Publications by authors named "Mahsima Khoshneviszadeh"

26 Publications

  • Page 1 of 1

The natural-based optimization of kojic acid conjugated to different thio-quinazolinones as potential anti-melanogenesis agents with tyrosinase inhibitory activity.

Bioorg Med Chem 2021 Apr 27;36:116044. Epub 2021 Jan 27.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Melanin pigment and melanogenesis are a two-edged sword. Melanin has a radioprotection role while melanogenesis has undesirable effects. Targeting the melanogenesis pathway, a series of kojyl thioether conjugated to different quinazolinone derivatives were designed, synthesized, and evaluated for their inhibitory activity against mushroom tyrosinase. All the synthesized compounds were screened for their anti-tyrosinase activity and all derivatives displayed better potency than kojic acid as the positive control. In this regard, 5j and 5h as the most active compounds showed an IC value of 0.46 and 0.50 µM, respectively. In kinetic evaluation against tyrosinase, 5j depicted an uncompetitive inhibition pattern. Designed compounds also exhibited mild antioxidant capacity. Moreover, 5j and 5h achieved good potency against the B16F10 cell line to reduce the melanin content, whilst showing limited toxicity against malignant cells. The proposed binding mode of new inhibitors evaluated through molecular docking was consistent with the results of structure-activity relationship analysis.
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http://dx.doi.org/10.1016/j.bmc.2021.116044DOI Listing
April 2021

Design, synthesis, in vitro and in silico studies of novel Schiff base derivatives of 2-hydroxy-4-methoxybenzamide as tyrosinase inhibitors.

Drug Dev Res 2020 Dec 19. Epub 2020 Dec 19.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Due to the fact that tyrosinase is responsible for biosynthesis and regulation of melanins and browning food products, tyrosinase inhibitors can be favorable agents in cosmetics and medicinal industries. A series of novel 2-hydroxy-4-methoxybenzohydrazide were designed, synthesized, and their new application as tyrosinase inhibitors was also disclosed. Based on in vitro tyrosinase inhibitory assay, 4d as the strongest inhibitor of tyrosinase with an IC value of 7.57 μM showed approximately 2.5-fold better inhibition than kojic acid as positive control followed by two compounds 4b (IC = 8.19 ± 0.25 μM) and 4j (IC = 8.92 ± 0.016) which displayed preferable tyrosinase inhibitory activity. Detailed investigations on the mechanism of action of the 4d reported mix type of inhibition. More importantly, molecular modeling assessments proposed the ability of 4d for potential interaction with Cu (metal)-His (residue) within tyrosinase active site. Overall, 4d is a promising candidate for the development of anti-tyrosinase agents.
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http://dx.doi.org/10.1002/ddr.21771DOI Listing
December 2020

4H-benzochromene derivatives as novel tyrosinase inhibitors and radical scavengers: synthesis, biological evaluation, and molecular docking analysis.

Mol Divers 2020 Jul 18. Epub 2020 Jul 18.

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

A series of ethyl 2-amino-4H-benzo[h]chromene-3-carboxylate derivatives, having phenyl ring with diverse substituents at C position of 4H-benzochromene nucleus, were synthesized via one-pot three-component reaction between various aromatic aldehydes, α-naphthol, and ethyl cyanoacetate. The synthesized compounds were screened for their antityrosinase activity. Compound 4i, bearing 4-dimethylamino substitution on C-phenyl ring, was the most potent tyrosinase inhibitor (IC = 34.12 μM). The inhibition kinetic analysis of 4i indicated that the compound was a competitive tyrosinase inhibitor. Compounds 4a, 4g, 4i and 4j were the effective radical scavengers with ECs in the range of 0.144-0.943 mM. According to the in silico drug-like and ADME predictions, 4i can be considered as a suitable candidate. Molecular docking results confirmed that the derivative was well accommodated within the mushroom tyrosinase binding site. Therefore, 4i can be introduced as a novel tyrosinase inhibitor that might be a promising lead in medicine, cosmetics, and food industry.
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http://dx.doi.org/10.1007/s11030-020-10123-0DOI Listing
July 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

1,2,3-Triazole-linked 5-benzylidene (thio)barbiturates as novel tyrosinase inhibitors and free-radical scavengers.

Arch Pharm (Weinheim) 2020 Oct 8;353(10):e2000058. Epub 2020 Jul 8.

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

In this study, benzyl-1,2,3-triazole-linked 5-benzylidene (thio)barbiturate derivatives 7a-d and 8a-h were designed as potential tyrosinase inhibitors and free-radical scavengers. The twelve derivatives were synthesized via the [3+2] cycloaddition reaction of the corresponding benzyl azide as a dipole and the corresponding alkyne as a dipolarophile in the presence of copper(I) species, generated in situ from copper(II)/ascorbate. The thiobarbiturate derivative 8h and the barbiturate derivative 8b bearing 4-fluoro and 4-bromo groups on the benzyl-triazole moiety were found to be the most potent tyrosinase inhibitors with IC values of 24.6 ± 0.9 and 26.8 ± 0.8 μM, respectively. Almost all the compounds showed a good radical scavenging activity with EC values in the range of 29.9-324.9 μM. Derivatives 7a, 8f, and 8h were the most potent free-radical scavengers with EC values of 29.9 ± 0.8, 36.8 ± 0.9, and 39.2 ± 1.1 μM, respectively. The kinetic analysis revealed that compound 8h was a mixed-type tyrosinase inhibitor. The molecular docking analysis indicated that 8b and 8h were well accommodated in the active site of the tyrosinase enzyme and possessed the most negative binding energy values of -8.55 and -8.81 kcal/mol, respectively. Moreover, it was found that the two residues, Asn81 and Glu322, played a significant role in forming stable enzyme-inhibitor complexes.
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http://dx.doi.org/10.1002/ardp.202000058DOI Listing
October 2020

Interplay between perivascular and perineuronal extracellular matrix remodelling in neurological and psychiatric diseases.

Eur J Neurosci 2020 Jun 28. Epub 2020 Jun 28.

German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.

Vascular damage, central nervous system (CNS) injury, seizure or even psychological stress may trigger activation of microglia and infiltration of other immune cells, accompanied by high levels of expression and activity of extracellular proteases, such as matrix metalloproteinases (MMPs), and degradation/remodelling of the perivascular and perineuronal extracellular matrix (ECM). This acute response is followed by the recovery/chronic phase, during which the activation of astrocytes leads to the upregulated synthesis of ECM molecules, which, in combination with elevated expression of tissue inhibitor of metalloproteinases (TIMP) proteins, increases the aggregation of ECM molecules. This biphasic dysregulation of local balance between extracellular proteases and the ECM activates multiple temporally overlapping signalling cascades, involving receptor-type protein tyrosine phosphatases, integrins, Toll-like receptors, cell adhesion molecules, and ion channels, resulting in impaired synaptic plasticity and cognition. An additional level of complexity is related to the leakage of blood plasma proteins, such as fibrinogen, and the diffusion of perivascularly overproduced MMPs, TIMPs and ECM molecules into the CNS parenchyma, leading to diverse effects on neurons and incorporation of these molecules into the interstitial neural ECM. This review aims to outline these complex common mechanisms in stroke, CNS injury, depression, epilepsy, multiple sclerosis and cerebral small vessel disease and to discuss translational strategies to advance the development of new therapies for these neurological and psychiatric diseases.
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http://dx.doi.org/10.1111/ejn.14887DOI Listing
June 2020

A Series of Benzylidenes Linked to Hydrazine-1-carbothioamide as Tyrosinase Inhibitors: Synthesis, Biological Evaluation and Structure-Activity Relationship.

Chem Biodivers 2020 Aug 3;17(8):e2000285. Epub 2020 Aug 3.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, 71348, Shiraz, Iran.

Tyrosinase is a type 3 copper enzyme responsible for skin pigmentation disorders, skin cancer, and enzymatic browning of vegetables and fruits. In the present article, 12 small molecules of 2-benzylidenehydrazine-1-carbothioamide were designed, synthesized and evaluated for their anti-tyrosinase activities followed by molecular docking and pharmacophore-based screening. Among synthesized thiosemicarbazone derivatives, one compound, (2E)-2-[(4-nitrophenyl)methylidene]hydrazine-1-carbothioamide, is the strongest inhibitor of mushroom tyrosinase with IC of 0.05 μM which demonstrated a 128-fold increase in potency compared to the positive control. Kinetic studies also revealed mix type inhibition by this compound. Docking studies confirmed the complete fitting of the synthesized compounds into the tyrosinase active site. The results underline the potential of 2-benzylidenehydrazine-1-carbothioamides as potent pharmacophore to extend the tyrosinase inhibition in drug discovery.
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http://dx.doi.org/10.1002/cbdv.202000285DOI Listing
August 2020

Oxytocinergic system mediates the proconvulsant effects of sildenafil: The role of calcineurin.

Horm Behav 2020 06 21;122:104753. Epub 2020 Apr 21.

Cellular and Molecular Research Center and Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Sildenafil is a phosphodiesterase type 5 inhibitor used to treat male erectile dysfunction and pulmonary hypertension. A potential side effect of sildenafil is a noticeable decrease in seizure threshold. Oxytocin (OXT) secretion and the subsequent cAMP-responsive element-binding (CREB) phosphorylation are involved in proconvulsant effects of sildenafil in experimental models. The aim of the present study was to investigate the potential role of OXT receptors and their downstream calcineurin (CN)/inducible nitric oxide synthase (iNOS) pathways in proconvulsant effects of sildenafil. The pentylenetetrazole (PTZ)-induced seizure was used as a standard convulsion model in this study. Cortical CN activity, hippocampal nitrite levels, and proinflammatory cytokine content were measured. Our results indicated that following PTZ administration, sildenafil significantly increased CN activity at 40 mg/kg, respectively, in the control group. The combination of sildenafil and OXT receptor antagonist, atosiban (10 μg/kg, i.c.v) 30 min before sildenafil administration significantly reduced the CN activity. Also, the subeffective dose of CN inhibitor cyclosporine (5 mg/kg) 30 min before the administration of effective dose of sildenafil (40 mg/kg) reversed proconvulsant actions of sildenafil. This effect was iNOS-dependent because pretreatment of a low dose of aminoguanidine (20 mg/kg) 15 min before the administration of a low dose of cyclosporine (1 mg/kg) reversed the proconvulsant action of sildenafil (40 mg/kg). Finally, sildenafil induced the elevation of tumor necrosis factor alpha (TNF-α) and the nitrite level was blocked by the administration of cyclosporine in PTZ-treated mice. Collectively, our data provide insights into the role of OXT receptor/CN/iNOS pathway in the proconvulsant aspect of sildenafil.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104753DOI Listing
June 2020

Synthesis, biological evaluation and molecular docking analysis of vaniline-benzylidenehydrazine hybrids as potent tyrosinase inhibitors.

BMC Chem 2020 Dec 7;14(1):28. Epub 2020 Apr 7.

1Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

In this work, 11 novel compounds based on vaniline and benzylidenehydrazine structure were synthesized with various substituents on phenyl aromatic ring of the molecule and evaluated as tyrosinase inhibitors. These new derivatives showed significant anti-tyrosinase activities, among which demonstrated to be the most potent compound, with IC values of 1.58 µM . The structure-activity relationship study of the novel constructed analogs was fully discussed. Kinetic study of compound showed uncompetitive inhibition towards tyrosinase. Furthermore, the high potency of was supported theoretically by molecular docking evaluations.
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http://dx.doi.org/10.1186/s13065-020-00679-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137441PMC
December 2020

Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands.

Bioorg Chem 2020 04 4;97:103649. Epub 2020 Feb 4.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that effects 50 million people worldwide. In this review, AD pathology and the development of novel therapeutic agents targeting AD were fully discussed. In particular, common approaches to prevent Aβ production and/or accumulation in the brain including α-secretase activators, specific γ-secretase modulators and small molecules BACE1 inhibitors were reviewed. Additionally, natural-origin bioactive compounds that provide AD therapeutic advances have been introduced. Considering AD is a multifactorial disease, the therapeutic potential of diverse multi target-directed ligands (MTDLs) that combine the efficacy of cholinesterase (ChE) inhibitors, MAO (monoamine oxidase) inhibitors, BACE1 inhibitors, phosphodiesterase 4D (PDE4D) inhibitors, for the treatment of AD are also reviewed. This article also highlights descriptions on the regulator of serotonin receptor (5-HT), metal chelators, anti-aggregants, antioxidants and neuroprotective agents targeting AD. Finally, current computational methods for evaluating the structure-activity relationships (SAR) and virtual screening (VS) of AD drugs are discussed and evaluated.
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http://dx.doi.org/10.1016/j.bioorg.2020.103649DOI Listing
April 2020

One-pot synthesis of thioxo-tetrahydropyrimidine derivatives as potent β-glucuronidase inhibitor, biological evaluation, molecular docking and molecular dynamics studies.

Bioorg Med Chem 2020 04 6;28(7):115359. Epub 2020 Feb 6.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

A series of N,N-diethyl phenyl thioxo-tetrahydropyrimidine carboxamide have been synthesized and investigated for their β-glucuronidase inhibitory activities. All molecules exhibited excellent inhibition with IC values ranging from 0.35 to 42.05 µM and found to be even more potent than the standard d-saccharic acid. Structure-activity relationship analysis indicated that the meta-aryl-substituted derivatives significantly influenced β-glucuronidase inhibitory activities while the para-substitution counterpart outperforming moderate potency. The most potent compound in this series was 4g bearing thiophene motif with IC of 0.35 ± 0.09 µM. To verify the SAR, molecular docking and molecular dynamics studies were also performed.
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http://dx.doi.org/10.1016/j.bmc.2020.115359DOI Listing
April 2020

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities.

Med Chem 2020 ;16(7):892-902

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti- tyrosinase agents.

Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated.

Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site.

Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex.

Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.
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http://dx.doi.org/10.2174/1573406415666190724142951DOI Listing
January 2020

Novel morpholine containing cinnamoyl amides as potent tyrosinase inhibitors.

Int J Biol Macromol 2019 Aug 29;135:978-985. Epub 2019 May 29.

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. Hence, tyrosinase inhibitors are important in the fields of medicine, cosmetics and agriculture. In this study, novel N-(2-morpholinoethyl)cinnamamide derivatives bearing different substituents on phenyl ring were designed, synthesized and evaluated for their tyrosinase diphenolase inhibitory activity. The compounds were found to be better tyrosinase inhibitors (ICs were in micro molar range) than cinnamic acid. (E)-3-(3-chlorophenyl)-N-(2-morpholinoethyl)acrylamide (B6) exhibited the highest inhibition with IC value of 15.2 ± 0.6 μM which was comparable to that of kojic acid. The inhibition kinetic analysis of B6 indicated that the compound was a mixed-type tyrosinase inhibitor. In silico ADME prediction indicated that B6 might show more skin penetration than kojic acid. Molecular docking analysis confirmed that the active inhibitors well accommodated in the mushroom tyrosinase active site and it was also revealed that B6 formed the most stable drug-receptor complex with the target protein. Therefore, cinnamamide B6 could be introduced as a potent tyrosinase inhibitor that might be a promising lead in cosmetics, medicine and food industry.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.05.201DOI Listing
August 2019

Veratric acid derivatives containing benzylidene-hydrazine moieties as promising tyrosinase inhibitors and free radical scavengers.

Bioorg Med Chem 2019 06 10;27(12):2644-2651. Epub 2019 Apr 10.

Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address:

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. A series of veratric acid derivatives containing benzylidene-hydrazine moieties with different substitutions were synthesized and their inhibitory effect on mushroom tyrosinase and free radical scavenging activity were evaluated. The results indicated that N'-(4-chlorobenzylidene)-3,4-dimethoxybenzohydrazide (D5) and N'-(2,3-dihydroxybenzylidene)-3,4-dimethoxybenzohydrazide (D12) showed the highest tyrosinase inhibitory activity with IC values of 19.72 ± 1.84 and 20.63 ± 0.79 μM, respectively, that were comparable with the IC value of kojic acid (19.08 ± 1.21 μM). D12 was also a potent radical scavenger with EC value of 0.0097 ± 0.0011 mM. The free radical scavenging activity of D12 was comparable with the standard quercetin. The inhibition kinetic analyzed by Lineweaver-Burk plots revealed that compound D5 was a competitive tyrosinase inhibitor. Molecular docking study was carried out for the derivatives demonstrating tyrosinase inhibitory activity. D5 and D12 possessed the most negative estimated free energies of binding in mushroom tyrosinase active site. Therefore, D5 and D12 could be introduced as potent tyrosinase inhibitors that might be promising leads in medicine, cosmetics and food industry.
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http://dx.doi.org/10.1016/j.bmc.2019.04.016DOI Listing
June 2019

The Healing Effect of and Mixture in Excisional Full Thickness Skin Wounds: Stereological Study.

World J Plast Surg 2019 Jan;8(1):51-57

Student Research Committee, International branch, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: Previous studies indicated that both and have anti-inflammatory, tissue regeneration, antioxidant, and immune-stimulatory effects. It is assumed that a mixture of these two herbal medicines may provide a potent material in treatment of skin wound injuries. Therefore, in this study we investigated the effects of and mixture in the process of wound healing in rat models according to stereological parameters.

Methods: In an experiential study, 36 male Sprague-Dawley rats (200±20 g) were randomly assigned into three groups (n=12): The control group which received no treatment, gel base treated group, and the 5% and 5% mixture gel treated group (PA group). Treatments were done every 24 hrs for 15 days. Wound closure rate, volume densities of the collagen bundles and the vessels, vessel's length density and mean diameter, and fibroblast populations were estimated using stereological methods.

Results: PA treated group showed faster wound closure rate in comparison with control and gel-base groups (<0.05). Numerical density of fibroblasts, volume density of collagen bundles, mean diameter, and volume densities of the vessels in PA group were significantly higher than the control and the gel-base treated groups (<0.05).

Conclusion: We showed that and mixture has the ability to improve wound healing by enhancing fibroblast proliferation, collagen bundle synthesis and re-vascularization in skin injuries.
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http://dx.doi.org/10.29252/wjps.8.1.51.DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409144PMC
January 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

Synthesis of New Benzimidazole-1,2,3-triazole Hybrids as Tyrosinase Inhibitors.

Chem Biodivers 2018 Jul 21;15(7):e1800120. Epub 2018 Jun 21.

Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, P.O. Box 14155, 6451, Tehran, Iran.

A novel series of benzimidazole-1,2,3-triazole hybrids containing substituted benzyl moieties were designed, synthesized and evaluated for their inhibitory activity against mushroom tyrosinase. The results indicated that 2-(4-{[1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzimidazole (6g) and 2-(4-{[1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzimidazole (6h) exhibited effective inhibitory activity with IC values of 9.42 and 10.34 μm, respectively, comparable to that of kojic acid as the reference drug (IC = 9.28 μm). Kinetic study of compound 6g confirmed mixed-type inhibitory activity towards tyrosinase indicating that it can bind to free enzyme as well as enzyme-substrate complex. Also, molecular docking analysis was performed to determine the binding mode of the most potent compounds (6g and 6h) in the active site of tyrosinase. Consequently, 6g and 6h derivatives might serve as promising candidates in cosmetics, medicine or food industry, and development of such compounds may be of an interest.
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http://dx.doi.org/10.1002/cbdv.201800120DOI Listing
July 2018

Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors.

Res Pharm Sci 2018 Feb;13(1):1-11

Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, I.R. Iran.

Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. , and exhibited good cytotoxic activity on both cell lines with an IC range of 6.42 - 20.20 μM. In general, substitution of a five-membered heterocyclic ring containing NO, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, , was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity.
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http://dx.doi.org/10.4103/1735-5362.220962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772076PMC
February 2018

Long Chain Alkyl Esters of Hydroxycinnamic Acids as Promising Anticancer Agents: Selective Induction of Apoptosis in Cancer Cells.

J Agric Food Chem 2017 Aug 8;65(33):7228-7239. Epub 2017 Aug 8.

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz, 71345-1149 Iran.

Cancer is the major cause of morbidity and mortality worldwide. Hydroxycinnamic acids (HCAs) are naturally occurring compounds and their alkyl esters may possess enhanced biological activities. We evaluated C4, C14, C16, and C18 alkyl esters of p-coumaric, ferulic, sinapic, and caffeic acids (19 compounds) for their cytotoxic activity against four human cancer cells and also examined their effect on cell cycle alteration and apoptosis induction. The tetradecyl (1c) and hexadecyl (1d) esters of p-coumaric acid and tetradecyl ester of caffeic acid (4c), but not the parental HCAs, were selectively effective against MOLT-4 (human lymphoblastic leukemia) cells with IC values of 0.123 ± 0.012, 0.301 ± 0.069 and 1.0 ± 0.1 μM, respectively. Compounds 1c, 1d, and 4c significantly increased apoptotic cells in sub-G1 phase and activated the caspase-3 enzyme in MOLT-4 cells. Compound 1c was 15.4 and 23.6 times more potent than doxorubicin and cisplatin, respectively, against the drug resistant MES-SA-DX5 uterine sarcoma cells. These p-coumarate esters were several times less effective against NIH/3T3 fibroblast cells. Docking studies showed that 1c may cause cytotoxicity by interaction with carbonic anhydrase IX. In conclusion, long chain alkyl esters of p-coumaric acid are promising scaffolds for selective apoptosis induction in cancer cells.
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http://dx.doi.org/10.1021/acs.jafc.7b01388DOI Listing
August 2017

Verapamil, a Calcium-Channel Blocker, Improves the Wound Healing Process in Rats with Excisional Full-Thickness Skin Wounds Based on Stereological Parameters.

Adv Skin Wound Care 2016 Aug;29(8):271-4

Soheil Ashkani-Esfahani, MD, is on the Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran. Omid Koohi Hosseinabadi, is a Laboratory Assistant at the Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. Parinaz Moezzi; Yalda Moafpourian; Sina Kardeh; and Reza Fatheazam are Medical Students and Shima Rafiee is a Researcher on the Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran. Ali Noorafshan is a Professor and Elham Nadimi is a Laboratory Assistant at the Histomorphometry & Stereology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran. Shayan Mehrvarz is a Pharmacology Student on the Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran. Mehdi Khoshneviszadeh is an Assistant Professor and Mahsima Khoshneviszadeh, MSc, is a Research Assistant, at the Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Objective: Calcium can play noticeable roles in the wound-healing process, such as its effects on organization of F-actinin collagen bundles by fibroblasts at the injury site. In addition, calcium-channel blockers such as verapamil have antioxidant activity by increasing nitric oxide production that promotes angiogenesis, proliferation of fibroblasts, and endothelial cells in the skin-regeneration process. Therefore, in this study, the authors' objective was to investigate the effects of verapamil on the process of wound healing in rat models according to stereological parameters.

Materials And Methods: In this experimental study, 36 male Wistar rats were randomly divided into 3 groups (n = 12): the control group that received no treatment, gel-base-treated group, and the 5% verapamil gel-treated group. Treatments were done every 24 hours for 15 days. Wound closure rate, volume densities of the collagen bundles and the vessels, vessel's length density and mean diameter, and fibroblast populations were estimated using stereological methods and were analyzed by the Kruskal-Wallis and Mann-Whitney U tests; P < .05 was considered statistically significant.

Results: The verapamil-treated group showed a faster wound closure rate in comparison with control and gel-base groups (P = .007 and P = .011). The numerical density of fibroblasts, volume density of collagen bundles, mean diameter, and volume densities of the vessels in the verapamil group were significantly higher than those in the control and the base groups (P < .005).

Conclusions: The authors showed that verapamil has the ability to improve wound healing by enhancing fibroblast proliferation, collagen bundle synthesis, and revascularization in skin injuries.
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http://dx.doi.org/10.1097/01.ASW.0000488666.03896.e6DOI Listing
August 2016

Oxytocin is involved in the proconvulsant effects of Sildenafil: Possible role of CREB.

Toxicol Lett 2016 Aug 21;256:44-52. Epub 2016 May 21.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Sildenafil is a phosphodiesterase type 5 inhibitor mainly used for male erectile dysfunction. One of rare yet serious adverse effects of Sildenafil is its potential to decrease seizure threshold. Ample evidence suggests that Sildenafil exerts central effects through induction of Oxytocin (OT) secretion and CREB phosphorylation. The aim of the present study is to evaluate potential roles of OT and CREB in the proconvulsant effects of Sildenafil. The Pentylenetetrazole-induced seizure was used as a standard convulsion model in this study. OT release and pCREB expression were evaluated in the hippocampus of mice using ELISA and western blot assays, respectively. Our results showed that Sildenafil at the dose of 10mgkg(-1) or higher, significantly decreased seizure threshold. Pretreatment with a non-effective dose of OT, potentiated while OT receptor antagonist, Atosiban, reversed fully the proconvulsant effects of Sildenafil (5mgkg(-1)). At biochemical inspection, Sildenafil markedly increased CREB which was attenuated by coadministration of Atosiban. The present study shows for the first time that OT release and the subsequent CREB phosphorylation are involved in the proconvulsant effects of acute Sildenafil treatment in an experimental model of seizure.
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http://dx.doi.org/10.1016/j.toxlet.2016.05.018DOI Listing
August 2016

Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities.

J Enzyme Inhib Med Chem 2016 Dec 30;31(6):1602-11. Epub 2016 Mar 30.

a Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences .

A set of 1,2,4-triazine derivatives were designed as cyclooxygenase-2 (COX-2) inhibitors. These compounds were synthesized and screened for inhibition of cyclooxygenases (COX-1 and COX-2) based on a cellular assay using human whole blood (HWB) and lipoxygenase (LOX-15) that are key enzymes in inflammation. The results showed that 3-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (G11) was identified as the most potent COX-2 inhibitor (78%) relative to COX-1 (50%). Ferric reducing anti-oxidant power (FRAP) assay revealed that compound G10 possesses the highest anti-oxidant activity. The compound G3 with IC50 value of 124 μM was the most potent compound in LOX inhibitory assay. Molecular docking was performed and a good agreement was observed between computational and experimental results.
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http://dx.doi.org/10.3109/14756366.2016.1158713DOI Listing
December 2016

Topical Nicotinamide Improves Tissue Regeneration in Excisional Full-Thickness Skin Wounds: A Stereological and Pathological Study.

Trauma Mon 2015 Nov 23;20(4):e18193. Epub 2015 Nov 23.

Payam-e-Nour University, Shiraz, IR Iran.

Background: Nicotinamide (NA), the active form of vitamin-B3, is hypothesized to have positive effects on the process of wound healing; it has anti-inflammatory, antioxidant, and immunomodulatory properties, as well as an epithelization inducing action.

Objectives: In the present study, we aimed to determine the effects of topical administration of NA on skin wounds, based on histomorphometrical and pathological criteria.

Materials And Methods: In this study, 36 male Sprague-Dawley rats (220 ± 20 g each), with 1 cm(2) circular full-thickness wounds on their backs were divided into three groups (n = 12): NA group, was treated daily with a Nicotinamide 2% gel , untreated group (control), and base group, which were treated with the vehicle (base) of the gel (carboxymethylcellulose). Skin biopsies were prepared for microscopic analyses. Inflammation, granulation tissue formation, ulceration, epithelization, wound closure rate, fibroblast proliferation, collagen synthesis, and vascularization were studied criteria.

Results: The results revealed that besides improving the wound healing by its anti-inflammatory, antioxidant, and epithelization inducing effects, NA also improved tissue regeneration through the increment of fibroblast proliferation, collagen synthesis, and vascularization.

Conclusions: In spite of the few reported side effects, NA can be introduced as an effective agent on the wound healing process, an adjuvant therapy and possibly a treatment by itself. However, its chemical characteristics, as well as possible adverse effects warrants further research.
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http://dx.doi.org/10.5812/traumamon.18193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727459PMC
November 2015

A COX/5-LOX Inhibitor Licofelone Revealed Anticonvulsant Properties Through iNOS Diminution in Mice.

Neurochem Res 2015 Sep 28;40(9):1819-28. Epub 2015 Jul 28.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box: 13145-784, Tehran, Iran.

Licofelone is a COX/5-LOX inhibitor, which recently was approved as an effective treatment for osteoarthritis. Beside its analgesic and anti-inflammatory effects, some reports show neuro-protective properties for this agent in central nervous system. Several lines of evidence declare the involvement of COX or LOX isoenzymes in epileptic disorders. To set the foundation for future research into the neurobiology of licofelone as a potential therapeutic agent, we studied the effect of licofelone in an animal model of epilepsy. Although different neurotransmitters and neuro-modulators like nitric oxide were introduced as suggested targets of licofelone, the underlying mechanisms of central effects of this drug are not still fully understood. We have utilized pentylenetetrazole-induced clonic seizure model to investigate the behavioral consequences of licofelone administration and its possible mechanisms in seizure susceptibility. Licofelone revealed anticonvulsant properties at the dose of 10 mg/kg (i.p) or higher in mice. Pre-treatment with NO (nitric oxide) donor, L-arginine, reversed this anticonvulsant effects dose dependently. L-NAME, as a non-selective nitric oxide synthase (NOS) inhibitor, potentiated the anticonvulsant effects of licofelone. A neuronal NOS inhibitor, 7-NI did not affect seizure threshold alone or in combination with licofelone. Using non-effective doses of selective inhibitors of inducible NOS, aminoguanidine or 1400W, significantly increased the seizure threshold when were accompanied by licofelone in low doses. These data support the involvement of NO as an important role player in the central neuro-protective properties of licofelone. Furthermore, it implies that down regulation of iNOS seems crucial for anticonvulsant properties of this COX/5-LOX inhibitor in seizure susceptibility.
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http://dx.doi.org/10.1007/s11064-015-1669-zDOI Listing
September 2015

Synthesis and cytotoxic activity of novel poly-substituted imidazo[2,1-c][1,2,4]triazin-6-amines.

Mol Divers 2015 May 23;19(2):273-81. Epub 2015 Jan 23.

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

A novel series of 3,4-diphenyl-7-(hetero)arylimidazo[2,1-c][1,2,4]triazin-6-amine derivatives were synthesized via three-component reaction of 5,6-diphenyl-1,2,4-triazin-3-amine, various aromatic aldehydes, and cyclohexyl isocyanide. All synthesized compounds were tested against HL60 (human promyelocytic leukemia), MOLT-4 (human T lymphoblastic leukemia), and MCF-7 (human breast adenocarcinoma) cell lines, as cytotoxic agents. The structure-activity relationships study revealed that the introduction of hydroxyl and methoxy groups on the 7-phenyl ring can modulate the cytotoxic activity of these compounds. Among the 7-aryl derivatives, 3-hydroxyphenyl and 3-hydroxy-4-methoxyphenyl derivatives (6h and 6o) were the most potent compounds against HL60 and MCF-7 cells (IC(50s) = 9.8 - 20.4 μM). However, the replacement of the 7-aryl moiety with pyridyl or furan-2-yl resulted in compounds 6p or 6r with more promising cytotoxicity against MOLT-4 cell line (IC50 values 12.1 and 13.0 μM, respectively). Also, the acridine orange/ethidium bromide staining assay in MCF-7 cells suggested that the cytotoxic activity of compound 6r occurs via apoptosis.
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http://dx.doi.org/10.1007/s11030-015-9566-6DOI Listing
May 2015

Topical simvastatin enhances tissue regeneration in full-thickness skin wounds in rat models.

Iran J Pharm Res 2014 ;13(1):263-9

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

Wounds and wound healing have always been one of the most important subjects that experimental researches were dedicated to. Simvastatin has been used for long as a common lipid lowering agent which was reported to have some pleiotropic effects such as antioxidation, anti-inflammation and immunomodulation. In this study we aimed to determine the effect of simvastatin on wound healing process in laboratory rats by means of stereological and histopathological analyses. 36 male Sprague-Dawley rats (220 ± 20 g) with a 1 cm(2) circular full-thickness wound on their back were divided into three groups: SS group that received a gel with 2% concentration of simvastatin; UW group that received no treatment but daily irrigation with normal saline; Base group that was treated with the gel base. Duration of the study was 12 days and at the end, wound closure rate, grade of inflammation, granulation-tissue formation, ulceration, epithelization, fibroblast proliferation, collagen-bundles synthesis, and vascularization were determined. Outcome of this study revealed that Simvastatin improves the wound healing by its anti-inflammatory and epithelization induction effect as well as statistically significant induction of fibroblast proliferation and collagen bundle synthesis which were reported by our stereological and histopathological investigations. Results of the present study demonstrated that topical Simvastatin enhances the wound healing process through affecting different aspects of tissue regeneration; however, further researches are needed to find the exact mechanism, advantages and disadvantages of this chemical agent.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985244PMC
April 2014