Publications by authors named "Maryam Iman"

37 Publications

The anti-cancer properties of neem () through its antioxidant activity in the liver; its pharmaceutics and toxic dosage forms; a literature review.

J Complement Integr Med 2021 May 10. Epub 2021 May 10.

Department of Physiology and Medical Physics, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.

Objectives: The neem () have been used in herbal medicine for the treatment of multiple diseases, particularly cancer. The mechanism of anti-cancer properties of neem are far from clear. However, it is well accepted that anti-cancer effects of neem is mediated via its hepatic anti-oxidant activity. In the present review, we are going to classify and studies about anti-cancer activity of neem via its hepatic anti-oxidant activity. We also summarize its active ingredients and some therapeutic and toxic dosage forms.

Methods: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for neem, , anti-cancer, anti-tumor, carcinogen, liver, antioxidant activity, neem ingredients, and glutathione. Electronic database searches combined and duplicates were removed.

Results: The neem plant have been used in herbal medicine for the treatment of various diseases, particularly cancer. The mechanisms of anti-cancer effects of neem are far from clear. Cancerous cells growth can induce imbalance the oxidant and anti-oxidant activity in various organs particularly in the liver. Therefore, it seems that neem have anti-cancer effects via restore of the antioxidant disturbances close to the control ones in the liver. Additionally, administration of neem extract can induce oncostatic potential via several mechanism including; suppression of the NF-κβ pathway, increased expression of tumor suppressor (such as p53 and pTEN), decreased expression of oncogenes (such as c-Myc), and increased apoptosis in cancerous cells. The median lethal dose (LD50) value for extracts of neem was higher than 2,500 mg/kg.

Conclusions: It is suggested that neem plays pivotal role in the prevention and treatment of cancer via its hepatic antioxidant activity. Indeed, application of neem extract can decreased tumor growth via restore of the antioxidant disturbances close to the control ones in the liver.
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http://dx.doi.org/10.1515/jcim-2021-0009DOI Listing
May 2021

Intracerebroventricular injection of propranolol blocked analgesic and neuroprotective effects of resveratrol following L spinal nerve ligation in rat.

J Complement Integr Med 2021 May 7. Epub 2021 May 7.

Department of Physiology and Medical Physics, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.

Objectives: Resveratrol as a natural polyphenolic agent can alleviate neuropathic pain symptoms. The mechanism of analgesic activity of resveratrol is far from clear. The current study examine whether analgesic activity of resveratrol is mediated by its neuroprotective and anti-oxidant activity in the neuropathic pain. We further examine whether analgesic activity of resveratrol is mediated by β-adrenoceptors in the brain.

Methods: Neuropathic pain induced by L spinal nerve ligation (SNL). Male Wistar rats assigned into sham, SNL, SNL + resveratrol (40 μg/5 μL), and SNL + resveratrol + propranolol (a non-selective β-adrenoceptor antagonist, 30 μg/5 μL) groups. Drugs injected intracerebroventricular (ICV) at day SNL surgery and daily for 6 days following SNL. Thermal allodynia and anxiety examined on days of -1, 2, 4, and 6 following SNL. Electrophysiological study performed on day 6 following SNL for evaluation of resveratrol effects on sciatic nerve conduction velocity (NCV). The activity of catalase (Cat) and superoxide dismutase (SOD) enzymes in the brain assessed on days 6 following SNL.

Results: Resveratrol significantly decreased thermal allodynia (and not anxiety) in all experimental days. Additionally, resveratrol significantly increased NCV, and also normalized the disrupted Cat and SOD activities following neuropathic pain. Furthermore, propranolol significantly blocked the analgesic and neuroprotective effects of resveratrol.

Conclusions: It is suggested that the analgesic effects of resveratrol is mediated by its neuroprotective and antioxidant activities in the neuropathic rats. Furthermore, propranolol blocked the analgesic and neuroprotective effects of resveratrol.
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http://dx.doi.org/10.1515/jcim-2020-0393DOI Listing
May 2021

Applications of western blot technique: From bench to bedside.

Biochem Mol Biol Educ 2021 07 13;49(4):509-517. Epub 2021 Apr 13.

Department of Biochemistry, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran.

Western blot (WB) or immunoblot is a workhorse method. It is commonly used by biologists for study of different aspects of protein biomolecules. In addition, it has been widely used in disease diagnosis. Despite some limitations such as long time, different applications of WB have not been limited. In the present review, we have summarized scientific and clinical applications of WB. In addition, we described some new generation of WB techniques.
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http://dx.doi.org/10.1002/bmb.21516DOI Listing
July 2021

Design and Synthesis of New Antifungals Based on N-Un-substituted Azoles as 14α Demethylase Inhibitor.

Curr Comput Aided Drug Des 2021 ;17(2):235-243

Department of Pharmaceutics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective: Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). Nearly all azole antifungal agents are Nsubstituted azoles. In addition, an azolylphenalkyl pharmacophore is uniquely shared by all azole antifungals. Due to the importance of nitrogen atom of azoles (N-3 of imidazole and N-4 of triazole) in coordination with heme in the binding site of the enzyme, here a group of N- un-substituted azoles in which both nitrogen are un-substituted was reported.

Materials And Methods: Designed compounds were synthesized by the reaction of imidazole-4- carboxaldehyde with appropriate arylamines and subsequently reduced to desired amine derivatives. Antifungal activity against Candida albicans and Saccharomyces cervisiae was done using a broth micro-dilution assay. Docking studies were done using AutoDock.

Results: Antimicrobial evaluation revealed that some of these compounds exhibited moderate antimicrobial activities against tested pathogenic fungi, wherein compounds 3, 7, and 8 were potent. Docking studies propose that all of the prepared azoles interacted with 14α-DM, wherein azoleheme coordination played the main role in drug-receptor interaction.

Conclusion: Our results offer some useful references for molecular design performance or modification of this series of compounds as a lead compound to discover new and potent antimicrobial agents.
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http://dx.doi.org/10.2174/1573409916666200217090855DOI Listing
January 2021

Dual function of interleukin-23 Aptamer to suppress brain inflammation via attachment to macrophage stimulating 1 kinase and interleukin-23.

Colloids Surf B Biointerfaces 2020 Jan 2;185:110619. Epub 2019 Nov 2.

Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran. Electronic address:

In the present study, the dual function of interleukin-23 (IL-23) Aptamer to suppress brain inflammation via attachment to macrophage stimulating 1 (MST1) kinase and IL-23, was introduced. Also, the anti-inflammatory property of IL-23 Aptamer has been investigated. This study showed that IL-23 Aptamer could reduce the clinical development of brain inflammation induced by Parathion, as an important organophosphate toxin. Both immunostaining and H&E staining indicated that the total inflammatory infiltration foci were remarkably decreased in IL-23 Aptamer-treated mice. Moreover, this study showed that IL-23 Aptamer reduced both absolute and relative numbers of MST1+CD4 + Th1 cells and IL-23-producing cells. Analysis of the Hippo signaling genes showed a sharp decrease of MST1 kinase compared with other genes (P < 0.001). Moreover, computer-assisted molecular docking demonstrated that both MST1 kinase and IL-23 could tightly attach to IL-23 Aptamer, and maybe block it. Taken together, IL-23 Aptamer coud decrease brain inflammation via suppressing MST1 kinase and IL-23.
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http://dx.doi.org/10.1016/j.colsurfb.2019.110619DOI Listing
January 2020

A nanocomposite prepared from reduced graphene oxide, gold nanoparticles and poly(2-amino-5-mercapto-1,3,4-thiadiazole) for use in an electrochemical sensor for doxorubicin.

Mikrochim Acta 2019 08 23;186(9):641. Epub 2019 Aug 23.

Physiology Research Center, Iran University of Medical Sciences, Tehran, 14496-14535, Iran.

A nanocomposite was prepared with reduced graphene oxide, gold nanoparticles and an electropolymerized film made from 2-amino-5-mercapto-1,3,4-thiadiazole. An electrochemical sensor for doxorubicin (DOX) was constructed by modifying a glassy carbon electrode (GCE) with the nanocomposite. The modified GCE was studied by electrochemical techniques which showed it to enable highly sensitive sensing of DOX. Response (typically measured at a typical working potential of -0.56 V vs. Ag/AgCl) is linear in the 30 pM to 30 nM and 30 nM to 30 μM DOX concentration ranges, with a limit of detection (LOD) of 9 pM (at an S/N ratio of 3). The method was applied to the determination of DOX in serum and gave recoveries that ranged between 92 and 108%. Graphical abstract A combination of materials consisting of reduced graphene oxide (rGO), gold nanoparticles (AuNPs) and an electropolymerized film of 2-amino-5-mercapto-1,3,4-thiadiazole (poly-AMT, PAMT) is described. The nanocomposite was placed on a glassy carbon elkectrode (GCE) in order to fabricate an electrochemical sensor for doxorubicin (DOX).
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http://dx.doi.org/10.1007/s00604-019-3761-6DOI Listing
August 2019

The Effects of Cinnamaldehyde (Cinnamon Derivatives) and Nystatin on and .

Open Access Maced J Med Sci 2019 Apr 10;7(7):1067-1070. Epub 2019 Apr 10.

Department of Oral Medicine, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Candida species are the most common opportunistic fungal infections. Today, cinnamon plants have been considered for anti-Candida properties.

Aim: This study aimed to investigate the effectiveness of cinnamaldehyde extract (from cinnamon derivatives) on and species and comparison with nystatin.

Material And Methods: In this study, cinnamaldehyde and nystatin were used. The specimens included and . Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were measured for each one by the microdilution method. This experiment was repeated three times.

Results: Cinnamaldehyde extract at a concentration of 62.5 μl/ml was able to prevent the growth of , at a concentration of 93.7 μl/ml, causing to disappear, at 48.8 μl/ml, to prevent the growth of , and in the concentration of 62.5 μl/ml, causes the loss of . In comparison, nystatin at 0.5 μg/ml concentration prevented the growth of , at concentrations of 1 μg/ml causing to be destroyed, at 4 μg/ml concentration to prevent the growth of , and at a concentration of 8 μg/ml causes the loss of . The results were the same every three times.

Conclusions: Although cinnamaldehyde extract had an effect on fungal growth in both and with a fatal effect; the effect on these two species was lower than nystatin.
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http://dx.doi.org/10.3889/oamjms.2019.245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490497PMC
April 2019

Gelatin hydrogel containing cerium oxide nanoparticles covered by interleukin-17 aptamar as an anti- inflammatory agent for brain inflammation.

J Neuroimmunol 2019 01 23;326:79-83. Epub 2018 Nov 23.

Department of Laboratory Sciences, School of Paramedicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Medical biotechnology Research Center, Ashkezar Branch, Islamic Azad University, Ashkezar, Yazd, Iran. Electronic address:

The purpose of this study was to evaluate the anti-inflammatory property of gelatin hydrogel containing cerium oxide nanoparticles coated with interleukin-17 Aptemer ([[email protected]]). Here, the brain inflammation model was induced by both proteolipid protein (PLP) and parathion. Then, the expression of some inflammatory genes and the serum level of related interleukins were evaluated. This study showed that the expression of IL-17, IL-10, and IL-6 genes and their serum levels were significantly decreased (P < .05) by administration of gelatin hydrogel containing [[email protected]].
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http://dx.doi.org/10.1016/j.jneuroim.2018.11.011DOI Listing
January 2019

Design and Synthesis of 4-flurophthalimides as potential anticonvulsant agents.

Iran J Pharm Res 2018 ;17(3):896-905

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

Anticonvulsant activity of phthalimide was discovered in 2000 by molecular hybridization of thalidomide and ameltolide. In our present research we report some new 4-substituted derivatives of phthalimide with good activity against the tonic and clonic seizures. A series of novel 4-flurophthalimides designed using bioisosteric replacement were synthesized by condensation of 4-flurophthalic anhydride with appropriate arylamines. The purity of these compounds was determined by TLC and the chemical structures were confirmed by IR and H-NMR spectroscopy. Anticonvulsant activity of prepared compounds was evaluated using MES and PTZ models. Some of the designed compounds significantly protected mice against the PTZ-induced seizure among which, compound with lipophilic and flexible aromatic moiety was more potent than the reference drug phenytoin and was the most potent in this series of phthalimide derivatives. In the MES model, the prepared phthalimide did not show efficient activity. The prepared compounds are active in clonic seizure.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094442PMC
January 2018

Synthesis, In Silico and In Vitro Cytostatic Activity of New Lipophilic Derivatives of Hydroxyurea.

Recent Pat Anticancer Drug Discov 2018 ;13(3):378-385

Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.

Background: Hydroxyurea (HU) is used to treat cancer. HU has a short half-life due to its small molecular weight and high polarity, therefore a high dosage of the drug should be used which introduces side effects and more rapid development of resistance.

Objective: The objective of the current study is to design new lipophilic analogues of hydroxyurea with higher stability and better cell penetration. The designed compounds were synthesized and then evaluated in terms of their cytostatic activities against two human cell lines.

Methods: The synthesis of designed ligands was achieved via two-step procedure. Detail of the synthesis and chemical characterization of the analogs are described. The cytotoxic activity of the designed ligands was evaluated in vitro against two different cancer cell lines at 24 and 48h using MTT test.

Results: Based on the IC50 values, all the designed and prepared compounds were more potent than hydroxyurea at 24 and 48h on both cell lines that the cytostatic activity at 48h was more than 24h. Drug-receptor interactions study indicated compound 7 as the most potent ligand, tightly bonded to surrounding amino acids in the active site of receptor via two strong hydrogen bonds and some hydrophobic interactions.

Conclusion: Compound 7 with the suitable volume, log p and shape is the most active ligand against both cell lines. It is concluded or suggested that the size, shape and hydrophobic character of substituents strongly affect the pharmacodynamics and pharmacokinetics of these type of ligands.
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http://dx.doi.org/10.2174/1574892813666180517102255DOI Listing
November 2018

Docking, Synthesis and Anticonvulsant Activity of N-substituted Isoindoline-1,3-dione.

Iran J Pharm Res 2017 ;16(2):586-595

Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.

A series of compounds related to ameltolide were studied for anticonvulsant potential in the subcutaneous pentylenetetrazol (sc Ptz) test in mice. These compounds were synthesized and characterized by TLC followed by IR and HNMR. screening data acquired indicate that most of analogs have the ability to protect against PTZ-induced seizure. Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. All compounds exerted their maximal effects 30 min after administration. Out of the 6 compounds, compound 2 at 40 mg/Kg dose is more potent than phenytoin (reference drug) on clonic seizure. Using a model of the open pore of the Na channel, docking study was performed by AutoDock 4.2 program. Docking study has revealed that these compounds are stabilized through at least one hydrogen bond rises from ketone of phthalimide and residue Thr-87 of domain G of sodium channel.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603866PMC
January 2017

Synthesis and DFT Study on Hantzsch Reaction to Produce Asymmetrical Compounds of 1,4-Dihydropyridine Derivatives for P-Glycoprotein Inhibition as Anticancer Agent.

Recent Pat Anticancer Drug Discov 2018 ;13(2):255-264

Chemical Injuries Research Center, System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.

Background: P-glycoprotein (P-gp) causes the efflux of cancer chemotherapy drugs from tumor cells, so its inhibition can be one target for designing and synthesis of new anticancer drugs.

Objective: In this study, new compounds of 1,4-dihydropyridine (DHP) were recommended as inhibitors of P-gp.

Methods: We synthesized new symmetrical DHP with 36% - 43% yield by the reaction of new reactants. In biological studies, these compounds have high lipophilicity, and thus low water solubility. Four reactants I with different reactivity was computed and compared using DFT study. The LUMO-map was differently distributed on each reactant. Amine intermediate underwent tautomerism as a transition state and it seems to play important role in reaction progress. Calculations were performed to select suitable reactants.

Results: Two different reactants I, including one polar group and a non-polar group, were used to produce asymmetric compounds with 49% - 60% yield. These asymmetric DHPs were more soluble than symmetric DHPs. In the final step, another selected symmetric product (by the elimination of chlorine atom) was synthesized in high yield (74%) by using DFT study.

Conclusion: In this study, selected reactants by DFT calculation have increased the yield of reaction from 36% to 74% without any catalyst. The diversity of products is a noticeable topic. Racemic asymmetric compounds with R and S enantiomers have the potential for enantiomeric separation. Each of these enantiomers could have a different physiological effect.
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http://dx.doi.org/10.2174/1574892813666180220112613DOI Listing
October 2018

Docking Studies, Synthesis, and Evaluation of Novel Oximes Based on Nitrones as Reactivators of Inhibited Acetylcholinesterase.

Iran J Pharm Res 2017 ;16(3):880-892

Department of Biology, Faculty of Science, Imam Hossein University, Tehran, Iran.

Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineat cholinergic synapsesand terminates the cholinergic effects. Some chemical agents like organophosphorus compounds (OPCs) including nerve agents and pesticides react with acetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and result in accumulation of acetylcholineand show toxic effects andcholinergic symptoms. The process of Acetylcholinesterase (AChE) inhibition can be reversed by a nucleophilic agent to dephosphorylate and reactivate the enzyme. In this study, design and docking studies of 15 novel nitrone based onoximes as reactivators were performed by using AutoDock program. Then, more effective reactivatorsoximes in terms of binding energy and orientation within the active site were synthesized and evaluated on human AChE (hAChE) inhibited by paraoxon and compared to standard hAChE reactivators (2-PAM and obidoxime). Our results used to design new derivatives of Oxim with better efficacy than 2-PAM and obidoxime. Syntheses of some selected bis-pyridiniumoximes based on the nitrones are underway.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610744PMC
January 2017

Effects of Chitosan-Zinc Oxide Nanocomposite Conduit on Transected Sciatic Nerve: An Animal Model Study.

Bull Emerg Trauma 2017 Oct;5(4):240-248

Department of Surgery and Diagnostic Imaging, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

Objective: To determine the effects of chitosan-zinc oxide nanocomposite conduit on transected sciatic nerve in animal model of rat.

Methods: Sixty male White Wistar rats were used in this study. A 10-mm sciatic nerve defect was bridged using a chitosan-zinc oxide nanocomposite conduit (CZON) filled with phosphate buffered saline. In chitosan group (CHIT) the chitosan conduit was filled with phosphate buffered saline solution. In sham-operated group (SHAM), sciatic nerve was exposed and manipulated. In transected group (TC), left sciatic nerve was transected and nerve cut ends were fixed in the adjacent muscle. The regenerated fibers were studied within 12 weeks after surgery.

Results: The behavioral and functional tests confirmed faster recovery of the regenerated axons in CZON group compared to Chitosan group (0.05). The mean ratios of gastrocnemius muscles weight were measured. There was statistically significant difference between the muscle weight ratios of CZON and Chitosan groups (0.05). Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers were significantly higher in CZON than in Chitosan. In immuohistochemistry, the location of reactions to S-100 in CZON was clearly more positive than Chitosan group.

Conclusion: Chitosan-zinc oxide nanocomposite conduit resulted in acceleration of functional recovery and quantitative morphometric indices of sciatic nerve.
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http://dx.doi.org/10.18869/acadpub.beat.5.4.521.DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694596PMC
October 2017

Th17/Treg immunoregulation and implications in treatment of sulfur mustard gas-induced lung diseases.

Expert Rev Clin Immunol 2017 12 23;13(12):1173-1188. Epub 2017 Oct 23.

a Chemical Injuries Research Center , Baqiyatallah University of Medical Sciences , Tehran , Iran.

Introduction: Sulfur mustard (SM) is an extremely toxic gas used in chemical warfare to cause massive lung injury and death. Victims exposed to SM gas acutely present with inhalational lung injury, but among those who survive, some develop obstructive airway diseases referred to as SM-lung syndrome. Pathophysiologically, SM-lung shares many characteristics with smoking-induced chronic obstructive pulmonary disease (COPD), including airway remodeling, goblet cell metaplasia, and obstructive ventilation defect. Some of the hallmarks of COPD pathogenesis, which include dysregulated lung inflammation, neutrophilia, recruitment of interleukin 17A (IL -17A) expressing CD4T cells (Th17), and the paucity of lung regulatory T cells (Tregs), have also been described in SM-lung. Areas covered: A literature search was performed using the MEDLINE, EMBASE, and Web of Science databases inclusive of all literature prior to and including May 2017. Expert commentary: Here we review some of the recent findings that suggest a role for Th17 cell-mediated inflammatory changes associated with pulmonary complications in SM-lung and suggest new therapeutic approaches that could potentially alter disease progression with immune modulating biologics that can restore the lung Th17/Treg balance.
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http://dx.doi.org/10.1080/1744666X.2017.1389646DOI Listing
December 2017

Systems Biology Approach to Bioremediation of Nitroaromatics: Constraint-Based Analysis of 2,4,6-Trinitrotoluene Biotransformation by Escherichia coli.

Molecules 2017 Aug 14;22(8). Epub 2017 Aug 14.

Young Researchers and Elite Club, Islamic Azad University, 46115655 Tehran, Iran.

Microbial remediation of nitroaromatic compounds (NACs) is a promising environmentally friendly and cost-effective approach to the removal of these life-threating agents. () has shown remarkable capability for the biotransformation of 2,4,6-trinitro-toluene (TNT). Efforts to develop as an efficient TNT degrading biocatalyst will benefit from holistic flux-level description of interactions between multiple TNT transforming pathways operating in the strain. To gain such an insight, we extended the genome-scale constraint-based model of to account for a curated version of major TNT transformation pathways known or evidently hypothesized to be active in in present of TNT. Using constraint-based analysis (CBA) methods, we then performed several series of in silico experiments to elucidate the contribution of these pathways individually or in combination to the TNT transformation capacity. Results of our analyses were validated by replicating several experimentally observed TNT degradation phenotypes in cultures. We further used the extended model to explore the influence of process parameters, including aeration regime, TNT concentration, cell density, and carbon source on TNT degradation efficiency. We also conducted an in silico metabolic engineering study to design a series of mutants capable of degrading TNT at higher yield compared with the wild-type strain. Our study, therefore, extends the application of CBA to bioremediation of nitroaromatics and demonstrates the usefulness of this approach to inform bioremediation research.
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http://dx.doi.org/10.3390/molecules22081242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152126PMC
August 2017

Novel derivatives of phthalimide with potent anticonvulsant activity in PTZ and MES seizure models.

Iran J Basic Med Sci 2017 Apr;20(4):430-437

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

Objectives: Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents.

Materials And Methods: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models.

Results: The screening results showed that all the analogs have the ability to protect against the maximal electroshock and PTZ. The compounds 3 and 9 elevated clonic seizure thresholds at 30 min which were more active than the standard medicine phenytoin. Compounds 3, 6, 7, 11, 13 and 14 with 100% protection were the most potent ones in tonic seizure. The most potent compound in the both PTZ and MES models was compound 3. Using a model of the open pore of sodium channel, all of the compounds were docked. Results of docking showed that the ligands interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and have additional hydrophobic interactions with other domains in the channel's inner pore.

Conclusion: Some of these compounds are more potent than phenytoin simultaneously in the clonic and tonic seizures.
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http://dx.doi.org/10.22038/IJBMS.2017.8586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425926PMC
April 2017

Biodistribution and Antileishmanial Activity of 1,2-Distigmasterylhemisuccinoyl--Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B.

Antimicrob Agents Chemother 2017 09 24;61(9). Epub 2017 Aug 24.

Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

1,2-Distigmasterylhemisuccinoyl--glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in -infected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip- and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in -infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly ( < 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly ( < 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation.
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http://dx.doi.org/10.1128/AAC.02525-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571372PMC
September 2017

Design, Synthesis and Anti-Tubercular Activity of Novel 1, 4-Dihydropyrine-3, 5-Dicarboxamide Containing 4(5)-Chloro-2-Ethyl- 5(4)-Imidazolyl Moiety.

Iran J Pharm Res 2016 ;15(4):791-799

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

Current researches have showed that N3, N5-diaryl-2, 6-dimethyl -1, 4-dihydropyrine-3, 5- dicarboxamide analogues demonstrate notable anti-tubercular activity. In this study, Hantzsch condensation was used to design and synthesize new analogues of dihydropyridine (DHP). Different diary carboxamides were inserted at positions 3 and 5 of the DHP ring. 4(5)-chloro-2-ethyl-5(4)-imidazolyl moiety was considered at position 4 of the DHP ring. The structures of prepared ligands were characterized using TLC followed by FT-IR, elemental analysis, Mass and proton NMR. Results of anti-tubercular activity have indicated all the prepared ligands 3a-f inhibit the mycobacterium tuberculosis growth and the most potent compounds were 3c (3,4-Cl) and 3b (4-Cl). The obtained data are agreement with our computational predictions in terms of partial atomic charge of carbonyl moieties at the positions 3 and 5 of dihydropyridine ring and the logP of the molecules.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316257PMC
January 2016

Docking and QSAR Studies of 1,4-Dihydropyridine Derivatives as Anti- Cancer Agent.

Recent Pat Anticancer Drug Discov 2017 ;12(2):174-185

Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.

Background: The multidrug resistance (MDR) of cancer cells has become a great barrier to the success of chemotherapy.

Objective: In this study, quantitative structure activity relationship (QSAR) modeling was applied to 46 1,4-dihydropyridine structures (DHPs), and some selected compounds were docked.

Methods: QSAR was used to generate models and predict the MDR inhibitory activity for a series of 1,4-dihydropyridines (DHP). The DHPs were built and optimized using the Sybyl program (x1.2 version). Descriptor generation was done by DRAGON package. Docking was carried out using Auto Dock 4.2 software. Multiple linear regression, and partial least square were performed as QSAR modelgeneration methods. External validation, cross-validation (leave one out) and y-randomization were used as validation methods.

Results: The constructed model using stepwise-MLR and GA-PLS revealed good statistical parameters. In the final step all compounds were divided into two parts: symmetric (PLS) and asymmetric (MLR) 1,4-dihydropyridines and two other models were built. The square correlation coefficient (R2) and root mean square error (RMSE) for train set for GA-PLS were (R2 = 0.734, RMSE train = 0.26).

Conclusion: The predictive ability of the models was found to be satisfactory and could be employed for designing new 1,4-dihydropyridines as potent MDR inhibitors in cancer treatment. 1,4- Dihydropyridine ring containing protonable nitrogen as scaffold could be proposed. Sulfur, ester, amide, acyle, ether, fragments are connected to a 1,4-dihydropyridine ring. Phenyl groups (with an electronegative substituent) as a lipophilic part are essential for the inhibitory effect.
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http://dx.doi.org/10.2174/1574892812666170126162521DOI Listing
November 2017

HOXB7 and Hsa-miR-222 as the Potential Therapeutic Candidates for Metastatic Colorectal Cancer.

Recent Pat Anticancer Drug Discov 2016 ;11(4):434-443

Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Recent studies have shown that the high mortality of patients with colorectal cancer (CRC) is related to its ability to spread the surrounding tissues, thus there is a need for designing and developing new drugs.

Objective: Here, we proposed a combinational therapy strategy, an inhibitory peptide in combination with miRNA targeting, for modulating CRC metastasis. In this study, some of the recent patents were also reviewed.

Methods: After data analysis with GEO2R and gene annotation using DAVID server, regulatory interactions of differentially expressed genes (DEGs) were obtained from STRING, GeneMANIA, KEGG and TRED databases. In parallel, the corresponding validated microRNAs (miRNAs) were obtained from mirDIP web server and a miRNA-DEG regulatory network was also reconstructed. Clustering and topological analyses of the regulatory networks were performed using Cytoscape plug-ins.

Results: We found the HOXB family as the most important functional complex in DEG-derived regulatory network. Accordingly, an anti-HOXB7 peptide was designed based on the binding interface of its coactivator, PBX1. Topological analysis of miRNA-DEG network indicated that hsa-miR-222 is one of the most important oncomirs involved in regulation of DEGs activities. Thus, this miRNA, along with HOXB7, was also considered as the potential target for inhibiting CRC metastasis. Molecular docking studies exhibited that the designed peptide can bind to desired binding pocket of HOXB7 in a highaffinity manner. Further confirmations were also observed in Molecular dynamics (MD) simulations carried out by GROMACS v5.0.2 simulation package.

Conclusion: In conclusion, our findings suggest that simultaneous targeting of key regulatory genes and miRNAs may be a useful strategy for prevention of CRC metastasis.
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http://dx.doi.org/10.2174/1574892811999160628114857DOI Listing
March 2017

Melissa of cinalis and Vitamin E as the Potential Therapeutic Candidates for Reproductive Toxicity Caused by Anti-cancer Drug, Cisplatin, in Male Rats.

Recent Pat Anticancer Drug Discov 2017 ;12(1):73-80

Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

Background: High doses of Cisplatin (CP) can disrupt the normal functioning of various tissues such as ovaries and testis. In almost all the patients, spermiotoxicity of CP causes temporary or permanent azoospermia.

Objective: In this study, the defensive effect of Melissa of cinalis and vitamin E against testicular injuries caused by CP in male rats was evaluated.

Method: Thirty six male rats were distributed into 6 groups. Group 1 was used as the negative control. In group 2, a single dose of CP (10 mg/kg) was administered on the first day. In groups 3 and 4, a single dose of CP (10 mg/kg) was administered on the first day and then treated with Melissa of cinalis at 1000 mg/kg/day and vitamin E at 100 mg/kg/day for 7 consecutive days, respectively. Groups 5 and 6 were treated with Melissa of cinalis and vitamin E for 7 consecutive days, respectively. After euthanasia, serum levels of testosterone, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) were evaluated. Testes were removed and weighed. Spermatic analysis was done on the tail of the epididymis. Tissue lipid peroxidation and activity of antioxidant enzymes in testes were evaluated as well.

Results: The results showed that Melissa of cinalis and vitamin E increased serum levels of testosterone, LH and FSH, weight of testes and sperm motility, count and vitality and decreased sperm cell abnormalities in rats given CP.

Conclusion: Our results are useful in designing a medication of Melissa of cinalis that can protect the testes against CP-induced testicular damage and infertility in cancerous male patients.
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http://dx.doi.org/10.2174/1574892811666161026111721DOI Listing
March 2017

Modeling and Proposed Molecular Mechanism of Hydroxyurea Through Docking and Molecular Dynamic Simulation to Curtail the Action of Ribonucleotide Reductase.

Recent Pat Anticancer Drug Discov 2016 ;11(4):461-468

Medicinal Chemistry, Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, 19419, Iran; Postal address: No 99, Yakhchal Street, Shariatie ave. Tehran, 19419, Iran.

Background: Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue.

Objective: In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of hydroxyurea in RNR inhibition as anticancer agent.

Method: The binding affinity of hydroxyurea and compound III to RNR was studied by docking method. The docking study was performed for the crystal structure of human RNR with the radical scavenger Hydroxyurea and its oxidized form to inhibit the human RNR. hydroxyurea and compound III bind at the active site with Tyr-176, which are essential for free radical formation. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. To confirm the binding mode of inhibitors, the molecular dynamics (MD) simulations were performed using GROMACS 4.5.5, based upon the docked conformation of inhibitors.

Results: Both of the studied compounds stayed in the active site. The results of MD simulations confirmed the binding mode of ligands, accuracy of docking and the reliability of active conformations which were obtained by AutoDock.

Conclusion: MD studies confirm our proposed mechanism in which compound III reacts with the active site residues specially Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR enzyme.
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http://dx.doi.org/10.2174/1574892811666160926143534DOI Listing
March 2017

New Oral Formulation and in Vitro Evaluation of Docetaxel-Loaded Nanomicelles.

Molecules 2016 Sep 21;21(9). Epub 2016 Sep 21.

Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 917751365, Iran.

Intravenous administration of Taxotere (a commercial form of docetaxel, DTX) leads to many problems such as hypersensitivity, hemolysis, cutaneous allergy, and patient refusal due to its prolonged injection. The oral absorption of DTX is very low due to its hydrophobic nature. The purpose of this study was to prepare and carry out an in vitro evaluation of DTX-loaded nanomicelles for oral administration in order to increase the oral delivery of DTX. Studied formulations were prepared with the two surfactants Tween 20 and Tween 80 and were characterized for their particle size, zeta potential, stability, encapsulation efficiency, stability studies in gastric fluid and intestinal fluid, toxicity studies in C26 colon carcinoma cell line, and cellular uptake. The prepared nanomicelles with particle size of around 14 nm and encapsulation efficiency of 99% were stable in gastric fluid and intestinal fluid for at least 6 h and IC50 decreased significantly after 72 h exposure compared to that of Taxotere. Nanomicelles increased the water solubility of DTX more than 1500 times (10 mg/mL in nanomicelles compared to 6 µg/mL in water). Results of this study reveal that the new formulation of DTX could be used for the oral delivery of DTX and merits further investigation.
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http://dx.doi.org/10.3390/molecules21091265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274371PMC
September 2016

Molecular Dynamics Simulation and Docking Studies of Selenocyanate Derivatives as Anti-Leishmanial Agents.

Comb Chem High Throughput Screen 2016 ;19(10):847-854

Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran 19419, Iran; Postal address: No 99, Yakhchal ave. Shariatie Street, Tehran 19419, Iran.. Iran, Islamic Republic of.

Background: Selenocyanate derivatives have been recently presented as potent anti-leishmanial agents.

Objective: In this research, thirty five selenocyanate and diselenide compounds were subjected to docking studies and compared to Edelfosine and Miltefosine as reference drugs and then molecular dynamics (MD) simulation analysis.

Methods: Desired Selenocyanates were built using the HyperChem program and docking calculations were performed on the crystal structure of trypanothione reductase from Leishmania infantum. Then, MD simulation analysis was performed to explore the interaction stability of selected compound during structural motions of the interacting molecules.

Results: Based on the binding energy, all of the aryl rings were more potent than Edelfosine and Miltefosine as reference drug. The best compound base on hydrogen bonding, π-π interactions and orientation within the active site with high binding energy was selected for MD simulation analysis. The selected compound is known as high-affinity selective inhibitor for trypanothione reductase.

Conclusion: These results can be used for future synthesis of new antileishmanial agents with better potency.
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http://dx.doi.org/10.2174/1386207319666160907102235DOI Listing
June 2017

Docking, Molecular Dynamics Simulation and Synthesis of New Fenobam Analogues as mGlu5 Receptor Antagonists.

Comb Chem High Throughput Screen 2016 ;19(9):764-770

Chemical Injuries Research Center, Baqiyatallah University of Medical Science, Molla-Sadra Street, P.O. Box: 19945-581, Tehran, Iran.

Background: Fenobam is a non-competitive mGluR5 antagonist as an anxiolytic agent.

Objective: In this research a new series of fenobam analogues containing thiazole moiety instead of imidazole ring were designed and synthesized.

Methods: The ureido-substituted products were synthesized from reaction of amino thiazole derivatives and isocyanate derivatives in dichloromethane solvent under microwave and ultrasonic irradiation condition. The synthesized compounds structures were established by means of IR, 1HNMR, 13CNMR spectroscopic data. Then, docking calculations were performed on the active site of mGLuR5 and compared to Fenobam as a reference drug by using AutoDock program. The molecular dynamics (MD) simulations were done using GROMACS 5.0.5.

Results: Docking studies suggested that all of the compounds possess better binding energy when compared to fenobam. The results of MD simulations might offer the binding mode of ligand (3b), accuracy of docking and the reliability of active conformations which obtained by AutoDock.

Conclusion: New derivatives of fenobam were designed and synthesized that have the better insilico results compared to fenobam and will evaluate in future studies.
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http://dx.doi.org/10.2174/1386207319666160831150500DOI Listing
August 2017

Design and Synthesis of 2-(Arylmethylideneamino) Isoindolines as New Potential Analgesic and Anti-Inflammatory Agents: A Molecular Hybridization Approach.

Curr Pharm Des 2016 ;22(37):5760-5766

Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, 19419, Iran.

Phthalimide and hydrazine pharmacophores have been demonstrated to be inhibitors of cyclooxygenases (COX) and lipoxygenases (LOX) and to possess a marked analgesic and anti-inflammatory activity. A new group of hybrid analogs of phthalimide and hydrazine (2-(arylmethylideneamino) isoindolines), possessing a variety of substituents (OMe, OH, NO2, Cl, and F) at different positions of the aryl ring, were synthesized and their analgesic and anti-inflammatory effects were evaluated. In vivo screening showed that all the analogs possessed analgesic and anti-inflammatory activity and compounds 10g, 10h and 10e were the most potent as analgesic and compounds 10b, 10c and 10i were the most potent as anti-inflammatory agents.
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http://dx.doi.org/10.2174/1381612822666160701072127DOI Listing
December 2017

Design and Synthesis of Curcumin-Like Diarylpentanoid Analogues as Potential Anticancer Agents.

Recent Pat Anticancer Drug Discov 2016 ;11(3):342-51

Department of Medicinal Chemistry, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran, Tehran, 19419, Iran.

Background: Curcumin is a polyphenolic natural compound with multiple targets that used for the prophylaxis and treatment of some type of cancers like cervical and pancreatic cancers. Some recent patent for curcumin for cancer has also been reviewed.

Objective: In this study, ten new curcumin derivatives were designed and synthesized and their cytostatic activity evaluated against the Hela and Panc cell lines that some of them showed more activity than curcumin.

Method: In the present study, a series of mono-carbonyl derivatives of curcumin were designed and prepared. The details of the synthesis and chemical characterization of the synthesized compounds are described. The cytostatic activities of the designed compounds are assessed in two different tumor cell lines using MTT test.

Results: In vitro screening for human cervix carcinoma cell lines (Hela) and pancreatic cell lines (Panc-1) at 24 and 48 hour showed that all the analogs possessed good activity against these tumor cell lines and compounds 5a, 5c and 6 with high potency can be used as a new lead compounds for the designing and finding new and potent cytostatic agents. Docking studies indicated that compound 5c readily binds the active site of human glyoxalase I protein via two strong hydrogen bonds engaging residues of Glu-99 and Lys-156.

Conclusion: Our results are useful in guiding a design of optimized ligands with improved pharmacokinetic properties and increased of anti-cancer activity vs. the prototype curcumin compound.
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http://dx.doi.org/10.2174/1574892811666160420141613DOI Listing
March 2017

Design, Synthesis and Evaluation of Antitubercular Activity of Novel Dihydropyridine Containing Imidazolyl Substituent.

Iran J Pharm Res 2015 ;14(4):1067-75

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

Recent studies have indicated that 1, 4-dihydropyridine-3, 5-dicarboxamide derivatives show significant anti-tubercular activity. In this research, new derivatives of 1, 4-dihydropyridine were designed and synthesized using Hantzsch condensation in which dicyclohexyl and different dicyclohexylcarbamoyl were substituted at C-3 and C-5 positions of the DHP ring. In addition, 4 (5)-chloro-2-methyl-5 (4)-imidazolyl moiety was substituted at C-4 position of DHP. The structure of synthetized compounds were characterized by TLC, IR, elemental analysis and proton NMR. Based on the in vitro screening data, all of the designed and synthetized compounds (3a-3g) showed a good ability to inhibit the mycobacterium tuberculosis growth in terms of MIC. Aromatic carboxamide containing compounds were more potent than cyclohexyl derivative and the most potent compound was 3a (4-nitrophenyl derivative). The experimental data are in agreement with our computational predictions in terms of partial atomic charge of carbonyl moieties at the C-3 and C-5 positions of DHP ring and partition coefficient of the molecules.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673934PMC
December 2015

Computational Study of Quinolone Derivatives to Improve their Therapeutic Index as Anti-malaria Agents: QSAR and QSTR.

Iran J Pharm Res 2015 ;14(3):775-84

Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran.

Malaria is a parasitic disease caused by five different species of Plasmodium. More than 40% of the world's population is at risk and malaria annual incidence is estimated to be more than two hundred million, malaria is one of the most important public health problems especially in children of the poorest parts of the world, annual mortality is about 1 million. The epidemiological status of the disease justifies to search for control measures, new therapeutic options and development of an effective vaccine. Chemotherapy options in malaria are limited, moreover, drug resistant rate is high. In spite of global efforts to develop an effective vaccine yet there is no vaccine available. In the current study, a series of quinolone derivatives were subjected to quantitative structure activity relationship (QSAR) and quantitative structure toxicity relationship (QSTR) analyses to identify the ideal physicochemical characteristics of potential anti-malaria activity and less cytotoxicity. Quinolone with desirable properties was built using HyperChem program, and conformational studies were performed through the semi-empirical method followed by the PM3 force field. Multi linear regression (MLR) was used as a chemo metric tool for quantitative structure activity relationship modeling and the developed models were shown to be statistically significant according to the validation parameters. The obtained QSAR model reveals that the descriptors PJI2, Mv, PCR, nBM, and VAR mainly affect the anti-malaria activity and descriptors MSD, MAXDP, and X1sol affect the cytotoxicity of the series of ligands.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518106PMC
September 2015
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