Publications by authors named "Alireza Foroumadi"

236 Publications

Design, synthesis and biological assessment of new 1-benzyl-4-((4-oxoquinazolin-3(4)-yl)methyl) pyridin-1-ium derivatives (BOPs) as potential dual inhibitors of acetylcholinesterase and butyrylcholinesterase.

Heliyon 2021 Apr 8;7(4):e06683. Epub 2021 Apr 8.

Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.

Alzheimer's disease (AD), is among the most growing neurodegenerative diseases, which is mainly caused by the acetylcholine neurotransmitter loss in the hippocampus and cortex. Emerging of the dual Acetylcholinesterase (AChE)/Butyrylcholinesterase (BuChE) inhibitors has increased for treating Alzheimer disease. In this study, we would like to report the design and synthesis of a new sequence of 1-benzyl-4-((4-oxoquinazolin-3(4)-yl)methyl) pyridin-1-ium derivatives (BOPs) assessed as BuChE and AChE inhibitors. Ellman's approach was used for the evaluation of AChE and BuChE inhibitory activities. Moreover, docking research was conducted to predict the action mechanism. Among all synthesized compounds, 1-(3-bromobenzyl)-3-((4-oxoquinazolin-3(4)-yl)methyl) pyridin-1-ium bromide (BOP-1) was found to be the most active compound with dual activity for inhibition of AChE (IC = 5.90 ± 0.07μM), and BuChE (IC = 6.76 ± 0.04μM) and 1-(4-chlorobenzyl)-3-((6,7-dimethoxy-4-oxoquinazolin-3(4)-yl)methyl) pyridin-1-ium chloride (BOP-8) showed the highest AChE inhibitory activity (ICs = 1.11 ± 0.09 μM). The synthesized compounds BOP-1 and BOP-8 could be proposed as valuable lead compounds for further drug discovery development against AD.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045006PMC
April 2021

Chromone derivatives bearing pyridinium moiety as multi-target-directed ligands against Alzheimer's disease.

Bioorg Chem 2021 May 19;110:104750. Epub 2021 Feb 19.

Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14176, Iran; Biomaterials Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411, Iran. Electronic address:

A new serise of 7-hydroxy-chromone derivatives bearing pyridine moiety were synthesized, and evaluated as multifunctional agents against Alzheimer's disease (AD). Most of the compounds were good AChE inhibitors (IC = 9.8-0.71 µM) and showed remarkable BuChE inhibition activity (IC = 1.9-0.006 µM) compared with donepezil as the standard drug (IC = 0.023 and 3.4 µM). Compounds 14 and 10 showed the best inhibitory activity toward AChE (IC = 0.71 µM) and BuChE (IC = 0.006 µM), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 14 and 10 could bind effectively to the peripheral anionic binding site (PAS) of the AChE and BuChE through mixed-type inhibition. In addition, the most potent compounds showed acceptable neuroprotective activity on HO- and Aβ-induced .neurotoxicity in PC12 cells, more than standard drugs. The compounds could block effectively self- and AChE-induced Aβ aggregation. All the results suggest that compounds 14 and 10 could be considered as promising multi-target-directed ligands against AD.
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http://dx.doi.org/10.1016/j.bioorg.2021.104750DOI Listing
May 2021

The situation of small molecules targeting key proteins to combat SARS-CoV-2: Synthesis, metabolic pathway, mechanism of action, and potential therapeutic applications.

Mini Rev Med Chem 2021 Mar 8. Epub 2021 Mar 8.

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

Due to the global epidemic and high mortality of 2019 coronavirus disease (COVID-19), there is an immediate need to discover drugs that can help before a vaccine becomes available. Given that the process of producing new drugs is so long, the strategy of repurposing existing drugs is one of the promising options for the urgent treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19 disease. Although FDA has approved Remdesivir for the use in hospitalized adults and pediatric patients suffering from COVID-19, no fully effective and reliable drug has been yet identified worldwide to treat COVID-19 specifically. Thus, scientists are still trying to find antivirals specific to COVID-19. This work reviews the chemical structure, metabolic pathway, mechanism of action of existing drugs with potential therapeutic applications for COVID-19. Further, we summarized the molecular docking stimulation of the medications related to key protein targets. These already drugs could be developed for further clinical trials to supply suitable therapeutic options for patients suffering from COVID-19.
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http://dx.doi.org/10.2174/1389557521666210308144302DOI Listing
March 2021

Synthesis, in-vitro evaluation, molecular docking, and kinetic studies of pyridazine-triazole hybrid system as novel α-glucosidase inhibitors.

Bioorg Chem 2021 Apr 1;109:104670. Epub 2021 Feb 1.

Drug Design and Development Research Center, 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:

In this study, we reported the discovery of pyridazine based 1,2,3-triazole derivatives as inhibitors of α-glucosidase. All target compounds exhibited significant inhibitory activities against yeast and rat α-glucosidase enzymes compared to positive control, acarbose. The most potent compound 6j, ethyl 3-(2-(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)ethyl)-5,6-diphenylpyridazine-4-carboxylate exhibited IC values of 58, and 73 µM. Docking studies indicated the responsibility of hydrophobic and hydrogen bonding interactions in the ligand-enzyme complex stability. The in-vitro safety against the normal cell line was observed by toxicity evaluation of the selected compounds.
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http://dx.doi.org/10.1016/j.bioorg.2021.104670DOI Listing
April 2021

Corrigendum to "Design, synthesis and evaluation of novel thienopyrimidine-based agents bearing diaryl urea functionality as potential inhibitors of angiogenesis" [Eur. J. Med. Chem 209 (2021) 112942].

Eur J Med Chem 2021 Mar 4;214:113228. Epub 2021 Feb 4.

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

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http://dx.doi.org/10.1016/j.ejmech.2021.113228DOI Listing
March 2021

Chromone-lipoic acid conjugate: Neuroprotective agent having acceptable butyrylcholinesterase inhibition, antioxidant and copper-chelation activities.

Daru 2021 Jan 9. Epub 2021 Jan 9.

Biomaterials Group, Pharmaceutical Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran.

Purpose: Alzheimer's disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD.

Methods: Chromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD.

Results: The primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 μM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aβ aggregation and selectively chelate with copper ions in 2:1 M ratio.

Conclusion: Compound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aβ aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability. A new chromone-lipoic acid hybrid was synthesized as anti-Alzheimer agent with BuChE inhibitory activity, anti-Aβ aggregation, metal-chelation and antioxidant properties.
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http://dx.doi.org/10.1007/s40199-020-00378-1DOI Listing
January 2021

Quinazolin-4(3H)-one based agents bearing thiadiazole-urea: Synthesis and evaluation of anti-proliferative and antiangiogenic activity.

Bioorg Chem 2021 Mar 13;108:104553. Epub 2020 Dec 13.

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

A series of quinazolin-4(3H)-one based agents containing thiadiazole-urea were designed, synthesized, and biologically evaluated. The proliferation rate of PC3 cells was moderately reduced by compound 9f (IC = 17.7 μM)which was comparable with sorafenib (IC = 17.3 μM). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC = 6.1 μM). To test the potential of compounds in inducing apoptosis, Annexin V-FITC/propidium iodide double staining assay was used. After the treatment of HUVEC cells with 9f, they underwent apoptotic effects. A substantial effort was dedicated to gathering comprehensive data across CAM assay. These data showed that 9f moderately inhibits the growth of corresponding blood vessels. Finally, the outcomes of Western blotting proposed a mechanism of action, by which the phosphorylation of VEGFR-2 is inhibited by compounds 9f and 9y.
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http://dx.doi.org/10.1016/j.bioorg.2020.104553DOI Listing
March 2021

A biocompatible theranostic nanoplatform based on magnetic gadolinium-chelated polycyclodextrin: in vitro and in vivo studies.

Carbohydr Polym 2021 Feb 23;254:117262. Epub 2020 Oct 23.

Biomaterials Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran; Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14176, Iran. Electronic address:

A novel theranostic nanoplatform was prepared based on FeO nanoparticles (NPs) coated with gadolinium ions decorated-polycyclodextrin (PCD) layer (FeO@PCD-Gd) and employed for Curcumin (CUR) loading. The dissolution profile of CUR indicated a pH sensitive release manner. FeO@PCD-Gd NPs exhibited no significant toxicity against both normal and cancerous cell lines (MCF 10A and 4T1, respectively); while the CUR-free NPs showed more toxicity against 4T1 than MCF 10A cells. In vivo anticancer study revealed appropriate capability of the system in tumor shrinking with no tissue toxicity and adverse effect on body weight. In vivo MR imaging of BALB/c mouse showed both T and T contrast enhancement on the tumor cells. FeO@PCD-Gd/CUR NPs showed significant features as a promising multifunctional system having appropriate T-T dual contrast enhancement and therapeutic efficacy in cancer theranostics.
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http://dx.doi.org/10.1016/j.carbpol.2020.117262DOI Listing
February 2021

Mono- and bis-pyrazolophthalazines: Design, synthesis, cytotoxic activity, DNA/HSA binding and molecular docking studies.

Bioorg Med Chem 2021 01 24;30:115944. Epub 2020 Dec 24.

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

In an attempt to find new potent cytotoxic compounds, several mono- and bis-pyrazolophthalazines 4a-m and 6a-h were synthesized through an efficient, one-pot, three- and pseudo five-component synthetic approach. All derivatives were evaluated for their in vitro cytotoxic activities against four human cancer cell lines of A549, HepG2, MCF-7, and HT29. Compound 4e showed low toxicity against normal cell lines (MRC-5 and MCF 10A, IC > 200 µM) and excellent cytotoxic activity against A549 cell line with IC value of 1.25 ± 0.19 µM, which was 1.8 times more potent than doxorubicin (IC = 2.31 ± 0.13 µM). In addition, compound 6c exhibited remarkable cytotoxic activity against A549 and MCF-7 cell lines (IC = 1.35 ± 0.12 and 0.49 ± 0.01 µM, respectively), more than two-fold higher than that of doxorubicin. The binding properties of the best active mono- and bis-pyrazolophthalazine (4e and 6c) with HSA and DNA were fully evaluated by various techniques including UV-Vis absorption, circular dichroism (CD), Zeta potential and dynamic light scattering analyses indicating interaction of the compounds with the secondary structure of HSA and significant change of DNA conformation, presumably via a groove binding mechanism. Additionally, molecular docking and site-selective binding studies confirmed the fundamental interaction of compounds 4e and 6c with base pairs of DNA. Compounds 4e and 6c showed promising features to be considered as potential lead structures for further studies in cancer therapy.
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http://dx.doi.org/10.1016/j.bmc.2020.115944DOI Listing
January 2021

Design, synthesis and evaluation of novel thienopyrimidine-based agents bearing diaryl urea functionality as potential inhibitors of angiogenesis.

Eur J Med Chem 2021 Jan 15;209:112942. Epub 2020 Oct 15.

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

Inhibition of angiogenesis is a promising strategy for the treatment of cancer. Herein, we describe the design and synthesis of thieno[2,3-d]pyrimidine-1,3,4-thiadiazole-aryl urea derivatives 11a-m to evaluate their efficacy in the chick chorioallantoic membrane (CAM) assay. Among target agents, 11i had a considerable activity against prostate cancer cell line, PC3 (IC = 3.6 μM). Moreover, induction of apoptosis, good inhibitory activity against the growth of capillary blood vessels, and inhibition of VEGFR-2 phosphorylation were noticeable parameters which convinced us that 11i could be considered as a promising candidate for the discovery of novel drugs to treat tumors, particularly prostate cancer.
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http://dx.doi.org/10.1016/j.ejmech.2020.112942DOI Listing
January 2021

Magnetic carnosine-based metal-organic framework nanoparticles: fabrication, characterization and application as arsenic adsorbent.

J Environ Health Sci Eng 2020 Dec 16;18(2):1163-1174. Epub 2020 Sep 16.

Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

This study centers on the controllable synthesis, characterization, and application of a novel magnetic bio-metal-organic framework (Bio-MOF) for the adsorption and subsequent removal of arsenic from aqueous solutions. Zinc ions and carnosine (Car) were exploited to construct the Car-based MOF on the surface of magnetite (FeO NPs). The Magnetite precoating with Car led to an increase in the yield and the uniform formation of the magnetic MOF. The prepared magnetic Bio-MOF nanoparticles (FeO-Car-MOF NPs) had semi-spherical shape with the size in the range of 35-77 nm, and the crystalline pattern of both magnetite and Car-based MOF. The NPs were employed as an adsorbent for arsenic (As) removal. The adsorption analyses revealed that all studied independent variables including pH, adsorbent dose, and initial arsenic concentration had a significant effect on the arsenic adsorption, and the adsorption data were well matched to the quadratic model. The predicted adsorption values were close to the experimental values confirming the validity of the suggested model. Furthermore, adsorbent dose and pH had a positive effect on arsenic removal, whereas arsenic concentration had a negative effect. The adsorption isotherm and kinetic studies both revealed that As adsorption fitted best to the Freundlich isotherm model. The maximum monolayer adsorption capacity (94.33 mg/g) was achieved at room temperature, pH of 8.5 and adsorbent dose of 0.4 g/L. Finally, the results demonstrated that the adsorbent could be efficiently applied for arsenic removal from aqueous environment.
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http://dx.doi.org/10.1007/s40201-020-00535-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721956PMC
December 2020

A review: Biologically active 3,4-heterocycle-fused coumarins.

Eur J Med Chem 2021 Feb 25;212:113034. Epub 2020 Nov 25.

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

The combination of heterocycles offers a new opportunity to create novel multicyclic compounds having improved biological activity. Coumarins are ubiquitous natural heterocycle widely adopted in the design of various biologically active compounds. Fusing different heterocycles with coumarin ring is one of the interesting approaches to generating novel hybrid molecules having highlighted biological activities. In the efforts to develop heterocyclic-fused coumarins, a wide range of 3,4-heterocycle-fused coumarins have been introduced bearing outstanding biological activity. The effect of heterocycles annulation at 3,4-positions of coumarin ring on the biological activity of the target structures were discussed. This review focuses on the important progress of 3,4-heterocycle-fused coumarins providing better insight for medicinal chemists on the design and preparation of biologically active heterocycle-fused coumarins with a significant therapeutic effect in the future.
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http://dx.doi.org/10.1016/j.ejmech.2020.113034DOI Listing
February 2021

Design, synthesis, molecular docking study, and antibacterial evaluation of some new fluoroquinolone analogues bearing a quinazolinone moiety.

Daru 2020 Dec 8;28(2):661-672. Epub 2020 Oct 8.

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

Background: Increasing bacterial resistance to quinolones is concerning. Hence, the development of novel quinolones by chemical modifications to overcome quinolone resistance is an attractive perspective in this context.

Objective: In this study, it is aimed to design and synthesize a novel series of functionalized fluoroquinolones using ciprofloxacin and sarafloxacin cores by hybridization of quinazolinone derivatives. This objective was tested by a comprehensive set of in vitro antibacterial assays in addition to SAR (structure-activity relationship) characterisation studies.

Methods: A nucleophilic reaction of ciprofloxacin and sarafloxacin with 2-(chloromethyl)quinazolin-4(3H)-one in the presence of NaHCO in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by H, C- NMR and IR spectroscopy, MS and elemental analysis. In silico pharmacokinetics prediction assays and molecular docking studies were performed to explore the binding characteristics and interactions. Antibacterial activities of the novel compounds were evaluated by Broth microdilution, well diffusion and disc diffusion assays against three gram-positive (Methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus and Enterococcus faecalis) and three gram-negative bacteria (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli).

Results: The compounds exhibited moderate to good activities against gram-positive bacteria and weak to moderate activities against gram-negative bacteria. Amongst all ciprofloxacin-derivatives, compound 5d was the most potent agent with high antibacterial activity against gram-positive bacteria, including MRSA and S. aureus ((minimum inhibitory concentration (MIC) = 16 nM for both), that is 60 times more potent than ciprofloxacin as parent drug. Compound 5i from sarafloxacin-derivatives was the most potent compound against MRSA and S. aureus (MIC = 0.125 μM). Well diffusion and disk diffusion assay results demonstrated confirmatory outcomes for the quantitative broth microdilution assay. Molecular docking study results were in accordance with the results of antibacterial activity assays.

Conclusion: The results of the current study demonstrated that the novel ciprofloxacin and sarafloxacin derivatives synthesized here have promising antibacterial activities. Particularly, compounds 5d and 5i have potential for wider antibacterial applications following further analysis.
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http://dx.doi.org/10.1007/s40199-020-00373-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704824PMC
December 2020

Exogenous Ghrelin Could Not Ameliorate 3,4-methylenedioxymethamphetamine-induced Acute Liver Injury in The Rat: Involved Mechanisms.

Iran J Pharm Res 2020 ;19(1):343-354

Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is often abused by youth as a recreational drug. MDMA abuse is a growing problem in different parts of the world. An important adverse consequence of the drug consumption is hepatotoxicity of different intensities. However, the underlying mechanism of this toxicity has not been completely understood. Ghrelin is a gut hormone with growth hormone stimulatory effect. It expresses in liver, albeit at a much lower level than in stomach, and exerts a hepatoprotective effect. In this study, we investigated hepatotoxicity effect of MDMA alone and its combination with ghrelin as a hepatoprotective agent. MDMA and MDMA+ ghrelin could transiently increase serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) followed by tissue necrosis. However, they could significantly decrease liver tumor necrosis factor-a (TNF-±) in both treatment groups. Unexpectedly, in MDMA treated rats, Bax, Bcl-xl, Bcl-2, Fas, Fas ligand (Fas-L), caspase 8, cytochrome c, caspase 3 gene expression, and DNA fragmentation were nearly unchanged. In addition, apoptosis in MDMA+ ghrelin group was significantly reduced when compared with MDMA treated animals. In all, MDMA could transiently increase serum transaminases and induce tissue necrosis and liver toxicity. Ghrelin, however, could not stop liver enzyme rise and MDMA hepatotoxicity. MDMA hepatotoxicity seems to be mediated via tissue necrosis than apoptotic and inflammatory pathways. Conceivably, ghrelin as an anti-inflammatory and anti-apoptotic agent may not protect hepatocytes against MDMA liver toxicity.
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http://dx.doi.org/10.22037/ijpr.2020.1100940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462488PMC
January 2020

History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action.

Bioorg Chem 2020 11 28;104:104240. Epub 2020 Aug 28.

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

With the increasing risk of invasive and life threating fungal infections, there is now a great concern regarding the lower discovery rate of antifungal drugs in comparison to antimicrobial agents. Drugs conventionally used in clinics are not adequate enough to combat the increasing fungal infections, especially fungal forms resistant to fluconazole. Among the limited antifungal agents in clinics, azoles have the largest number of drug candidates in clinical trials and are partly marketed due to the particular focus of pharmaceutical companies and medicinal scientific centers. With the rise in the number of papers on azole antifungal design and discovery, a more in-depth understanding the most recent and authentic information about this class of drugs might be beneficial. To this end, we for the first time summarized the state-of-the-art information about azole drugs, with a specific focus on those in the pipelines of pharmaceutical companies, into four generations with regard to their structural similarity. More importantly, this review highlights information on the structure activity relationship (SAR), target description, hybrid antifungal agents as possible future generation, and other useful issues to streamline research towards designing new efficient azole antifungal structures in future.
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http://dx.doi.org/10.1016/j.bioorg.2020.104240DOI Listing
November 2020

Synthesis and radioligand-binding assay of 2,5-disubstituted thiadiazoles and evaluation of their anticonvulsant activities.

Arch Pharm (Weinheim) 2020 Dec 27;353(12):e2000066. Epub 2020 Aug 27.

Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.

In this study, a number of 2,5-disubstituted 1,3,4-thiadiazoles were synthesized using an appropriate synthetic route, and their anticonvulsant activity was determined by the maximal electroshock seizure (MES) test and their neurotoxicity was evaluated by the rotarod test. Additionally, their hypnotic activity was tested using the pentobarbital-induced sleep test. Compounds 7 (ED  = 1.14 and 2.72 μmol/kg in the MES and sleep tests, respectively) and 11 (ED  = 0.65 and 2.70 μmol/kg in the MES and sleep tests, respectively) were the most potent ones in the sleep test and anticonvulsant test, showing a comparable activity with diazepam as the reference drug. The results of in vivo studies, especially the antagonistic effects of flumazenil, and also the radioligand-binding assay confirmed the involvement of benzodiazepine (BZD) receptors in the anticonvulsant and hypnotic activity of compounds 7 and 11. Finally, the docking study of compound 11 in the BZD-binding site of the GABA (gamma-aminobutyric acid) receptor confirmed the possible binding of the compound to the BZD receptors. We concluded that the novel 1,3,4-thiadiazole derivatives with appropriate substitution at positions 2 and 5 of the heterocyclic ring had a good affinity to BZD receptors and showed significant efficacy in the pharmacological tests.
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http://dx.doi.org/10.1002/ardp.202000066DOI Listing
December 2020

Efficient synthesis, biological evaluation, and docking study of isatin based derivatives as caspase inhibitors.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1674-1684

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

ABTRACT In this paper, a new series of isatin-sulphonamide based derivatives were designed, synthesised and evaluated as caspase inhibitors. The compounds containing 1-(pyrrolidinyl)sulphonyl and 2-(phenoxymethyl)pyrrolidin-1-yl)sulphonyl substitution at C5 position of isatin core exhibited better results compared to unsubstituted derivatives. According to the results of caspase inhibitory activity, compound showed moderate inhibitory activity against caspase-3 and -7 compared to Ac-DEVD-CHO (IC = 0.016 ± 0.002 μM). Among the studied compounds, some active inhibitors with IC in the range of 2.33-116.91 μM were identified. The activity of compound was rationalised by the molecular modelling studies exhibiting the additional van der Waals interaction of N-phenylacetamide substitution along with efficacious T-shaped π-π and pi-cation interactions. The introduction of compound with good caspase inhibitory activity will help researchers to find more potent agents.
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http://dx.doi.org/10.1080/14756366.2020.1809388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470124PMC
December 2020

Design and synthesis of novel pyridazine N-aryl acetamides: In-vitro evaluation of α-glucosidase inhibition, docking, and kinetic studies.

Bioorg Chem 2020 09 6;102:104071. Epub 2020 Jul 6.

Drug Design and Development Research Center, 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:

We herein applied the four step-synthetic route to prepare the pyridazine core attached to the various N-aryl acetamides. By this approach, a new series of pyridazine-based compounds were synthesized, characterized and evaluated for their activities against α-glucosidase enzyme. In-vitro α-glucosidase assay established that twelve compounds are more potent than acarbose. Compound 7a inhibited α-glucosidase with the IC value of 70.1 µM. The most potent compounds showed no cytotoxicity against HDF cell line. Molecular docking and kinetic studies were performed to determine the modes of interaction and inhibition, respectively.
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http://dx.doi.org/10.1016/j.bioorg.2020.104071DOI Listing
September 2020

Evaluation of hepatic CYP2D1 activity and hepatic clearance in type I and type II diabetic rat models, before and after treatment with insulin and metformin.

Daru 2020 Dec 6;28(2):479-487. Epub 2020 May 6.

Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Conversion in the metabolism of drugs occurs in diabetes mellitus. Considering the importance of metabolic enzymes' activities on the efficacy and safety of medicines, the changes in liver enzymatic activity of CYP2D1 and its related hepatic clearance, by using Dextromethorphan as probe in the animal model of type I and type II diabetes, before and after treatment, was assessed in this study.

Methods: Male Wistar rats were randomly divided into 6 groups. Seven days after induction of diabetes type I and type II, treatment groups were received insulin and metformin daily for 14 days, respectively. In day 21, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing Dextromethorphan as CYP2D1 probe. Perfusate samples were analyzed by HPLC fluorescence method in order to evaluate any changes in CYP2D1 activity.

Results: The average metabolic ratio of dextromethorphan and hepatic clearance were changed from 0.012 ± 0.004 and 6.3 ± 0.1 in the control group to 0.006 ± 0.0008 and 5.2 ± 0.2 in the untreated type I diabetic group, and 0.008 ± 0.003 and 5.0 ± 0.6 in the untreated type II diabetic rats. Finally, the mean metabolic ratio and hepatic clearance were changed to 0.008 ± 0.001 and 5.4 ± 0.1, and 0.013 ± 0.003 and 6.1 ± 0.4 in the treated groups with insulin and metformin, respectively.

Conclusion: In type I diabetic rats, corresponding treatment could slightly improve enzyme activity, whereas the hepatic clearance and enzyme activity reached to the normal level in type II group. Graphical abstract .
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http://dx.doi.org/10.1007/s40199-020-00350-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704830PMC
December 2020

A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy.

Bioorg Chem 2020 06 2;99:103811. Epub 2020 Apr 2.

Drug Design and Development Research Center, 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:

The identification of molecular agents inhibiting specific functions in cancer cells progression is considered as one of the most successful plans in cancer treatment. The epidermal growth factor receptor (EGFR) over-activation is observed in a vast number of cancers, so, targeting EGFR and its downstream signaling cascades are regarded as a rational and valuable approach in cancer therapy. Several synthetic EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in recent years, mostly exhibited clinical efficacy in relevant models and categorized into first, second, third and fourth-generation. However, studies are still ongoing to find more efficient EGFR inhibitors in light of the resistance to the current inhibitors. In this review, the importance of targeting EGFR signaling pathway in cancer therapy and related epigenetic mutations are highlighted. The recent advances on the discovery and development of different EGFR inhibitors and the use of various therapeutic strategies such as multi-targeting agents and combination therapies have also been reviewed.
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http://dx.doi.org/10.1016/j.bioorg.2020.103811DOI Listing
June 2020

Novel 5-(nitrothiophene-2-yl)-1,3,4-Thiadiazole Derivatives: Synthesis and Antileishmanial Activity against promastigote stage of Leishmania major.

Iran J Pharm Res 2019 ;18(4):1816-1822

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

In this study, a series of novel compounds based on 5-(5-nitrothiophene-2-yl)-1,3,4-thiadiazole possessing (het) aryl thio pendant at C-2 position of thiadiazole ring is developed and evaluated as antileishmanial agents using MTT colorimetric assay. 10 New compounds containing aryl and heteroaryl derivatives, started from thiophene-2-carbaldehyde in five steps, were synthesized in good to excellent yields and characterized by H-NMR, C-NMR, and IR spectroscopy. Through the compounds , methylimidazole containing derivative was recognized as the most active compound against promastigotes exhibiting IC values of 11.2µg/mL and 7.1µg/mL after 24 and 48 h, respectively. This compound is > 4 fold more effective than Glucantime as a standard drug (IC = 50 µg/mL after 24 h and 25 µg/mL after 48 h).
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http://dx.doi.org/10.22037/ijpr.2019.14547.12476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059068PMC
January 2019

Bucladesine Attenuates Spatial Learning and Hippocampal Mitochondrial Impairments Induced by 3, 4-Methylenedioxymethamphetamine (MDMA).

Neurotox Res 2020 Jun 27;38(1):38-49. Epub 2020 Feb 27.

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

Neurotoxic effects of systemic administration of 3, 4- methylenedioxymethamphetamine (MDMA) has been attributed to MDMA and its metabolites. However, the role of the parent compound in MDMA-induced mitochondrial and memory impairment has not yet been investigated. Moreover, it is not yet studied that analogs of 3', 5'-cyclic adenosine monophosphate (cAMP) could decrease these neurotoxic effects of MDMA. We wished to investigate the effects of the central administration of MDMA on spatial memory and mitochondrial function as well as the effects of bucladesine, a membrane-permeable analog of cAMP, on these effects of MDMA. We assessed the effects of pre-training bilateral intrahippocampal infusion of MDMA (0.01, 0.1, 0.5, and 1 μg/side), bucladesine (10 and 100 μM) or combination of them on spatial memory, and different parameters of hippocampal mitochondrial function including the level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outer membrane damage, the amount of cytochrome c release as well as hippocampal ADP/ATP ratio. The results showed that MDMA caused spatial memory impairments as well as mitochondrial dysfunction as evidenced by the marked increase in hippocampal ADP/ATP ratio, ROS level, the collapse of MMP, mitochondrial swelling, and mitochondrial outer membrane damage leading to cytochrome c release from the mitochondria. The current study also found that bucladesine markedly reduced the destructive effects of MDMA. These results provide evidence of the role of the parent compound (MDMA) in MDMA-induced memory impairments through mitochondrial dysfunction. This study highlights the role of cAMP/PKA signaling in MDMA-induced memory and mitochondrial defects.
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http://dx.doi.org/10.1007/s12640-020-00183-3DOI Listing
June 2020

An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity.

Sci Rep 2020 02 13;10(1):2595. Epub 2020 Feb 13.

Department of Medicinal Chemistry, Faculty of Pharmacy and The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.

In an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones.
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http://dx.doi.org/10.1038/s41598-020-59079-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018746PMC
February 2020

Proton Pump Inhibitor-Treated H. pylori Adjust Cell Envelope Fatty Acid and Cholesterol Content to Survive.

Arch Iran Med 2020 01 1;23(1):7-14. Epub 2020 Jan 1.

Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: Proton pump inhibitors (PPIs) with lipophilic nature may interact with lipid components of H. pylori cell membrane, disrupting cell structure and viability. In this study, the effect of PPIs on fatty acid and cholesterol components of H. pylori cell membrane was assessed.

Methods: One H. pylori isolate was treated with 1X and 2X MICs (μg/mL) of lansoprazole (LPZ: 8 and 16) and pantoprazole (PAN: 128 and 256) in brain heart infusion broth plus serum. Treated H. pylori was cultured on brucella blood agar (BBA) and tetrazolium egg yolk agar (TEYA). Bacterial cells stained with Live/Dead kit were examined by fluorescent microscopy. Fatty acid and cholesterol contents of treated H. pylori were measured by gas chromatography.

Results: PPI-treated H. pylori did not grow on BBA but grew on TEYA. Fluorescent microscopy showed H. pylori stained red. Analyses showed high frequency of saturated fatty acids, C14:0, C16:0 and C18:0. Among unsaturated fatty acids, C18:1 and C18:2c were increased, while five were eliminated and five were synthesized de novo. Cholesteryl-6-O-tetradecanoyl-α-D- glucopyranoside was detected as the only glycosylated cholesterol in treated H. pylori. Growth of PPI-treated H. pylori on cholesterol-rich TEYA showed that occurrence of cholesterol can reverse the growth inhibition by PPIs. Red- bacilli form of H. pylori showed dye entry through damaged cell membrane without lysis.

Conclusion: Incorporation of lipophilic PPI into H. pylori cell membrane disrupted lipids and inhibited growth. However, H. pylori adjusted the defected membrane by replacing the lipid components and resisted lysis.
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January 2020

Design and synthesis of benzodiazepine-1,2,3-triazole hybrid derivatives as selective butyrylcholinesterase inhibitors.

Mol Divers 2020 Nov 17;24(4):997-1013. Epub 2019 Dec 17.

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

A new series of compounds based on benzodiazepine-1,2,3-triazole were synthesized and evaluated as cholinesterase inhibitors by Ellman's method. The compounds proved to be selective inhibitors of butyrylcholinesterase (BuChE) over acetylcholinesterase. The most potent compound was 3,3-dimethyl-11-(3-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one, identified as a submicromolar inhibitor of BuChE with IC value of 0.2 µM. In addition, the amyloid-β self-aggregation evaluation studies for selected compounds showed potent inhibitory effects compared to donepezil. The docking and cell viability studies supported the potential of compound 9b-6 as significant BuChE inhibitor.
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http://dx.doi.org/10.1007/s11030-019-10008-xDOI Listing
November 2020

6-Cinnamoyl-4-arylaminothienopyrimidines as highly potent cytotoxic agents: Design, synthesis and structure-activity relationship studies.

Eur J Med Chem 2020 Jan 18;185:111786. Epub 2019 Oct 18.

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

In this paper, we described the synthesis and cytotoxic activities of two new series of thieno[2,3-d]pyrimidine and thieno[3,2-d] pyrimidine derivatives. Most of the synthesized compounds had significant antiproliferative activities against PC3, MDA-MB-231, A549, and HeLa cell lines in comparison to the reference drug, erlotinib. Compounds N-(4-((3,5-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)cinnamamide 8e and (E)-N-(4-((3,4-dichlorophenyl)amino)thieno[2,3-d]pyrimidin-6-yl)-3-(4-methoxyphenyl)acrylamide 8g with IC values of 4 nM and 33 nM, respectively, against HeLa cell line were chosen for further studies. The apoptosis induced activity and cell cycle arrest were determined and the results provided evidence that these compounds induced cell death via apoptosis and arrested cell growth in sub-G1 phase. In addition, western blot analysis manifested the promising result of suppressing the EGFR signaling pathway (p-EGFR/p-ERK1/2). The docking studies appreciated the considerable potency of compound 8e based on hydrogen and covalent binding interactions. Eventually, in silico pharmacokinetic prediction indicated the acceptable bioavailability of all final compounds.
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http://dx.doi.org/10.1016/j.ejmech.2019.111786DOI Listing
January 2020

Folic acid decorated magnetic nanosponge: An efficient nanosystem for targeted curcumin delivery and magnetic resonance imaging.

J Colloid Interface Sci 2019 Nov 13;556:128-139. Epub 2019 Aug 13.

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

Magnetic drug delivery system is one of the most important strategies for cancer diagnosis and treatment. In this study, a novel theranostic system was fabricated based on cyclodextrin nanosponge (CDNS) polymer anchored on the surface of Magnetite nanoparticles (FeO/CDNS NPs) which was then decorated with folic acid (FA) as a targeting agent (FeO/CDNS-FA). Curcumin (CUR), a hydrophobic model drug, was next loaded into the cyclodextrin cavity and polymeric matrix of CDNS (FeO/CDNS-FA@CUR). The system was fully characterized. The in vitro release study revealed pH-sensitive behavior. Cytotoxicity assays indicated a negligible toxicity for CUR free FeO/CDNS-FA NPs against both of M109 cancerous cells and MCF 10A normal cells. CUR-loaded FeO/CDNS-FA NPs exhibited higher toxicity against M109 cancerous cells than MCF 10A normal cells (p < 0.05). FeO/CDNS-FA@CUR NPs resulted in much more cell viability on normal cells than pure CUR (p < 0.05). Moreover, blood compatibility study showed minor hemolytic activity. In vitro MRI studies illustrated negative signal increase in cells affirming acceptable diagnostic ability of the nanocarrier. The T MR signal intensity for FeO/CDNS-FA@CUR NPs in M109 cells was around 2-fold higher than that of MCF 10A cells. This implies two times higher selective cellular uptake of the FeO/CDNS-FA@CUR NPs into M109 cell compared to MCF 10A. The multifunctional nanocarrier could be considered as promising candidate for cancer theranostics because of the smart drug release, selective cytotoxicity, suitable hemocompatibility, and proper T MRI contrast efficiency.
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http://dx.doi.org/10.1016/j.jcis.2019.08.046DOI Listing
November 2019

In Vitro Interaction of Geldanamycin with Triazoles and Echinocandins Against Common and Emerging Candida Species.

Mycopathologia 2019 Oct 10;184(5):607-613. Epub 2019 Aug 10.

Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

The aim of this study was to determine the in vitro interactions of geldanamycin (Hsp90-inhibitor) with triazoles and echinocandins against common and emerging Candida species. Twenty clinically important Candida strains comprising C. auris, C. albicans, C. parapsilosis, and C. glabrata (each five strains) were included. In vitro interactions of geldanamycin with fluconazole, itraconazole, caspofungin and anidulafungin were determined using a checkerboard method. The results were interpreted as synergistic, indifferent and antagonistic based on the fractional inhibitory concentration index (FICI). In vitro combination of fluconazole with geldanamycin resulted in synergistic effect against C. albicans (100%), C. glabrata (80%) and C. parapsilosis (80%) (FICI range 0.009-0.5), while indifferent interactions were obtained against C. auris (FICI range 1.5-2). The overall minimum inhibitory concentration (MIC) range of fluconazole against C. albicans, C. glabrata and C. parapsilosis reduced from 16-256 to 0.25-64 mg/L when combined with geldanamycin. Regarding the synergistic effect of geldanamycin with itraconazole against all strains of C. albicans, C. glabrata and C. parapsilosis (FICI range 0.009-0.375), the MIC range of this antifungal was reduced from 0.125-32 mg/L when tested alone, to 0.03-1 mg/L. Combinations of geldanamycin with fluconazole and itraconazole against C. auris, as well as combination of geldanamycin with caspofungin and anidulafungin against all studied Candida species, resulted in indifferent effects. No antagonism was observed. Simultaneous targeting of Hsp90 and lanosterol 14-α demethylase seems an effective approach against C. albicans, C. glabrata and C. parapsilosis. However, this combination is ineffective against the emerging pathogen C. auris.
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http://dx.doi.org/10.1007/s11046-019-00370-7DOI Listing
October 2019

New classes of carbazoles as potential multi-functional anti-Alzheimer's agents.

Bioorg Chem 2019 10 29;91:103164. Epub 2019 Jul 29.

The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, 1417614411, Iran. Electronic address:

Multi-Target approach is particularly promising way to drug discovery against Alzheimer's disease. In the present study, we synthesized a series of compounds comprising the carbazole backbone linked to the benzyl piperazine, benzyl piperidine, pyridine, quinoline, or isoquinoline moiety through an aliphatic linker and evaluated as cholinesterase inhibitors. The synthesized compounds showed IC values of 0.11-36.5 µM and 0.02-98.6 µM against acetyl- and butyrylcholinesterase (AChE and BuChE), respectively. The ligand-protein docking simulations and kinetic studies revealed that compound 3s could bind effectively to the peripheral anionic binding site (PAS) and anionic site of the enzyme with mixed-type inhibition. Compound 3s was the most potent compound against AChE and BuChE and showed acceptable inhibition potency for self- and AChE-induced Aβ aggregation. Moreover, compound 3s could significantly protect PC12 cells against HO-induced toxicity. The results suggested that the compounds 3s could be considered as a promising multi-functional agent for further drug discovery development against Alzheimer's disease.
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http://dx.doi.org/10.1016/j.bioorg.2019.103164DOI Listing
October 2019

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