments revealed different, the same, or stronger binding modes for most of the synthesized compounds, with both polar and hydrophobic interactions with the 1WDA and 1J95 receptors compared to benzoyl l-arginine amide and 4-aminopyridine, respectively. These results introduce the synthesized compounds as K channel blockers that could be considered for in vivo CNS disease studies.
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http://dx.doi.org/10.1002/ardp.201800247DOI Listing
March 2019

Super paramagnetic core-shells anchored onto silica grafted with C/NH nano-particles for ultrasound-assisted magnetic solid phase extraction of imipramine and desipramine from plasma.

J Chromatogr B Analyt Technol Biomed Life Sci 2018 Mar 31;1077-1078:52-59. Epub 2018 Jan 31.

Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Iran.

In current work the FeO magnetic nano-particles anchored to core-shells of SiO which grafted by C/NH dual mixed groups, have been synthesized. The magnetic nano-particles were characterized by scanning electron microscopy, X-ray diffraction spectroscopy, and zeta-potential reader. The resulted nano-particles have spherical structure with diameters in the range of 105 to 110 nm. A magnetic solid phase extraction method was developed for extraction of imipramine and desipramine from human plasma samples under ultrasonic conditions by using of prepared NPs as sorbent. The MNPs were dispersion in plasma under sonicated conditions, accumulated by an external magnetic field and washed with Briton-Robinson buffer-acetonitrile solution (0.05 mol l, pH = 5, 10%V/V). The drugs were removed by methanol and quantified by gas chromatography. The calibration curves (correlation coefficient > 0.99) for IMP and DES were linear in the concentration range of 0.005 to 5 and 0.01 to 4 μg ml, respectively. The LOD, LOQ, intra and inter-day precision values were measured too. The proposed FeO/SiO/C/NH MNPs could be applied for 3.0 times.
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http://dx.doi.org/10.1016/j.jchromb.2018.01.033DOI Listing
March 2018

Identification of a New Isoindole-2-yl Scaffold as a Qo and Qi Dual Inhibitor of Cytochrome bc Complex: Virtual Screening, Synthesis, and Biochemical Assay.

Interdiscip Sci 2018 Dec 18;10(4):781-791. Epub 2017 Sep 18.

Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Respiratory chain ubiquinol-cytochrome (cyt) c oxidoreductase (cyt bc or complex III) has been demonstrated as a promising target for numerous antibiotics and fungicide applications. In this study, a virtual screening of NCI diversity database was carried out in order to find novel Qo/Qi cyt bc complex inhibitors. Structure-based virtual screening and molecular docking methodology were employed to further screen compounds with inhibition activity against cyt bc complex after extensive reliability validation protocol with cross-docking method and identification of the best score functions. Subsequently, the application of rational filtering procedure over the target database resulted in the elucidation of a novel class of cyt bc complex potent inhibitors with comparable binding energies and biological activities to those of the standard inhibitor, antimycin.
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http://dx.doi.org/10.1007/s12539-017-0241-8DOI Listing
December 2018

Arylhydrazone derivatives of naproxen as new analgesic and anti-inflammatory agents: Design, synthesis and molecular docking studies.

J Mol Graph Model 2016 06 24;67:127-36. Epub 2016 May 24.

Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. Electronic address:

A series of new arylidenehydrazone derivatives of naproxen were synthesized and evaluated for their analgesic and anti-inflammatory activities. Some of the synthesized analogues showed comparable activities when compared against naproxen for their analgesic and anti-inflammatory properties. 2-(6-methoxy-2-naphthyl)-N'-[(pyridine-4-yl)methylene]propanoic acid hydrazide 4j was found to be the most active analgesic agent. 2-(6-methoxy-2-naphthyl)-N'-[4-nitrobenzylidene]propanoic acid hydrazide 4g showed highest anti-inflammatory activity in comparison to the naproxen. Molecular modeling study of the synthesized compounds suggested that the designed molecules were well located and bound to the COX-1 and COX-2 active sites. Compound 4g showed the highest selectivity for COX-2 (RCOX-2/COX-1=1.94) and higher affinity rather than naproxen in COX-2 active site (RCOX-2/naproxen=1.28). Moreover, the structural analyses confirmed that the E-ap rotamer is the preferred structure for the arylidenehydrazone derivatives.
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http://dx.doi.org/10.1016/j.jmgm.2016.05.009DOI Listing
June 2016

Discovery of novel dual inhibitors against Mdm2 and Mdmx proteins by in silico approaches and binding assay.

Life Sci 2016 Jan 30;145:240-6. Epub 2015 Dec 30.

Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran. Electronic address:

Aims: The p53 protein, also called guardian of the genome, has a key role in cell cycle regulation. It is activated under stressful circumstances, such as DNA damage which results in permanent arrest or cell death. The protein is disabled in several types of human cancer due to over-expression of the two regulators, Mdm2 and Mdmx. As a result, inhibiting Mdm subtypes could reactivate p53 and bring about a promising therapeutic strategy in cancers.

Main Methods: Here a structure-based pharmacophore search and docking simulation are presented in order to filter our in-house library which contains 1035 compounds to find novel scaffolds that inhibit Mdm2 and Mdmx concomitantly. Afterwards, fluorescence polarization binding assay was used to obtain inhibition constant of final compounds.

Key Findings: Thirty two ligands were introduced to bioassay as a result of in-silico methods. Twelve of them inhibit both proteins with almost balanced Ki value ranging from 18 to 162μM for Mdm2 and 18 to 233μM for Mdmx. It was observed that all compounds fill Phe19 and Trp23 pockets of Mdm2/x binding sites and form a hydrogen bond with Trp23 pocket's neighbor amino acids in a manner similar to p53 protein. Additionally, it was concluded that Trp23 pocket of Mdmx has a bigger hydrophobic volume comparing with the one of Mdm2.

Significance: Three structure-activity relationship patterns are supposed which one of them presents usefulness features and can be used in future studies. This study presents first qualitative SAR for dual inhibitors against Mdm2/x.
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http://dx.doi.org/10.1016/j.lfs.2015.12.047DOI Listing
January 2016

The effect of information provision on reduction of errors in intravenous drug preparation and administration by nurses in ICU and surgical wards.

Acta Med Iran 2012 ;50(11):771-7

Department of Clinical Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Malpractice in preparation and administration of intravenous (IV) medications has been reported frequently. Inadequate knowledge of nurses has been reported as a cause of such errors. We aimed to evaluate the role of nurses' education via installation of wall posters and giving informative pamphlets in reducing the errors in preparation and administration of intravenous drugs in 2 wards (ICU and surgery) of a teaching hospital in Tehran, Iran. A trained observer stationed in 2 wards in different work shifts. He recorded the nurses' practice regarding the preparation and administration of IV drugs and scored them before and after the education process. 400 observations were evaluated. Of them, 200 were related to before education and 200 were related to after education. On a 0-10 quality scale, mean ± SD scores of before and after education were determined. Mean ± SD scores of before and after education at the 2 wards were 4.51 (± 1.24) and 6.15 (± 1.23) respectively. There was a significant difference between the scores before and after intervention in ICU (P<0.001), surgery (P<0.001), and total two wards (P<0.001). Nurses' education by using wall poster and informative pamphlets regarding the correct preparation and administration of IV drugs can reduce the number of errors.
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July 2013

Large-scale virtual screening for the identification of new Helicobacter pylori urease inhibitor scaffolds.

J Mol Model 2012 Jul 3;18(7):2917-27. Epub 2011 Dec 3.

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, 16 Azar Ave, Tehran, Iran.

Here, we report a structure-based virtual screening of the ZINC database (containing about five million compounds) by computational docking and the analysis of docking energy calculations followed by in vitro screening against H. pylori urease enzyme. One of the compounds selected showed urease inhibition in the low micromolar range. Barbituric acid and compounds 1a, 1d, 1e, 1f, 1g, 1h were found to be more potent urease inhibitors than the standard inhibitor hydroxyurea, yielding IC(50) values of 41.6, 83.3, 66.6, 50, 58.8, and 60 μM, respectively (IC(50) of hydroxyurea = 100 μM). 5-Benzylidene barbituric acid has enhanced biological activities compared to barbituric acid. Furthermore, the results indicated that among the substituted 5-benzylidene barbiturates, those with para substitution have higher urease inhibitor activities. This may be because the barbituric acid moiety is closer to the bimetallic nickel center in unsubstituted or para-substituted than in ortho- or meta-substituted analogs, so it has greater chelating ability.
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http://dx.doi.org/10.1007/s00894-011-1310-2DOI Listing
July 2012

Endo-inulinase stabilization by pyridoxal phosphate modification: a kinetics, thermodynamics, and simulation approach.

Appl Biochem Biotechnol 2011 Dec 30;165(7-8):1661-73. Epub 2011 Sep 30.

Department of Food Science and Engineering, Faculty of Biosystem Engineering, University of Tehran, Tehran, Iran.

The structural and storage and functional thermostabilization of endo-inulinase (EC 3.2.1.7) through semi-rational modification of surface accessible lysine residues by pyridoxal-5'-phosphate (PLP) and ascorbate reduction have been explored. Improved stability was observed on modifications in the absence or presence of inulin, which indicates storage or functional thermostabilization, respectively. Comparisons have been made between non-modified and modified enzyme by the determination of Tm as an indicator of structural stability, temperature-dependent half-lives (t1/2), energy barrier of the inactivation process, and thermodynamic parameters (ΔH, ΔG, and ΔS) in a storage thermostability approach. These parameters coincided well with the observed stabilization of the engineered enzyme. Moreover, relative activities with sucrose and inulin were determined for non-modified and modified endo-inulinases at different temperatures. A comparison of the sucrose-to-inulin ratios of the initial rate of hydrolysis as an indicator of substrate specificity revealed about twofold improvement in inulinase versus sucrose activity by enzyme modification. Molecular dynamics simulations and molecular docking approaches were employed to explain the observed structural and functional thermostabilization of endo-inulinase upon modification. We hypothesize the establishment of intramolecular interactions between the covalently attached PLP-Lys381 and Arg526 and Ser376 residues as a representative of modification-originated intramolecular contacts in the modified enzyme.
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http://dx.doi.org/10.1007/s12010-011-9385-xDOI Listing
December 2011

Theoretical investigation of interaction of sorbitol molecules with alcohol dehydrogenase in aqueous solution using molecular dynamics simulation.

Cell Biochem Biophys 2011 Mar;59(2):79-88

Department of Chemistry, Faculty of Sciences, Shahid Beheshti University G.C., Evin, Tehran, Iran.

The nature of protein-sorbitol-water interaction in solution at the molecular level, has been investigated using molecular dynamics simulations. In order to do this task, two molecular dynamics simulations of the protein ADH in solution at room temperature have been carried out, one in the presence (about 0.9 M) and another in the absence of sorbitol. The results show that the sorbitol molecules cluster and move toward the protein, and form hydrogen bonds with protein. Also, coating by sorbitol reduces the conformational fluctuations of the protein compared to the sorbitol-free system. Thus, it is concluded that at moderate concentration of sorbitol solution, sorbitol molecules interact with ADH via many H-bonds that prevent the protein folding. In fact, at more concentrated sorbitol solution, water and sorbitol molecules accumulate around the protein surface and form a continuous space-filling network to reduce the protein flexibility. Namely, in such solution, sorbitol molecules can stabilize a misfolded state of ADH, and prevent the protein from folding to its native structure.
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http://dx.doi.org/10.1007/s12013-010-9116-xDOI Listing
March 2011

Molecular modeling of Helicobacter pylori arginase and the inhibitor coordination interactions.

J Mol Graph Model 2010 Apr 29;28(7):626-35. Epub 2009 Dec 29.

Department of Medicinal Chemistry, Faculty of Pharmacy, 16 Azar Ave., Tehran University of Medical Sciences, Tehran, Iran.

Arginase of the Helicobacter pylori hydrolyzes l-arginine to l-ornithine and urea. H. pylori urease hydrolyzes urea to carbon dioxide and ammonium, which neutralizes acid. Both enzymes are involved in H. pylori nitrogen metabolism. The role of arginase in the physiology of H. pylori is metabolically upstream of urease which contributes in pathogeneses of this bacterium, so arginase could be potential drug target for H. pylori infection. We performed homology modeling of H. pylori arginase using the crystal structure of Bacillus caldovelox arginase as a template, and then refined the model through molecular dynamics (MD) simulations. Different criteria measured by PROCHECK, VERIFY-3D and PROSA were indicative of the proper fold for the predicted structural model of H. pylori arginase. Further evaluation on the model quality was performed by investigating the interaction of some arginase inhibitors with the modeled enzyme. Such interactions were determined employing Autodock 3.0.5 program. Our results are compatible with the published data on contribution of four aspartic acids: D116, D120, D234, D236 and three histidines: H91, H118, H133 for catalysis and stability of binuclear metal center of arginase that have important role in binding and catalytic activity in active site. In the absence of the experimental structure of H. pylori arginase we hope that our model will be useful to provide rational design of novel anti-H. pylori drugs.
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http://dx.doi.org/10.1016/j.jmgm.2009.12.007DOI Listing
April 2010

Determination of fluoride in the bottled drinking waters in iran.

Iran J Pharm Res 2010 ;9(1):37-42

Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Fluoride is recognized as an effective agent for dental caries prevention. Generally, the main source of fluoride intake is drinking water. In this study, fluoride content in 18 commercial brands of bottled waters was investigated. Six samples from each batch of 18 Iranian commercial brands of bottled waters were supplied. The fluoride content of samples was analyzed by Fluoride Ion Selective Electrode. The mean ± SD fluoride content of the bottled waters was 0.202 ± 0.00152 mg/L with a range from 0.039 to 0.628 mg/L which was lower than the accepted limits for fluoride content of drinking water (1 mg/L). This finding suggested that in the region which water has high fluoride content, drinking bottled water is preferred to drinking tap water, as it could lower the risk of fluorosis. However, the risk of dental caries increases in people who mainly drink bottled waters; thus, they should use fluoride supplements.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869560PMC
December 2013