24 results on '"Toolabi M"'
Search Results
2. Guidelines for selecting the dimensions of adhesively bonded end-loaded split joints: An approach based on numerical cohesive zone length
- Author
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Toolabi, M. and Blackman, B.R.K.
- Published
- 2018
- Full Text
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3. Enhanced mixed interpolation XFEM formulations for discontinuous Timoshenko beam and Mindlin-Reissner plate
- Author
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Toolabi, M., primary, Fallah, A.S., additional, Baiz, P.M., additional, and Louca, L.A., additional
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- 2018
- Full Text
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4. Dynamic analysis of a viscoelastic orthotropic cracked body using the extended finite element method
- Author
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Toolabi, M., primary, Fallah, A.S., additional, Baiz, P.M., additional, and Louca, L.A., additional
- Published
- 2013
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5. Allergic and nonallergic asthma in children: Are they distinct phenotypes?
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Mahdaviani, S. A., Mohajerani, S. A., Fakhri, M., Ebrahimi, M., Bashardoost, B., Razavi, S. J., Toolabi, M., Tajik, A., Khalilzadeh, S., and Mohammadreza Masjedi
- Subjects
Male ,Adolescent ,lcsh:R ,Age Factors ,lcsh:Medicine ,Asthma ,Cross-Sectional Studies ,Sex Factors ,Allergic ,Phenotype ,Non allergic ,Humans ,Female ,Child ,Children - Abstract
The aim of current study is to describe clinical similarities and differences between atopic and non-atopic asthma in children. In a cross-sectional study, 95 asthmatic children (75 allergics and 20 nonallergics) were included in the study. Demographic, clinical, and familial history were compared between two groups. There was no significant differences between variables like sex, age of onset (p=0.75), severity (p=0.70), and family history among the two groups (p=0.42). Patients with allergic asthma were significantly older than those with non- allergic asthma (11.28 ± 3.19 and 9.75 ± 2.35 years, respectively, p=0.02). The controversy lingers over the presence of a completely distinct phenotype of non-atopic asthma in children. Our study suggested that phenotypes of allergic and non-allergic asthma in children were not entirely distinct.
6. Synthesis of novel 3,4-dihydropyrimidine derivatives, cytotoxic activity evaluation, Apoptosis, Molecular docking studies, and MD simulations.
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Mortazavi SF, Ebadi A, Mohammadian MN, Mojaddami A, and Toolabi M
- Abstract
In this study, twelve 3,4-dihydropyrimidines derivatives were synthesized through Biginelli multi-component reaction. The efficacy of these compounds against MCF-7, A549, and HeLa cells was evaluated using the MTT method. The results showed that designed derivatives were more effective against A549 cancer cells than MCF-7 and HeLa cells. Compound 5l (bearing 4-Cl-phenyl at C4 of 3, 4-dihydropyrimidin-2(1H)-one ring) was the most potent analogue (A549: 18.65±1.87μM, HeLa: 26.59±2.71 μM, MCF-7: 31.82±2.64 μM). The presence of an electron-withdrawing group with optimum lipophilicity at the C4 position of the phenyl ring increased the cytotoxic effect. The flow cytometry findings indicated that compound 5l induced apoptosis in A549 cancer cells in a dose-dependent manner. Eg5 and AKT1 were selected as molecular modeling target by applying pharmacology network analyses. The molecular docking results indicated that both enantiomers of compound 5l had significant interactions with key residues in both Eg5 (Gly117 and Glu116) and AKT1 (Ala123 and Glu121) active sites. However, MD simulation revealed that the R enantiomer had a more stable complex and a higher binding affinity to the Eg5 enzyme active site than the S-enantiomer. The affinity of 5l (R enantiomer) to Eg5 was predicted more than AKT1., (© 2024 Wiley‐VCH GmbH.)
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- 2024
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7. Anti-Nociceptive Effect of Sufentanil Polymeric Dissolving Microneedle on Male Mice by Hot Plate Technique
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Pourmansouri Z, Malekkhatabi A, Toolabi M, Akbari M, Shahbazi MA, and Rostami A
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- Animals, Male, Mice, Polymers chemistry, Analgesics administration & dosage, Analgesics pharmacology, Pain drug therapy, Hot Temperature, Drug Liberation, Drug Delivery Systems methods, Drug Delivery Systems instrumentation, Solubility, Sufentanil administration & dosage, Sufentanil pharmacokinetics, Needles
- Abstract
Background: Despite the widespread use of opioids to manage severe pain, its systemic administration results in side effects. Among the subcutaneous and transdermal drug delivery systems developed to deal with adverse effects, microneedles have drawn attention due to their rapid action, high drug bioavailability, and improved permeability. Sufentanil (SUF) is an effective injectable opioid for treating severe pain. In this study, we investigated the analgesic effects of SUF using dissolvable microneedles., Methods: SUF polymeric dissolvable microneedles were constructed through the mold casting method and characterized by SEM and FTIR analysis. Its mechanical strength was also investigated using a texture analyzer. Fluorescence microscopy was applied in vitro to measure the penetration depth of microneedle arrays. Irritation and microchannel closure time, drug release profile, and hemocompatibility test were conducted for the validation of microneedle efficiency. Hot plate test was also used to investigate the analgesic effect of microneedle in an animal model., Results: Local administration of SUF via dissolving microneedles had an effective analgesic impact. One hour after administration, there was no significant difference between the subcutaneous and the microneedle groups, and the mechanical properties were within acceptable limits., Conclusion: Microneedling is an effective strategy in immediate pain relief compared to the traditional methods.
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- 2024
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8. Synthesis, biological activities, and molecular docking studies of triazolo[4,3-b]triazine derivatives as a novel class of α-glucosidase and α-amylase inhibitors.
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Seyfi S, Salarinejad S, Moghimi S, Toolabi M, Sadeghian N, Tüzün B, Firoozpour L, Ketabforoosh SHME, Taslimi P, and Foroumadi A
- Subjects
- Structure-Activity Relationship, Molecular Structure, Dose-Response Relationship, Drug, Humans, Triazoles pharmacology, Triazoles chemistry, Triazoles chemical synthesis, Molecular Docking Simulation, Glycoside Hydrolase Inhibitors pharmacology, Glycoside Hydrolase Inhibitors chemical synthesis, Glycoside Hydrolase Inhibitors chemistry, alpha-Amylases antagonists & inhibitors, alpha-Amylases metabolism, alpha-Glucosidases metabolism, Triazines pharmacology, Triazines chemical synthesis, Triazines chemistry
- Abstract
In diabetes mellitus, amylase and glucosidase enzymes are the primary triggers. The main function of these enzymes is to break macromolecules into simple sugar units, which directly affect blood sugar levels by increasing blood permeability. To overcome this metabolic effect, there is a need for a potent and effective inhibitor capable of suppressing the enzymatic conversion of sugar macromolecules into their smaller units. Herein, we reported the discovery of a series of substituted triazolo[4,3-b][1,2,4]triazine derivatives as α-glucosidase and α-amylase inhibitors. All target compounds demonstrated significant inhibitory activities against α-glucosidase and α-amylase enzymes compared with acarbose as the positive control. The most potent compound 10k, 2-[(6-phenyl-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)thio]-N-[4-(trifluoromethyl)phenyl]acetamide, demonstrated IC
50 values of 31.87 and 24.64 nM against α-glucosidase and α-amylase enzymes, respectively. To study their mechanism of action, kinetic studies were also done, which determined the mode of inhibition of both enzymes. Molecular docking was used to confirm the binding interactions of the most active compounds., (© 2024 Deutsche Pharmazeutische Gesellschaft.)- Published
- 2024
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9. Design, synthesis, and biological evaluation of new biaryl derivatives of cycloalkyl diacetamide bearing chalcone moiety as type II c-MET kinase inhibitors.
- Author
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Salarinejad S, Seyfi S, Hayashi S, Moghimi S, Toolabi M, Taslimi P, Firoozpour L, Usui T, and Foroumadi A
- Abstract
Many human cancers have been associated with the deregulation of the mesenchymal-epithelial transition factor tyrosine kinase (MET) receptor, a promising drug target for anticancer drug discovery. Herein, we report the discovery of a novel structure of potent chalcone-based derivatives type II c-Met inhibitors which are comparable to Foretinib (IC
50 = 14 nM) as a potent reference drug. Based on our design strategy, we also expected an anti-tubulin activity for the compounds. However, the weak inhibitory effects on microtubules were confirmed by cell cycle analyses implicated that the observed cytotoxicity against HeLa cells probably was not derived from tubulin inhibition. Compounds 14q and 14k with IC50 values of 24 nM and 45 nM, respectively, demonstrated favorable inhibition of MET kinase activity, and desirable bonding interactions in the ligand-MET enzyme complex stability in molecular docking studies., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)- Published
- 2024
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10. Synthesis, α-Glucosidase inhibitory activity and docking studies of Novel Ethyl 1,2,3-triazol-4-ylmethylthio-5,6-diphenylpyridazine-4-carboxylate derivatives.
- Author
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Firoozpour L, Moghimi S, Salarinejad S, Toolabi M, Rafsanjani M, Pakrad R, Salmani F, Shokrolahi SM, Sadat Ebrahimi SE, Karima S, and Foroumadi A
- Abstract
In this work, a novel series of pyridazine-triazole hybrid molecules were prepared and evaluated as inhibitors of rat intestinal α-glucosidase enzyme. Amongst all newly synthesized compounds, 10k showed good inhibition in the series with IC
50 value of 1.7 µM which is 100 folds stronger than positive control, acarbose. The cytotoxicity revealed that this compound is not toxic against normal cell line, HDF. The docking studies showed that triazole ring plays an important role in the binding interactions with the active site. The insertion of compound 10k into the active pocket of α-glucosidase and formation of hydrogen bonds with Leu677 was observed from docking studies. The kinetic studies revealed that this compound has uncompetitive mode of inhibition against α-glucosidase enzyme., (© 2023. The Author(s).)- Published
- 2023
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11. Imidazo[1,2-a]quinazolines as novel, potent EGFR-TK inhibitors: Design, synthesis, bioactivity evaluation, and in silico studies.
- Author
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Hasanvand Z, Oghabi Bakhshaiesh T, Peytam F, Firoozpour L, Hosseinzadeh E, Motahari R, Moghimi S, Nazeri E, Toolabi M, Momeni F, Bijanzadeh H, Khalaj A, Baratte B, Josselin B, Robert T, Bach S, Esmaeili R, and Foroumadi A
- Subjects
- Oxygen Isotopes pharmacology, Molecular Docking Simulation, Cell Line, Tumor, Drug Screening Assays, Antitumor, ErbB Receptors, Structure-Activity Relationship, Cell Proliferation, Protein Kinase Inhibitors, Quinazolines pharmacology, Antineoplastic Agents
- Abstract
Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo[1,2-a]quinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o, in particular) had great anti-proliferative activities with IC
50 values in the micromolar (µM) range against PC3, HepG2, HeLa, and MDA-MB-231 comparing with Erlotinib as reference marketed drug. Further evaluations on some derivatives revealed their potential to induce apoptotic cell death and cell growth arrest at G0 phase of the cell cycle. Afterwards, the kinase assay on the most potent compounds 18a and 18o demonstrated their inhibitory potencies and selectivity toward EGFR (with EGFR-IC50 values of 82.0 µM and 12.3 µM, respectively). Additionally, western blot analysis on these compounds 18a and 18o exhibited that they inhibited the phosphorylation of EGFR and its downstream molecule extracellular signal-regulated kinase (ERK1/2). However, the level of B-Actin phosphorylation was not changed. Finally, density functional theory calculations, docking study, and independent gradient model (IGM) were performed to illustrate the structure-activity relationship (SAR) and to assess the interactions between proteins and ligands. The results of molecular docking studies had great agreement with the obtained EGFR inhibitory results through in vitro evaluations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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12. Multifunctional Self-Assembled Peptide Hydrogels for Biomedical Applications.
- Author
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Sedighi M, Shrestha N, Mahmoudi Z, Khademi Z, Ghasempour A, Dehghan H, Talebi SF, Toolabi M, Préat V, Chen B, Guo X, and Shahbazi MA
- Abstract
Self-assembly is a growth mechanism in nature to apply local interactions forming a minimum energy structure. Currently, self-assembled materials are considered for biomedical applications due to their pleasant features, including scalability, versatility, simplicity, and inexpensiveness. Self-assembled peptides can be applied to design and fabricate different structures, such as micelles, hydrogels, and vesicles, by diverse physical interactions between specific building blocks. Among them, bioactivity, biocompatibility, and biodegradability of peptide hydrogels have introduced them as versatile platforms in biomedical applications, such as drug delivery, tissue engineering, biosensing, and treating different diseases. Moreover, peptides are capable of mimicking the microenvironment of natural tissues and responding to internal and external stimuli for triggered drug release. In the current review, the unique characteristics of peptide hydrogels and recent advances in their design, fabrication, as well as chemical, physical, and biological properties are presented. Additionally, recent developments of these biomaterials are discussed with a particular focus on their biomedical applications in targeted drug delivery and gene delivery, stem cell therapy, cancer therapy and immune regulation, bioimaging, and regenerative medicine.
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- 2023
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13. Synthesis of novel 2-acetamide-5-phenylthio-1,3,4-thiadiazole-containing phenyl urea derivatives as potential VEGFR-2 inhibitors.
- Author
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Toolabi M, Safari F, Ayati A, Fathi P, Moghimi S, Salarinejad S, Foroumadi R, Ketabforoosh SHME, and Foroumadi A
- Subjects
- Acetamides pharmacology, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Protein Kinase Inhibitors pharmacology, Structure-Activity Relationship, Thiadiazoles, Urea pharmacology, Vascular Endothelial Growth Factor A pharmacology, Antineoplastic Agents pharmacology, Vascular Endothelial Growth Factor Receptor-2
- Abstract
A novel series of 2-acetamide-5-phenylthio-1,3,4-thiadiazol derivatives containing a phenyl urea warhead were synthesized and evaluated as antiproliferative agents. The cytotoxic activities of the newly synthesized compounds were evaluated toward three human cancer cell lines, including HT-29, A431, and PC3, as well as normal HDF cells, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The biological results revealed the highest degree of cytotoxic effects for the 4-chloro-containing compound 9e against the A431 cell line. Further assessment by Western blot analysis assay confirmed the induction of apoptosis by compound 9e, with upregulation of Bax and downregulation of Bcl-2 proteins in A431 cancer cells. In addition, compound 9e inhibited the phosphorylation of vascular endothelial growth factor and its receptor (VEGFR-2) in A431 cancer cells while the total level of actin protein was unchanged. These results were confirmed by a three-dimensional cell culture method using the hanging drop technique., (© 2022 Deutsche Pharmazeutische Gesellschaft.)
- Published
- 2022
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14. Pyrimidine-based EGFR TK inhibitors in targeted cancer therapy.
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Ayati A, Moghimi S, Toolabi M, and Foroumadi A
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- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Humans, Molecular Structure, Neoplasms metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrimidines chemical synthesis, Pyrimidines chemistry, Antineoplastic Agents pharmacology, Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology
- Abstract
Despite significant improvements of new treatment options, cancer continues to represent as one of the most common and fatal disease. The EGFR signaling pathway is considered as a significant approach in targeted therapy of cancers. Blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR have shown considerable improvement in cancer therapy. In an effort to identify EGFR tyrosine kinase inhibitors (TKI), several small molecules especially pyrimidine containing derivatives have been designed by applying molecular simulation and evaluated the emergence of epigenetic mutation and resistance problems restricted the long-term effectiveness of such medication and explained the need for further investigations in this field. In recent years, the studies have been focused on genetic alterations on EGFR tyrosine kinase domain, which led to the design and synthesis of more selective and effective inhibitors. Herein, we give an overview of the importance and status of EGFR inhibitors in cancer therapy. In addition, we provide an update of the recent advances in design, discovery and development of novel pyrimidine containing compounds as promising selective EGFR TK inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2021
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15. Synthesis, in-vitro evaluation, molecular docking, and kinetic studies of pyridazine-triazole hybrid system as novel α-glucosidase inhibitors.
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Moghimi S, Salarinejad S, Toolabi M, Firoozpour L, Esmaeil Sadat Ebrahimi S, Safari F, Madani-Qamsari F, Mojtabavi S, Faramarzi MA, Karima S, Pakrad R, and Foroumadi A
- Subjects
- Binding Sites, Cell Line, Drug Design, Glycoside Hydrolase Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Protein Binding, Protein Conformation, Pyridazines chemistry, Saccharomyces cerevisiae enzymology, Structure-Activity Relationship, Triazoles chemistry, alpha-Glucosidases metabolism, Pyridazines pharmacology, Triazoles pharmacology
- Abstract
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
50 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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16. Quinazolin-4(3H)-one based agents bearing thiadiazole-urea: Synthesis and evaluation of anti-proliferative and antiangiogenic activity.
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Faraji A, Motahari R, Hasanvand Z, Oghabi Bakhshaiesh T, Toolabi M, Moghimi S, Firoozpour L, Boshagh MA, Rahmani R, Ketabforoosh SHME, Bijanzadeh HR, Esmaeili R, and Foroumadi A
- Subjects
- Angiogenesis Inhibitors chemical synthesis, Angiogenesis Inhibitors chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Quinazolinones chemical synthesis, Quinazolinones chemistry, Structure-Activity Relationship, Thiadiazoles chemistry, Urea chemistry, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, Quinazolinones pharmacology, Thiadiazoles pharmacology, Urea pharmacology
- Abstract
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
50 = 17.7 μM)which was comparable with sorafenib (IC50 = 17.3 μM). There was also a significant reduction in the number of HUVEC cells, when they were exposed to compound 9y (IC50 = 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2021
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17. 5-[Aryloxypyridyl (or nitrophenyl)]-4H-1,2,4-triazoles as novel flexible benzodiazepine analogues: Synthesis, receptor binding affinity and lipophilicity-dependent anti-seizure onset of action.
- Author
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Navidpour L, Shabani S, Heidari A, Bashiri M, Ebrahim-Habibi A, Shahhosseini S, Shafaroodi H, Abbas Tabatabai S, and Toolabi M
- Subjects
- Animals, Anticonvulsants chemical synthesis, Anticonvulsants chemistry, Benzodiazepines chemical synthesis, Benzodiazepines chemistry, Binding, Competitive drug effects, Dose-Response Relationship, Drug, Hydrophobic and Hydrophilic Interactions, Male, Molecular Structure, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Anticonvulsants pharmacology, Benzodiazepines pharmacology, Receptors, GABA-A chemistry, Seizures drug therapy, Triazoles pharmacology
- Abstract
A new series of 5-(2-aryloxy-4-nitrophenyl)-4H-1,2,4-triazoles and 5-(2-aryloxy-3-pyridyl)-4H-1,2,4-triazoles, possessing C-3 thio or alkylthio substituents, was synthesized and evaluated for their benzodiazepine receptor affinity and anti-seizure activity. These analogues revealed similar to significantly superior affinity to GABA
A /benzodiazepine receptor complex (IC50 values of 0.04-4.1 nM), relative to diazepam as the reference drug (IC50 value of 2.4 nM). To determine the onset of anti-seizure activity, the time-dependent effectiveness of i.p. administration of compounds on pentylenetetrazole induced seizure threshold was studied and a very good relationship was observed between the lipophilicity (cLogP) and onset of action of studied analogues (r2 = 0.964). The minimum effective dose of the compounds, determined at the time the analogues showed their highest activity, was demonstrated to be 0.025-0.1 mg/kg, relative to diazepam (0.025 mg/kg)., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2021
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18. Synthesis and radioligand-binding assay of 2,5-disubstituted thiadiazoles and evaluation of their anticonvulsant activities.
- Author
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Toolabi M, Khoramjouy M, Aghcheli A, Ayati A, Moghimi S, Firoozpour L, Shahhosseini S, Shojaei R, Asadipour A, Divsalar K, Faizi M, and Foroumadi A
- Subjects
- Animals, Anticonvulsants chemical synthesis, Anticonvulsants metabolism, Anticonvulsants toxicity, Binding Sites, Disease Models, Animal, Drug Design, Electric Stimulation, Hypnotics and Sedatives chemical synthesis, Hypnotics and Sedatives metabolism, Hypnotics and Sedatives toxicity, Male, Mice, Molecular Docking Simulation, Molecular Structure, Motor Activity drug effects, Protein Binding, Radioligand Assay, Receptors, GABA-A metabolism, Rotarod Performance Test, Seizures metabolism, Seizures physiopathology, Structure-Activity Relationship, Thiadiazoles chemical synthesis, Thiadiazoles toxicity, Anticonvulsants pharmacology, Hypnotics and Sedatives pharmacology, Receptors, GABA-A drug effects, Seizures prevention & control, Sleep drug effects, Thiadiazoles pharmacology
- Abstract
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
50 = 1.14 and 2.72 μmol/kg in the MES and sleep tests, respectively) and 11 (ED50 = 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 GABAA (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., (© 2020 Deutsche Pharmazeutische Gesellschaft.)- Published
- 2020
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19. Design, synthesis, molecular docking study, and antibacterial evaluation of some new fluoroquinolone analogues bearing a quinazolinone moiety.
- Author
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Norouzbahari M, Salarinejad S, Güran M, Şanlıtürk G, Emamgholipour Z, Bijanzadeh HR, Toolabi M, and Foroumadi A
- Subjects
- Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Ciprofloxacin analogs & derivatives, Ciprofloxacin chemistry, Fluoroquinolones chemistry, Fluoroquinolones pharmacology, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Anti-Bacterial Agents chemical synthesis, Fluoroquinolones chemical synthesis, Gram-Negative Bacteria drug effects, Gram-Positive Bacteria drug effects, Quinazolinones chemistry
- Abstract
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
3 in dimethylformamide (DMF) was performed to obtain the desired compounds 5a-j. Novel compounds were characterised by1 H,13 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.- Published
- 2020
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20. Design and synthesis of benzodiazepine-1,2,3-triazole hybrid derivatives as selective butyrylcholinesterase inhibitors.
- Author
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Mehrazar M, Hassankalhori M, Toolabi M, Goli F, Moghimi S, Nadri H, Bukhari SNA, Firoozpour L, and Foroumadi A
- Subjects
- Acetylcholinesterase metabolism, Drug Design, Molecular Docking Simulation, Structure-Activity Relationship, Benzodiazepines chemistry, Butyrylcholinesterase metabolism, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors chemistry, Triazoles chemistry
- Abstract
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
50 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.- Published
- 2020
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21. Design and synthesis of novel pyridazine N-aryl acetamides: In-vitro evaluation of α-glucosidase inhibition, docking, and kinetic studies.
- Author
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Moghimi S, Toolabi M, Salarinejad S, Firoozpour L, Sadat Ebrahimi SE, Safari F, Mojtabavi S, Faramarzi MA, and Foroumadi A
- Subjects
- Acetamides pharmacology, Drug Design, Glycoside Hydrolase Inhibitors pharmacology, Humans, Kinetics, Molecular Structure, Structure-Activity Relationship, Acetamides therapeutic use, Glycoside Hydrolase Inhibitors chemical synthesis, Glycoside Hydrolase Inhibitors therapeutic use, Molecular Docking Simulation methods, alpha-Glucosidases metabolism
- Abstract
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
50 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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22. 6-Cinnamoyl-4-arylaminothienopyrimidines as highly potent cytotoxic agents: Design, synthesis and structure-activity relationship studies.
- Author
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Toolabi M, Moghimi S, Bakhshaiesh TO, Salarinejad S, Aghcheli A, Hasanvand Z, Nazeri E, Khalaj A, Esmaeili R, and Foroumadi A
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Cycle drug effects, Cell Line, Tumor, Cinnamates chemical synthesis, Cinnamates chemistry, Cytotoxins chemical synthesis, Cytotoxins chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Docking Simulation, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Cinnamates pharmacology, Cytotoxins pharmacology, Drug Design, Pyrimidines pharmacology
- Abstract
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
50 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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
23. 2-(Bipiperidin-1-yl)-5-(nitroaryl)-1,3,4-thiadiazoles: Synthesis, evaluation of in vitro leishmanicidal activity, and mechanism of action.
- Author
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Mojallal-Tabatabaei Z, Foroumadi P, Toolabi M, Goli F, Moghimi S, Kaboudanian-Ardestani S, and Foroumadi A
- Subjects
- Antiprotozoal Agents pharmacology, Molecular Structure, Structure-Activity Relationship, Thiadiazoles pharmacology, Antiprotozoal Agents chemical synthesis, Antiprotozoal Agents therapeutic use, Leishmania major drug effects, Thiadiazoles chemical synthesis, Thiadiazoles therapeutic use
- Abstract
The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4'-bipiperidin]-1'-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (IIc) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of L. major cells to IIa and IIc led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of IIa and IIc is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
24. Allergic and nonallergic asthma in children: are they distinct phenotypes?
- Author
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Mahdaviani SA, Mohajerani SA, Fakhri M, Ebrahimi M, Bashardoost B, Razavi SJ, Toolabi M, Tajik A, Khalilzadeh S, and Masjedi MR
- Subjects
- Adolescent, Age Factors, Child, Cross-Sectional Studies, Female, Humans, Male, Sex Factors, Asthma epidemiology, Phenotype
- Abstract
The aim of current study is to describe clinical similarities and differences between atopic and non-atopic asthma in children. In a cross-sectional study, 95 asthmatic children (75 allergics and 20 nonallergics) were included in the study. Demographic, clinical, and familial history were compared between two groups. There was no significant differences between variables like sex, age of onset (p=0.75), severity (p=0.70), and family history among the two groups (p=0.42). Patients with allergic asthma were significantly older than those with non- allergic asthma (11.28 ± 3.19 and 9.75 ± 2.35 years, respectively, p=0.02). The controversy lingers over the presence of a completely distinct phenotype of non-atopic asthma in children. Our study suggested that phenotypes of allergic and non-allergic asthma in children were not entirely distinct.
- Published
- 2014
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