Publications by authors named "Saeed Emami"

159 Publications

Synthesis and Biological Evaluation of Tc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging.

Mol Pharm 2021 Jun 24;18(6):2360-2374. Epub 2021 May 24.

Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.

With a poor prognosis, glioblastoma multiforme is the most aggressive tumor of the central nervous system in humans. The aim of this study was to develop novel tracers for the tumor targeting and imaging of overexpressed serotonin-7 receptors (5-HTRs) in U-87 MG glioma xenografted nude mice. Two phenylpiperazine derivatives named as and were designed, and the corresponding radiotracers Tc- and Tc- were synthesized in high radiochemical purity (>95%). Tc- showed a higher affinity to 5-HTRs on U-87 MG cells compared to Tc-. In biodistribution studies, the radiocomplexes showed good brain uptake at 15 min combined with good radioactivity retention in the brain for 240 min. Regional rabbit brain studies indicated a higher radioactivity concentration in the hippocampus and diencephalon than in the cerebellum. Compared to Tc-, the Tc- exhibited a significantly increased tumor uptake at 15 and 60 min, but the rapid blood clearance of Tc- led to enhanced tumor-to-muscle ratios at 240 min. A significant reduction in tumor uptake 60 min after an injection of pimozide (5-HT receptor antagonist) confirms the tumor uptake was receptor-mediated specifically. The tumor-to-contralateral muscle tissue ratio of Tc- and Tc- in nude mice with U-87 MG xenograft was measured (5.25 and 4.65) at 60 min as well as (6.25 and 6.76) at 240 min, respectively.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00172DOI Listing
June 2021

Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents.

Bioorg Chem 2021 Jul 24;112:104943. Epub 2021 Apr 24.

Department of Pharmacology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran. Electronic address:

In this study, a series of new isatin aroylhydrazones (5a-e and 6a-e) was synthesized and evaluated for their anticonvulsant activities. The (Z)-configuration of compounds was confirmed by H NMR. In vivo studies using maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy in mice revealed that while most of compounds had no effect on chemically-induced seizures at the higher dose of 100 mg/kg but showed significant protection against electrically-induced seizures at the lower dose of 5 mg/kg. Certainly, N-methyl analogs 6a and 6e were found to be the most effective compounds, displaying 100% protection at the dose of 5 mg/kg. Protein binding and lipophilicity(logP) of the selected compounds (6a and 6e) were also determined experimentally. In silico evaluations of title compounds showed acceptable ADME parameters, and drug-likeness properties. Distance mapping and docking of the selected compounds with different targets proposed the possible action of them on VGSCs and GABA receptors. The cytotoxicity evaluation of 6a and 6e against SH-SY5Y and Hep-G2 cell lines indicated safety profile of compounds on the neuronal and hepatic cells.
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http://dx.doi.org/10.1016/j.bioorg.2021.104943DOI Listing
July 2021

Synthesis and biological assessment of ciprofloxacin-derived 1,3,4-thiadiazoles as anticancer agents.

Bioorg Chem 2020 12 15;105:104383. Epub 2020 Oct 15.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

The quinolone-3-carboxylic acid scaffold is essential structure for antibacterial activity of fluoroquinolones such as ciprofloxacin. Modification of 3-carboxylic functionality in this structure can be used for switching its activity from antibacterial to anticancer. Accordingly, a series of C-3 modified ciprofloxacin derivatives containing N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-carboxamide moiety was synthesized as novel anticancer agents. Most of compounds showed significant activity against MCF-7, A549 and SKOV-3 cancer cells in the MTT assay. In particular, compounds 13a-e and 13g were found to be as potent as standard drug doxorubicin against MCF-7 cell line (ICs = 3.26-3.90 µM). Furthermore, the 4-fluorobenzyl derivatives 13h and 14b with IC values of 3.58 and 2.79 µM exhibited the highest activity against SKOV-3 and A549 cells, being as potent as doxorubicin. Two promising compounds 13e and 13g were further tested for their apoptosis inducing activity and cell cycle arrest. Both compounds could significantly induce apoptosis in MCF-7 cells, while compound 13e was more potent apoptosis inducer resulting in an 18-fold increase in the proportion of apoptotic cells at the IC concentration in MCF-7 cells. The cell cycle analysis revealed that compounds 13e and 13g could increase cell portions in the sub-G1 phase, inducing oligonucleosomal DNA fragmentation and apoptosis confirmed by comet assay.
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http://dx.doi.org/10.1016/j.bioorg.2020.104383DOI Listing
December 2020

Data on molecular docking of tautomers and enantiomers of ATTAF-1 and ATTAF-2 selectivty to the human/fungal lanosterol-14α-demethylase.

Data Brief 2020 Aug 27;31:105942. Epub 2020 Jun 27.

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

The data have been obtained for tautomers and enantiomers of ATTAF-1 and ATTAF-2 that were developed based on antifungal standard drugs with triazole scaffold. These compounds were docked into the human and fungal lanosterol-14α-demethylase. In order to validate the data, 8 standard triazole antifungal drugs (Fluconazole, Itraconazole, Posaconazole, Ravuconazole, Albaconazole, Voriconazole, Isavuconazole and Efinaconazole) were also docked into the human and fungal lanosterol-14α-demethylase. The binding conformations of these molecules and their interactions with lanosterol-14α-demethylase may inform the development of further small molecule lanosterol-14α-demethylase inhibitors with significant selectivity toward this enzyme. The analysis has done on the basis of type of interactions (bond type and distance). The length of the Fe-N coordination bond for ()-N2-ATTAF-1 and ()-N1-ATTAF-2 complexes is obtained 6.36 and 4.19 Å, respectively and about 2 Å in the other tautomer and enantiomer complexes, reflecting the lower basicity of the N-4 atom in the 1,2,4-triazole ring of ()-N2-ATTAF-1 and ()-N1-ATTAF-2 in comparison with the N-4 atom in the 1,2,4-triazole ring in other tautomers and enantiomers and supporting higher selectivity of ()-N2-ATTAF-1 and ()-N1-ATTAF-2 towards the target CYP51 enzymes vs. human. Interestingly, we have investigated unfavorable interactions (donor-donor) with TRP239 and MET378 for ()-N2-ATTAF-1 and ()-N1-ATTAF-2, respectively. These unfavorable interactions also have been seen in case of posaconazole and isavuconazole. The data presented in this article are related to the research paper entitled " prediction of ATTAF-1 and ATTAF-2 selectivity towards human/fungal lanosterol 14α-demethylase using molecular dynamic simulation and docking approaches".
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http://dx.doi.org/10.1016/j.dib.2020.105942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341365PMC
August 2020

Kojic acid-natural product conjugates as mushroom tyrosinase inhibitors.

Eur J Med Chem 2020 Sep 16;201:112480. Epub 2020 Jun 16.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

As part of our effort to develop potential tyrosinase inhibitors, we have conjugated the well-known tyrosinase inhibitor kojic acid (KA) with several phenolic natural products such as umbelliferone, sesamol, thymol, carvacrol, eugenol, isoeugenol, vanillin, isovanillin, and apocynin that some reports have shown their activity on tyrosinase enzyme. The designed compounds were synthesized using click reaction and 1,2,3-triazole formation. All compound showed potent anti-tyrosinase activity significantly higher than KA. The best activities were observed with apocynin and 4-coumarinol analogs (10c and 16c) displaying IC values of 0.03 and 0.02 μM, respectively. The potency of 16c was >460-times more than that of KA. Cell-based assays against B16F10 and HFF cells revealed that the representative compounds can efficiently suppress the melanogenesis without significant toxicity on cells.
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http://dx.doi.org/10.1016/j.ejmech.2020.112480DOI Listing
September 2020

Tropolone alkaloids from Colchicum kurdicum (Bornm.) Stef. (Colchicaceae) as the potent novel antileishmanial compounds; purification, structure elucidation, antileishmanial activities and molecular docking studies.

Exp Parasitol 2020 Jun 27;213:107902. Epub 2020 Apr 27.

Department of Pharmacognosy and Biotechnology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.

Natural compounds played an important role for prevention and treatment of the disease as well as are the important compounds for the design of the new bioactive compounds. In this study, eight tropolone alkaloids were isolated from Colchicum kurdicum including colchicoside, 2-demethyl colchicine, 3-demethyl colchicine, demecolcine, colchifoline, N-deacetyl-N-formyl colchicine, colchicine and cornigerine by column and preparative thin layer chromatography. The chemical structures were identified by H NMR and C NMR spectroscopy. Moreover, the antileishmanial activity on Leishmania major, anti-inflammatory activity, iron chelating activity and toxicity studies including hemolytic activity, brine shrimp toxicity, cytotoxicity and acute toxicity and docking study of all isolated bioactive compounds were evaluated. As result, colchicoside and colchicine had potent leishmanicidal effects and N-deacetyl-N-formyl colchicine and cornigerine had the highest anti-inflammatory effects. All compounds had the significant iron chelating activity. According to toxicity studies, isolated compounds showed the low hemolytic activity and cytotoxicity, high LC, LC and LD. In the molecular docking study, colchicoside had the high dockscore. According to the study, with future studies all isolated compounds could be used for design the novel antileishmanial drugs.
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http://dx.doi.org/10.1016/j.exppara.2020.107902DOI Listing
June 2020

Synthesis, computational study and cytotoxicity of 4-hydroxycoumarin-derived imines/enamines.

Mol Divers 2021 May 22;25(2):1011-1024. Epub 2020 Apr 22.

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

In this study, we applied a direct condensation between 3-acetyl-4-hydroxy-2H-chromen-2-one and different amines (anilines and benzyl amines) in order to synthesize some coumarin-based imines/enamines (3a-o) as cytotoxic agents. All the compounds were characterized by means of FT-IR, NMR, mass spectroscopy and elemental analyses. Since the title compounds can exist as different forms including (s-cis)-imine and (s-trans)-imine or (E and Z)-enamines, their conformational and geometrical aspects were investigated computationally by DFT method. The optimized geometry parameters, ΔE, ΔG, ΔH, Mulliken atomic charge, HOMO and LUMO energy, and NBO analysis suggested that these compounds can exist predominantly in (E)-enamine form. All the synthesized compounds (3a-o) were evaluated in vitro for their cytotoxic activities against cancer cell lines (MCF-7 and A549) and normal cell line (BEAS-2B) using the MTT assay. The 4-hydroxybenzyl derivative 3k was found to be the most potent cytotoxic agent with no selectivity, similar to doxorubicin. However, the 4-chlorobenzyl analog 3o could be considered as an equipotent compound respect to doxorubicin with higher selectivity.
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http://dx.doi.org/10.1007/s11030-020-10086-2DOI Listing
May 2021

The effect of edelfosine on GRA1 and MIC3 expressions in acute toxoplasmosis.

Parasitol Res 2020 Apr 22;119(4):1371-1380. Epub 2020 Jan 22.

Toxoplasma Research Center, Mazandaran University of Medical Sciences, Sari, Iran.

Phosphoinositide-dependent phospholipase-C (PI-PLC) triggers the calcium signaling pathway which plays an important role in dense granule and microneme secretion and pathogenesis of Toxoplasma gondii (T. gondii). There are limited data about the effects of phospholipid analogues against T. gondii. The current study assessed the effect of edelfosine, as a phospholipid analogue, on GRA1 and MIC3 expressions using in vitro and in vivo models of acute toxoplasmosis. Infected Vero cells were treated by edelfosine in two subgroups: 24 h following the cell infection and treatment at the same time of cell infection. Animal study was performed on forty mice in four groups including non-infected, infected untreated, infected edelfosine-treated, and infected pyrimethamine-treated. Gene and protein expression analyses were done using quantitative real-time PCR and western blot, respectively. Edelfosine significantly reduced the GRA1 (P < 0.01) and MIC3 (P < 0.01) mRNA and protein expressions in 24 h following the cell infection and at the same time of cell infection groups. In vivo study showed that the edelfosine significantly reduced the GRA1 expression in eye, and MIC3 expression in brain and liver. Moreover, the edelfosine-treated infected mice had significant higher survival rate compared with uninfected mice. The reducing effect of edelfosine on GRA1 and MIC3 mRNA and protein levels 24 h following the cell infection was more than treatment at the same time of cell infection group. Moreover, the effect of edelfosine on GRA1 and MIC3 expression in animal tissues was variable. These data showed that the edelfosine may decrease the T. gondii excretory/secretory antigens through inhibition of PI-PLC.
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http://dx.doi.org/10.1007/s00436-020-06601-xDOI Listing
April 2020

Indole-derived chalcones as anti-dermatophyte agents: In vitro evaluation and in silico study.

Comput Biol Chem 2020 Feb 23;84:107189. Epub 2019 Dec 23.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

A series of indole-derived methoxylated chalcones were described as anti-dermatophyte agents. The in vitro antifungal susceptibility testing against different dermatophytes revealed that most of compounds had potent activity against the dermatophyte strains. In particular, the 4-ethoxy derivative 4d with MIC values of 0.25-2 μg/ml was the most potent compound against Trichophyton interdigitale, Trichophyton veruccosum and Microsporum fulvum. Moreover, the 4-butoxy analog 4i displaying MIC values in the range of 1-16 μg/ml had the highest inhibitory activity against Trichophyton mentagrophytes, Microsporum canis, and Arthroderma benhamiae. To predict whether the synthesized compounds interact with tubulin binding site of dermatophytes, the 3D-structure of target protein was modeled by homology modeling and then used for molecular docking and molecular dynamics (MD) simulation studies. Docking simulation revealed that the promising compound 4d can properly bind with tubulin. The molecular dynamics analysis showed that interactions of compound 4d with the active site of target protein have binding stability throughout MD simulation. The results of this study could utilize in the design of more effective antifungal drugs with tubulin inhibition mechanism against keratinophilic fungi.
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http://dx.doi.org/10.1016/j.compbiolchem.2019.107189DOI Listing
February 2020

Modification of 7-piperazinylquinolone antibacterials to promising anticancer lead compounds: Synthesis and in vitro studies.

Eur J Med Chem 2020 Feb 15;187:111970. Epub 2019 Dec 15.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

Amongst the fluoroquinolone antibacterials, the 7-piperazinyl containing chemotypes such as norfloxacin, enoxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, ofloxacin, levofloxacin, gatifloxacin and sparfloxacin have been shown to possess non-classical activities including cytotoxicity against different cancer cell lines, induction of apoptosis, and cell cycle arrest at the S/G2 stage. Additionally, piperazinylquinolones (PQs) have enough flexibility for chemical modification via their N-4 of piperazine ring and carboxylic acid at C-3. Therefore, PQs have been considered as a starting point for design and development of new anticancer agents. This review has focused on the recent synthetic modifications of PQs which led to N-substituted and/or C-3 modified PQs with potential anticancer activity.
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http://dx.doi.org/10.1016/j.ejmech.2019.111970DOI Listing
February 2020

New thiazole-2(3H)-thiones containing 4-(3,4,5-trimethoxyphenyl) moiety as anticancer agents.

Eur J Med Chem 2020 Jan 15;185:111784. Epub 2019 Oct 15.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

A new series of thiazole-2(3H)-thiones containing 4-(3,4,5-trimethoxyphenyl) moiety were synthesized as diaryl-heterocylic analogs of combretastatin A-4 with anticancer activity. The cytotoxicity evaluation of synthesized compounds against cancer cell lines (A549, MCF-7 and SKOV3) revealed that most of them had potent cytotoxic activity toward all tested cell lines (ICs < 10 μg/mL). Among them, 3-(chlorobenzyl) derivatives 5c and 5d showed the best inhibitory effect on MCF-7 cells (IC values of 1.14 and 2.41 μg/mL, respectively). Furthermore, the ability of tubulin polymerization inhibition and apoptosis induction were evaluated for the promising compounds 5c and 5d. Results suggested that these compounds remarkably inhibit tubulin polymerization and induce apoptosis resulting in cell death. In vitro studies revealed that these compounds had no significant cytotoxicity against normal cells at the concentrations required for growth inhibition of cancer cells. In vitro biding assay and in silico docking study also confirmed the binding of prototype compound to the colchicine binding site of tubulin.
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http://dx.doi.org/10.1016/j.ejmech.2019.111784DOI Listing
January 2020

Design, synthesis and biological evaluation of flexible and rigid analogs of 4H-1,2,4-triazoles bearing 3,4,5-trimethoxyphenyl moiety as new antiproliferative agents.

Bioorg Chem 2019 12 21;93:103300. Epub 2019 Sep 21.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

Several flexible and rigid analogs of 4H-1,2,4-triazoles (compounds 8a-g and 9a-g) bearing trimethoxyphenyl pharmacophoric unit, were designed and synthesized as potential anticancer agents. The in vitro cytotoxic assay indicated that both flexible and rigid analogs (8 and 9, respectively) can potentially inhibit the growth of cancerous cells (A549, MCF7, and SKOV3), with IC values less than 5.0 µM. Furthermore, compounds 10a-l as regional isomers of compounds 9 exhibited remarkable cytotoxic activity with IC values ranging from 0.30 to 5.0 µM. The rigid analogs 9a, 10h and 10k were significantly more potent than etoposide against MCF7, SKOV3 and A549 cells, respectively. These compounds showed high selectivity towards cancer cells over normal cells, as they had no significant cytotoxicity against L929 cells. In addition, the representative compounds 9a and 10h could inhibit the tubulin polymerization at micro-molar levels. By determining changes in the colchicine-tubulin fluorescence, it was suggested that compound 10h could bind to the tubulin at the colchicine pocket. The molecular docking study further confirmed the inhibitory activity of promising compounds 9a, 10h and 10k on tubulin polymerization through binding to the colchicine-binding site.
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http://dx.doi.org/10.1016/j.bioorg.2019.103300DOI Listing
December 2019

Synthesis and in vitro anti-Toxoplasma gondii activity of a new series of aryloxyacetophenone thiosemicarbazones.

Mol Divers 2020 Nov 20;24(4):1223-1234. Epub 2019 Aug 20.

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

A new series of aryloxyacetophenone thiosemicarbazones 4a-q have been synthesized as anti-Toxoplasma gondii agents. All compounds showed significant inhibitory activity against T. gondii-infected cells (IC values 1.09-25.19 μg/mL). The 4-fluorophenoxy derivative (4l) was the most potent compound with the highest selectivity toward host cells (SI = 19), being better than standard drug pyrimethamine. SAR study indicated that the concurrence of proper substituents on both aryl ring of phenoxyacetophenone is important for potency and safety profile. Further in vitro experiments with the representative compounds 4l and 4p revealed that these compounds at the concentration of 5 μg/mL can significantly reduce the viability of T. gondii tachyzoites, as well as their infectivity rate and intracellular proliferation, comparable to those of pyrimethamine.
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http://dx.doi.org/10.1007/s11030-019-09986-9DOI Listing
November 2020

Thiazole in the targeted anticancer drug discovery.

Future Med Chem 2019 08 17;11(15):1929-1952. Epub 2019 Jul 17.

Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.

Cancer is known as one of the main causes of death in the world; and many compounds have been synthesized to date with potential use in cancer therapy. Thiazole is a versatile heterocycle, found in the structure of many drugs in use as well as anticancer agents. This review provides an overview of recent advances in thiazole-bearing compounds as anticancer agents with particular emphasis on their mechanism of action in cancerous cells. Chemical designs, structure-activity relationships and relevant preclinical properties have been comprehensively described.
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http://dx.doi.org/10.4155/fmc-2018-0416DOI Listing
August 2019

New potent antifungal triazole alcohols containing N-benzylpiperazine carbodithioate moiety: Synthesis, in vitro evaluation and in silico study.

Bioorg Chem 2019 09 12;90:103060. Epub 2019 Jun 12.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

A number of 1H-1,2,4-triazole alcohols containing N-(halobenzyl)piperazine carbodithioate moiety have been designed and synthesized as potent antifungal agents. In vitro bioassays against different Candida species including C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis revealed that the N-(4-chlorobenzyl) derivative (6b) with MIC values of 0.063-0.5 µg/mL had the best profile of activity, being 4-32 times more potent than fluconazole. Docking simulation studies confirmed the better fitting of compound 6b in the active site of lanosterol 14α-demethylase (CYP51) enzyme, the main target of azole antifungals. Particularly, the potential of compound 6b against fluconazole-resistant isolates along with its minimal toxicity against human erythrocytes and HepG2 cells make this prototype compound as a good lead for discovery of potent and safe antifungal agents.
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http://dx.doi.org/10.1016/j.bioorg.2019.103060DOI Listing
September 2019

Novel Tc-2-arylimidazo[2,1-b]benzothiazole derivatives as SPECT imaging agents for amyloid-β plaques.

Eur J Med Chem 2019 Aug 29;175:149-161. Epub 2019 Apr 29.

Department of Radiopharmacy, Faculty of Pharmacy, Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

Six novel 2-arylimidazo[2,1-b]benzothiazole (IBT) derivatives were synthesized as potential tridentate radiotracers for AD imaging purposes. Two of these ligands (6a,b) were successfully labeled with Tc radionuclide at high radiochemical purity using fac-[Tc(CO)(HO)] synthon. [Tc]7a and [Tc]7b were evaluated as single photon emission computed tomography (SPECT) imaging agents for Aβ plaque in AD. [Tc]7a and [Tc]7b exhibited suitable affinity toward Aβ aggregates with IC values of 33.2 and 102.5 nM, respectively. The IC value of these radiotracers depends on the length of the spacer (alkyl chain). In biodistribution study, these complexes showed good initial brain uptakes (0.78 and 0.86% ID/g at 2 min post-injection) and fast blood clearance. Autoradiography results confirmed that these small Tc complexes (Mw about 600 Da) can bind to Aβ plaques in the brain sections of the rat AD model. Histopathological staining with Congo red approved the presence of Aβ plaques in these brain sections.
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http://dx.doi.org/10.1016/j.ejmech.2019.04.069DOI Listing
August 2019

In vitro and in vivo evaluation of kojic acid against Toxoplasma gondii in experimental models of acute toxoplasmosis.

Exp Parasitol 2019 May 20;200:7-12. Epub 2019 Mar 20.

Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; Department of Parasitology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

As current toxoplasmosis chemotherapies have many side effects along with toxicity on patients, we examined the anti-Toxoplasma effect of a biologically important natural antibiotic, kojic acid, in vitro and in vivo. Vero cells were incubated with different concentrations of kojic acid or pyrimethamine (positive control), and the cellular viability was determined. Next, Vero cells were infected with T. gondii (RH strain) and treated with drugs. Then, we calculated the infection index, T. gondii intracellular proliferation and the number and measure of plaque. Moreover, the effect of kojic acid on survival times, serum levels of IFN-γ and TNF-α and histopathological changes in the liver and spleen of Balb/c mice infected with T. gondii were determined. Kojic acid reduced the infection index, intracellular proliferation, the number and measure of plaque in vitro when compared to untreated infected cells. Kojic acid (100 mg/kg/day) also showed a better survival rate than infected untreated control mice (P < 0.05). IFN-γ and TNF-α secretions were significantly increased by kojic acid treatment in comparison to untreated groups (P < 0.05). In addition, its inhibitory effects on inflammatory alterations, apoptosis, and necrosis have been shown in sections of liver and spleen. We conclude that kojic acid exhibit potent anti-Toxoplasma activity with direct and indirect effects on the parasite, although further studies are needed before consideration of clinical trials.
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http://dx.doi.org/10.1016/j.exppara.2019.03.009DOI Listing
May 2019

Current advances of triazole alcohols derived from fluconazole: Design, in vitro and in silico studies.

Eur J Med Chem 2019 May 11;170:173-194. Epub 2019 Mar 11.

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

Currently, the available antifungal agents have significant clinical incompetency in terms of their clinical efficacy, antifungal spectrum, unfavorable pharmacokinetic profiles, substantial side effects and drug-drug interactions. Thus, the optimization and improvement of existing drugs and identification of new antifungal agents are urgently needed. Fluconazole is the first triazole alcohol drug with good in vivo efficacy against yeasts and well-known targets in fungal cells. However, the wide use of fluconazole as a first-line antifungal therapy has led to the development of resistance in clinical isolates of Candida species including Candida albicans and the emerging non-albicans Candida spp. In the last years, extensive efforts inflected to design and discovery of triazole alcohols derived from fluconazole by replacing one triazole ring with the proper side chain. In this paper, we have reviewed the structural modification of fluconazole to pursuit potent triazole alcohols with improved anti-Candida activity, and have highlighted their in vitro activities and in silico studies.
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http://dx.doi.org/10.1016/j.ejmech.2019.03.020DOI Listing
May 2019

Repurposing azole antifungals into antileishmanials: Novel 3-triazolylflavanones with promising in vitro antileishmanial activity against Leishmania major.

Parasitol Int 2019 Apr 21;69:103-109. Epub 2018 Dec 21.

Infectious and Tropical Diseases Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.

Previously, we have described a series of azole antifungals namely 3-(1,2,4-triazol-1-yl)flavanones (TFs) containing an N-(phenethyl)azole framework required for sterol 14α-demethylase (CYP51) inhibitory activity. Similar mechanism of action of azoles in fungi and protozoan parasites prompted us to investigate the potential effects of TFs against promastigote and amastigote forms of Leishmania major (L. major), as well as their toxicity against macrophages, apoptosis induction and in silico interactions with the target enzyme. All compounds showed more potent anti-parasitic activity against L. major in comparison with reference azole drug fluconazole and standard antileishmanial agent glucantime. Among the tested compounds, the 4-chloro derivative (TF-2) was found to be the most potent one, being about 13 times more potent than fluconazole against promastigotes. TF-2 decreased both mean infection rate of macrophages (MIR) and mean number of amastigotes per macrophages (MNAPM), significantly more than fluconazole (P < .001). Furthermore, the cytotoxicity assay against J774.A.1 macrophages revealed that this compound displays high selectivity against amastigotes over macrophages (SI = 30.21). The in silico study showed that TF-2 can properly accommodated in the active site of parasitic CYP51 and coordinated to the heme. The SAR analysis showed that the introduction of 4-chloro on 2-phenyl moiety results in the best profile of activity and selectivity. Accordingly, the compound TF-2 prototype can be considered as promising candidate for development of new antileishmanial agents.
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http://dx.doi.org/10.1016/j.parint.2018.12.006DOI Listing
April 2019

Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer's agents.

Bioorg Chem 2019 03 13;83:559-568. Epub 2018 Nov 13.

The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411, Iran; Departmnt of Pharmaceutical Biomaterials, Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2-aminophenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N-benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of Aβ self-aggregation as well as AChE-induced Aβ aggregation. Meanwhile, these compounds could significantly protect PC12 cells against HO-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer's disease.
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http://dx.doi.org/10.1016/j.bioorg.2018.11.010DOI Listing
March 2019

1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design, synthesis and biological evaluation.

Bioorg Chem 2019 02 31;82:414-422. Epub 2018 Oct 31.

Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address:

A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (ICs = 0.06-6.80 µM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31-155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells.
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http://dx.doi.org/10.1016/j.bioorg.2018.10.069DOI Listing
February 2019

Ultrastructural Investigation of Promastigotes Treated with A New Potent Antileishmanial Azole Using Scanning Electron and Atomic Force Microscopes.

Recent Pat Antiinfect Drug Discov 2018 ;13(3):246-255

Immunogenetics Research Center, Department of Medical Nanotechnology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Aim And Background: Azoles as antifungal drugs have been used to treat leishmaniasis for many years. Several evidences suggesting that the primary target of azoles is the heme protein, which co-catalyzes cytochrome P-450-dependent 14α-demethylation of lanosterol. Little is known about the structural changes caused by azoles with atomic force microscopy (AFM) or scanning electron microscopy (SEM). In the current work, several patented antileishmanial agents reviewed (US8809555) (US 0269803 A1) (TW201802093 A). The present study aimed to determine ultrastructural damage in Leishmania major (L.major) induced by the newly synthesized azole.

Methods: In this study, we investigated the morphological alterations of the parasite treated with our new synthesized azole namely trans-2-(4-chlorophenyl)-2,3-dihydro-3-(1Himidazol- 1-yl)-4H-1-benzopyran-4-one (IF-2) against L.major promastigotes stage using two high-resolution microscopic techniques: atomic force microscopy and scanning electron microscopy.

Results: The results showed remarkable topographical and morphological alterations in the cell membrane at promastigote stage of L. major treated with the potent investigated azole (IF-2) ( IC50 values ≤8.9 µg/mL). Both techniques revealed membrane damage and also losing the flagellum in the observed cells.

Conclusion: Our results strongly confirm the Leishmania cell wall as a potent target for the new synthesized azole (IF-2). Accordingly, focus on membrane integrity and glycoconjugates of Leishmania parasite to design new therapeutic agents is recommended.
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http://dx.doi.org/10.2174/1574891X13666180918121628DOI Listing
April 2019

Acetophenone benzoylhydrazones as antioxidant agents: Synthesis, in vitro evaluation and structure-activity relationship studies.

Food Chem 2018 Dec 19;268:292-299. Epub 2018 Jun 19.

Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.

Acetophenone and its analogues are naturally-occurring compounds found in many foods and plants. In this study, a series of acetophenone benzoylhydrazones 5a-o were designed and synthesized as new potential antioxidant agents. Designed molecules contain hydrazone and phenolic hydroxyl moieties which possibly contribute to antioxidant activity. The antioxidant properties of compounds 5a-o in terms of reducing ability and radical-scavenging activity were assessed by using FRAP and DPPH tests, respectively. While the unsubstituted compound 5a had the superior capacity in the FRAP assay, the 2,4-dihydroxyacetophenone analogue 5g was the most potent radical scavenger in the DPPH method. The antioxidant potential of representative compounds 5a and 5g was further confirmed by TEAC and ORAC assays. Cell viability assays revealed that while the promising compounds 5a and 5g had no significant toxicity against HepG2 and NIH3T3 cells, they potently protected HepG2 cells against HO-induced oxidative damage at low concentrations. Furthermore, spectroscopic studies with different biometals demonstrated that 5g was able to interact with Cu to form a 1:1 complex.
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http://dx.doi.org/10.1016/j.foodchem.2018.06.083DOI Listing
December 2018

Synthesis and biological evaluation of new coumarins bearing 2,4-diaminothiazole-5-carbonyl moiety.

Eur J Med Chem 2018 Jul 7;155:483-491. Epub 2018 Jun 7.

The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

A series of new coumarin-containing compounds 3a-l and 4a-c was designed and synthesized based on the chalcone-type 4-amino-5-cinnamoylthiazole scaffold 2, and screened for their in vitro anticancer and antioxidant activities. Representatively, the 2-thiomorpholinothiazole derivative 3k with IC values of 7.5-16.9 μg/ml demonstrated good cytotoxic effects against tested cell lines MCF-7, HepG2 and SW480. Further investigation by flow cytometric analysis confirmed that this compound induces apoptotic cell death in MCF-7 cells and cause G1-phase arrest in the cell cycle. Moreover, most of compounds had intrinsic potential for radical scavenging activity and ferric-reducing power as investigated by DPPH and FRAP assays.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.015DOI Listing
July 2018

New 7-piperazinylquinolones containing (benzo[d]imidazol-2-yl)methyl moiety as potent antibacterial agents.

Mol Divers 2018 Nov 7;22(4):815-825. Epub 2018 Jun 7.

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

A series of 7-piperazinylquinolones containing a (benzo[d]imidazol-2-yl)methyl moiety were designed and synthesized as new antibacterial agents. The antibacterial activity of title compounds was evaluated against Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia) microorganisms. Among the tested compounds, the N1-cyclopropyl derivative 4a showed the highest activity against S. aureus, S. epidermidis, B. subtilis and E. coli ([Formula: see text] [Formula: see text]g/mL), being 2-4 times more potent than reference drug norfloxacin. A structure-activity relationship study demonstrated that the effect of the nitro group on the benzimidazole ring depends on the pattern of substitutions on the piperazinylquinolone.
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http://dx.doi.org/10.1007/s11030-018-9834-3DOI Listing
November 2018

Promising antileishmanial activity of novel imidazole antifungal drug luliconazole against Leishmania major: In vitro and in silico studies.

J Glob Antimicrob Resist 2018 09 21;14:260-265. Epub 2018 May 21.

Pharmaceutical Sciences Research Center, Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.

Objectives: Pentavalent antimonials have been used for the treatment of leishmaniasis for over 70 years, however they are limited by their toxicity. Unfortunately, the efficacy of first-line drugs for the treatment of leishmaniasis has decreased and resistance is noticeable. Luliconazole is a new azole with unique effects on fungi that has not yet been tested on Leishmania parasites.

Methods: In this study, the cytotoxicity and antileishmanial activity of luliconazole were evaluated in vitro against promastigotes and intracellular amastigotes of Leishmania major. The docking simulation with the target enzyme, sterol 14α-demethylase (CYP51) was performed using AutoDock 4.2 program.

Results: The IC (concentration of test compound required for 50% inhibition) against promastigotes revealed that luliconazole (IC=0.19μM) has greater potency than ketoconazole (KET), meglumine antimoniate (MA) and amphotericin B (AmB) (IC values of 135, 538 and 2.52μM, respectively). Against the amastigote stage, luliconazole at a concentration of 0.07μM decreased the mean infection rate and the mean number of amastigotes per macrophage more effectively than MA (P<0.004) and KET (P<0.043), but there was no difference compared with AmB (P>0.05). A docking study of luliconazole with the cytochrome P450 enzyme sterol 14α-demethylase (CYP51) revealed that this azole drug can properly interact with the target enzyme in Leishmania mainly via coordination with heme and multiple hydrophobic interactions.

Conclusion: These results show the potent activity of luliconazole at extremely low concentrations against L. major. It may therefore be considered as a new candidate for treatment of leishmaniasis in the near future.
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http://dx.doi.org/10.1016/j.jgar.2018.05.007DOI Listing
September 2018

Novel 3-phenylcoumarin-lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer's disease.

Bioorg Chem 2018 09 2;79:223-234. Epub 2018 May 2.

Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

New series of triazole-containing 3-phenylcoumarin-lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer's disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against HO-induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against HO-induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.bioorg.2018.04.030DOI Listing
September 2018

Design, synthesis and evaluation of novel multi-target-directed ligands for treatment of Alzheimer's disease based on coumarin and lipoic acid scaffolds.

Eur J Med Chem 2018 May 2;152:600-614. Epub 2018 May 2.

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

A novel series of coumarin-lipoic acid conjugates were synthesized via cycloaddition click reaction to find out new multi-target-directed ligands (MTDLs) for treatment of Alzheimer's disease (AD). All of synthesized compounds were screened for neuroprotective and anti-cholinesterase activities. Based on primary screening, two compounds (5 and 11) were subjected to further biological evaluations. In particular, compound 11 which was the most potent AChE inhibitor showed good inhibitory effect on Aβ-aggregation and intracellular ROS (reactive oxygen species) formation, as well as the ability of selective bio-metal chelation and neuroprotection against HO- and Aβ-induced cytotoxicity. In the light of these results, the applied hybridization approach introduced new promising lead compound with desired multifunctional properties, being useful in the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.ejmech.2018.04.058DOI Listing
May 2018

Discovery of benzylthio analogs of fluconazole as potent antifungal agents.

Future Med Chem 2018 05 23;10(9):987-1002. Epub 2018 Apr 23.

Department of Medicinal Chemistry & Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.

Aim: A new series of triazole alcohol antifungals 8a-j were designed by introducing benzylthio functionality on one triazole ring of fluconazole.

Results: The antifungal activity evaluation of target compounds against 16 Candida isolates indicated that all compounds with MIC values of 0.063-1 μg/ml had better profile of activity in respect to fluconazole (MICs = 0.5-4 μg/ml) against fluconazole-susceptible isolates. In particular, the representative compounds 8b and 8e were also active against fluconazole-resistant isolates of Candida albicans and Candida parapsilosis (MICs = 0.063-16 μg/ml). Cytotoxicity assay against Hep-G2 and NIH-3T3 cell lines revealed that these compounds can display potent antifungal activity at noncytotoxic concentrations.

Conclusion: The prototype compound 8b could be considered as a new lead for design and development of potent antifungal agents. [Formula: see text].
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http://dx.doi.org/10.4155/fmc-2017-0295DOI Listing
May 2018

99mTc-labeled Small Molecules for Diagnosis of Alzheimer's Disease: Past, Recent and Future Perspectives.

Curr Med Chem 2019 ;26(12):2166-2189

Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.

Background: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease. Its prominent hallmarks are extracellular deposition of β-amyloids (amyloid plaques), intracellular neurofibrillary tangles (NTFs), neurodegeneration and finally loss of cognitive function. Hence, AD diagnosis in the early stage and monitoring of the disease are of great importance.

Methods: In this review article, we have reviewed recent efforts for design, synthesis and evaluation of 99mTc labeled small molecule for AD imaging purposes.

Results: These small molecules include derivatives of Congo red, benzothiazole, benzofuran, benzoxazole, naphthalene, biphenyl, chalcone, flavone, aurone, stilbene, curcumin, dibenzylideneacetone, quinoxaline, etc. The different aspects of 99mTc-labeled small molecules including chemical structure, their affinity toward amyloid plaques, BBB permeation and in vivo/vitro stability will be discussed.

Conclusion: The findings of this review confirm the importance of 99mTc-labeled small molecules for AD imaging. Future studies based on the pharmacophore of these designed compounds are needed for improvement of these molecules for clinical application.
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http://dx.doi.org/10.2174/0929867325666180410104023DOI Listing
July 2019