Publications by authors named "Nadjet Rezki"

21 Publications

  • Page 1 of 1

Design of molecular hybrids of phthalimide-triazole agents with potent selective MCF-7/HepG2 cytotoxicity: Synthesis, EGFR inhibitory effect, and metabolic stability.

Bioorg Chem 2021 Jun 22;111:104835. Epub 2021 Mar 22.

Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 11884 Nasr City, Cairo, Egypt.

This study reports an efficient and convenient click chemistry synthesis of a novel series of phthalimide scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of newly synthesized compounds were well characterized by different spectroscopic tools. In vitro MTT cytotoxicity assay was performed comparing the cytotoxic effects of newly synthesized compounds to staurosporine using three different types: human liver cancer cell line (HepG2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). The initial screening showed excellent to moderate anticancer activity for these newly synthesized compounds with high degree of cell line selectivity with micromolar (µM) half maximal inhibitory concentration (IC) values against tumor cells. The SAR analysis of these derivatives confirmed the role of molecular fragments including phthalimide, linker, triazole, and terminal tails in correlation to activity. In addition, enzymatic inhibitory assay against wild type EGFR was performed for the most active compounds to get more details about their mechanism of action. In order to further explore their binding affinities, molecular docking simulation was studied against EGFR site. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. One of the most prominent analogs is (6f) with terminal disubstituted ring and amide linker showed selective MCF-7 cytotoxicity profile with IC 0.22 µM and 79 nM to EGFR target. Extensive structure activity relationship (SAR) analyses were also carried out. The pharmacokinetic profile of (6f) was studied showing good metabolic stability and long duration behavior. This design offered a potent selective anticancer phthalimide-triazole leads for further optimization in cancer drug discovery.
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http://dx.doi.org/10.1016/j.bioorg.2021.104835DOI Listing
June 2021

Design and Synthesis of Novel Imidazole Derivatives Possessing Triazole Pharmacophore with Potent Anticancer Activity, and In Silico ADMET with GSK-3β Molecular Docking Investigations.

Int J Mol Sci 2021 Jan 25;22(3). Epub 2021 Jan 25.

Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.

A library of novel imidazole-1,2,3-triazole hybrids were designed and synthesized based on the hybrid pharmacophore approach. Therefore, copper(I)catalyzed click reaction of thiopropargylated-imidazole 2 with several organoazides yielded two sets of imidazole-1,2,3-triazole hybrids carrying different un/functionalized alkyl/aryl side chains and . After full spectroscopic characterization using different spectral techniques (IR, H, C NMR) and elemental analyses, the resulted adducts were screened for their anticancer activity against four cancer cell lines (Caco-2, HCT-116, HeLa, and MCF-7) by the MTT assay and showed significant activity. In-silico molecular docking study was also investigated on one of the prominent cancer target receptors, i.e., glycogen synthase kinase-3β (GSK-3β), revealing a good binding interaction with our potent compound, and was in agreement with the in vitro cytotoxic results. In addition, the ADMET profile was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes. Finally, this research design and synthesis offered click chemistry products with interesting biological motifs mainly 1,2,3 triazoles linked to phenyl imidazole as promising candidates for further investigation as anticancer drugs.
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http://dx.doi.org/10.3390/ijms22031162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866082PMC
January 2021

Design, Synthesis, Molecular Modeling, Anticancer Studies, and Density Functional Theory Calculations of 4-(1,2,4-Triazol-3-ylsulfanylmethyl)-1,2,3-triazole Derivatives.

ACS Omega 2021 Jan 31;6(1):301-316. Epub 2020 Dec 31.

Chemistry Department, College of Sciences, Yanbu, Taibah University, Yanbu 30799, Saudi Arabia.

New conjugates of substituted 1,2,3-triazoles linked to 1,2,4-triazoles were synthesized starting from the appropriate S-propargylated 1,2,4-triazoles and . Ligation of 1,2,4-triazoles to the 1,2,3-triazole core was performed through Cu(I)-catalyzed cycloaddition of 1,2,4-triazole-based alkyne side chain and/or with several un/functionalized alkyl- and/or aryl-substituted azides to afford the desired 1,4-disubstituted 1,2,3-triazoles , using both classical and microwave methods. After their spectroscopic characterization (infrared, H, C nuclear magnetic resonance, and elemental analyses), an anticancer screening was carried out against some cancer cell lines including human colon carcinoma (Caco-2 and HCT116), human cervical carcinoma (HeLa), and human breast adenocarcinoma (MCF-7). The outcomes of this exploration revealed that compounds , , and had a significant anticancer activity against MCF-7 and Caco-2 cancer cell lines with IC values of 0.31 and 4.98 μM, respectively, in relation to the standard reference drug, doxorubicin. Enzyme-docking examination was executed onto cyclin-dependent kinase 2; a promising aim for cancer medication. Synthesized compounds acquiring highest potency showcased superior interactions with the active site residue of the target protein and exhibited minimum binding energy. Finally, the density functional theory (DFT) calculations were carried out to confirm the outcomes of the molecular docking and the experimental findings. The chemical reactivity descriptors such as softness (δ), global hardness (η), electronegativity (χ), and electrophilicity were calculated from the levels of the predicted frontier molecular orbitals and their energy gap. The DFT results and the molecular docking calculation results explained the activity of the most expectedly active compounds , , and .
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http://dx.doi.org/10.1021/acsomega.0c04595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807778PMC
January 2021

Novel scaffold hopping of potent benzothiazole and isatin analogues linked to 1,2,3-triazole fragment that mimic quinazoline epidermal growth factor receptor inhibitors: Synthesis, antitumor and mechanistic analyses.

Bioorg Chem 2020 10 23;103:104133. Epub 2020 Jul 23.

Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.

A series of benzothiazole/isatin linked to 1,2,3-triazole moiety and terminal sulpha drugs 5a-e and 6a-e were synthesized and evaluated for cytotoxic activity against a panel of cancer cell lines. The novel compounds showed variable IC range of activity and some of them were potent compared to reference drug. The promising compounds were subjected as postulated the mimicry proposal for quinazoline-based EGFR inhibitors for their inhibitory profile against EGFR TK enzyme. That data obtained revealed that most of these compounds were potent EGFR TK inhibitors at nanomolar concentrations. Among these, compounds 5a and 5b showed more potent activity on EGFR compared to erlotinib (IC 103 and 104 versus 67.6 nM). Based upon the results, molecular docking analysis was performed on EGFR receptor and proved the strong contribution of fragments; benzothiazole, isatin, and triazole to the binding ATP pocket. When these selected compounds 5a and 5b were tested in an HepG2 model, they could effectively inhibited tumor growth, strongly induced cancer cell apoptosis, and suppressed cell cycle progression leading to DNA fragmentation. Well-DMET profile of the most active derivatives was presented and compared to the reference drugs. Taken together, we introduced novel triazole-sulpha drug hybrid for the first time as EGFR inhibitors and the results of our studies indicate that the newly discovered inhibitors have significant potential for anticancer treatment.
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http://dx.doi.org/10.1016/j.bioorg.2020.104133DOI Listing
October 2020

Synthesis, Characterization, DNA Binding, Anticancer, and Molecular Docking Studies of Novel Imidazolium-Based Ionic Liquids with Fluorinated Phenylacetamide Tethers.

ACS Omega 2020 Mar 9;5(10):4807-4815. Epub 2020 Mar 9.

Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.

Newer imidazolium ionic liquid (IL) halides appending variety of fluorinated phenylacetamide side chains were designed and synthesized through quaternization of 1-methyl and/or 1,2-dimethylimidazole with appropriate 2-chloro--(fluorinatedphenyl)acetamides. The resulting ILs were converted to their respective ionic liquid analogues carrying fluorinated counteranions (PF, BF, and/or CFCOO) . All newly synthesized ILs were fully characterized using several spectroscopic experiments such as H, C, B, F, P NMR, and mass analysis. The synthesized ionic liquids were investigated for their DNA binding and anticancer activities. The obtained DNA binding constants ranged from 1.444 × 10 to 3.518 × 10, indicating a reasonably good binding affinity. The percentage of anticancer activities ranged from 48 to 59 with H-1229 cell line, showing quite good anticancer potential. The modeling studies indicated the interactions of the reported molecules with DNA hydrogen bonds. These were in agreement with those of DNA binding and anticancer results. Briefly, the designed ionic liquids may be used as good anticancer candidates for treating human cancer.
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http://dx.doi.org/10.1021/acsomega.9b03468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081306PMC
March 2020

Introducing of acyclonucleoside analogues tethered 1,2,4-triazole as anticancer agents with dual epidermal growth factor receptor kinase and microtubule inhibitors.

Bioorg Chem 2020 01 23;94:103446. Epub 2019 Nov 23.

Department of Chemistry, Faculty of Sciences, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia; Laboratoire de Chimie & Electrochimie des Complexes Métalliques (LCECM) USTO-MB, Department of Chemistry, Faculty of Sciences, University of Sciences and Technology Mohamed Boudiaf, B.p. 1505 El M nouar, Oran 31000, Algeria.

This study reports an efficient and convenient regioselective synthesis of a novel series of S- and S,N-bis(acyclonucleoside) analogues carrying 5-(2-chlorophenyl)-2,4-dihydro-1,2,4-triazole-3-thione. A facile and straightforward synthesis of thiazolotriazole and triazolothiazines has also been reported. Structures of all newly synthesized compounds were well characterized by infrared IR, H and C nuclear magnetic resonance (NMR) and mass (MS) spectra analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using staurosporine as a reference drug against three different types: human liver cancer cell line (Hep G2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the S-acyclonucleoside analogues and S,N-bis(acyclonucleoside) analogues showed excellent activity with micromolar (µM) half maximal inhibitory concentration (IC) values against tumor cells. EGFR assay and tubulin inhibition assay analysis were performed for the most active compounds to get more details about their mechanism of action. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. Extensive structure activity relationship (SAR) analyses were also carried out.
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http://dx.doi.org/10.1016/j.bioorg.2019.103446DOI Listing
January 2020

A Profile of the In Vitro Anti-Tumor Activity and In Silico ADME Predictions of Novel Benzothiazole Amide-Functionalized Imidazolium Ionic Liquids.

Int J Mol Sci 2019 Jun 12;20(12). Epub 2019 Jun 12.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan.

A focused array of green imidazolium ionic liquids (ILs) encompassing benzothiazole ring and amide linkage were designed and synthesized using quaternization and metathesis protocols. The synthesized ILs have been fully characterized by usual spectroscopic methods and screened for their anticancer activities against human cancer cell lines originating from breast and colon cancers. Collectively, our biological data demonstrate that the newly synthesized series has variable anticancer activities in the examined cancer types. The synthesized ILs , and comprising the methyl and methyl sulfonyl benzothiazole ring emerged as the most potent compounds with promising antiproliferative activities relative to their benzothiazole ring counterparts. Furthermore, the mechanism underlying the observed anticancer activity was investigated. The most active compound appears to exert its anticancer effect through apoptosis dependent pathway in breast cancer cells. Interestingly, compound has also shown good in silico absorption (81.75%) along with high gastro-intestinal absorption as per ADME predictions.
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http://dx.doi.org/10.3390/ijms20122865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627815PMC
June 2019

Novel amphiphilic pyridinium ionic liquids-supported Schiff bases: ultrasound assisted synthesis, molecular docking and anticancer evaluation.

Chem Cent J 2018 Nov 22;12(1):118. Epub 2018 Nov 22.

Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, Medina, 30002, Saudi Arabia.

Background: Pyridinium Schiff bases and ionic liquids have attracted increasing interest in medicinal chemistry.

Results: A library of 32 cationic fluorinated pyridinium hydrazone-based amphiphiles tethering fluorinated counteranions was synthesized by alkylation of 4-fluoropyridine hydrazone with various long alkyl iodide exploiting lead quaternization and metathesis strategies. All compounds were assessed for their anticancer inhibition activity towards different cancer cell lines and the results revealed that increasing the length of the hydrophobic chain of the synthesized analogues appears to significantly enhance their anticancer activities. Substantial increase in caspase-3 activity was demonstrated upon treatment with the most potent compounds, namely 8, 28, 29 and 32 suggesting an apoptotic cellular death pathway.

Conclusions: Quantum-polarized ligand docking studies against phosphoinositide 3-kinase α displayed that compounds 2-6 bind to the kinase site and form H-bond with S774, K802, H917 and D933.
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http://dx.doi.org/10.1186/s13065-018-0489-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768046PMC
November 2018

Design, synthesis, ADME prediction and pharmacological evaluation of novel benzimidazole-1,2,3-triazole-sulfonamide hybrids as antimicrobial and antiproliferative agents.

Chem Cent J 2018 Nov 1;12(1):110. Epub 2018 Nov 1.

Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21500, Egypt.

Background: Nitrogen heterocyclic rings and sulfonamides have attracted attention of several researchers.

Results: A series of regioselective imidazole-based mono- and bis-1,4-disubstituted-1,2,3-triazole-sulfonamide conjugates 4a-f and 6a-f were designed and synthesized. The first step in the synthesis was a regioselective propargylation in the presence of the appropriate basic catalyst (EtN and/or KCO) to afford the corresponding mono-2 and bis-propargylated imidazoles 5. Second, the ligation of the terminal C≡C bond of mono-2 and/or bis alkynes 5 to the azide building blocks of sulfa drugs 3a-f using optimized conditions for a Huisgen copper (I)-catalysed 1,3-dipolar cycloaddition reaction yielded targeted 1,2,3-triazole hybrids 4a-f and 6a-f. The newly synthesized compounds were screened for their in vitro antimicrobial and antiproliferative activities. Among the synthesized compounds, compound 6a emerged as the most potent antimicrobial agent with MIC values ranging between 32 and 64 µg/mL. All synthesized molecules were evaluated against three aggressive human cancer cell lines, PC-3, HepG2, and HEK293, and revealed sufficient antiproliferative activities with IC values in the micromolar range (55-106 μM). Furthermore, we conducted a receptor-based electrostatic analysis of their electronic, steric and hydrophobic properties, and the results were in good agreement with the experimental results. In silico  ADMET prediction studies also supported the experimental biological results and indicated that all compounds are nonmutagenic and noncarcinogenic.

Conclusion: In summary, we have successfully synthesized novel targeted benzimidazole-1,2,3-triazole-sulfonamide hybrids through 1,3-dipolar cycloaddition reactions between the mono- or bis-alkynes based on imidazole and the appropriate sulfonamide azide under the optimized Cu(I) click conditions. The structures of newly synthesized sulfonamide hybrids were confirmed by means of spectroscopic analysis. All newly synthesized compounds were evaluated for their antimicrobial and antiproliferative activities. Our results showed that the benzimidazole-1,2,3-triazole-sulfonamide hybrids inhibited microbial and fungal strains within MIC values from 32 to 64 μg/mL. The antiproliferative evaluation of the synthesized compounds showed sufficient antiproliferative activities with IC values in the micromolar range (55-106 μM). In conclusion, compound 6a has remarkable antimicrobial activity. Pharmacophore elucidation of the compounds was performed based on in silico ADMET evaluation of the tested compounds. Screening results of drug-likeness rules showed that all compounds follow the accepted rules, meet the criteria of drug-likeness and follow Lipinski's rule of five. In addition, the toxicity results showed that all compounds are nonmutagenic and noncarcinogenic.
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http://dx.doi.org/10.1186/s13065-018-0479-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768023PMC
November 2018

Design, Synthesis and Anticancer Screening of Novel Benzothiazole-Piperazine-1,2,3-Triazole Hybrids.

Molecules 2018 Oct 27;23(11). Epub 2018 Oct 27.

Faculty of Science, Al al-Bayt University, Al-Mafraq 25113, Jordan.

A library of novel regioselective 1,4-di and 1,4,5-trisubstituted-1,2,3-triazole based benzothiazole-piperazine conjugates were designed and synthesized using the click synthesis approach in the presence and absence of the Cu(I) catalyst. Some of these 1,2,3-triazole hybrids possess in their structures different heterocyclic scaffold including 1,2,4-triazole, benzothiazole, isatin and/or benzimidazole. The newly designed 1,2,3-triazole hybrids were assessed for their antiproliferative inhibition potency against four selected human cancer cell lines (MCF7, T47D, HCT116 and Caco2). The majority of the synthesized compounds demonstrated moderate to potent activity against all the cancer cell lines examined. Further, we have established a structure activity relationship with respect to the in silico analysis of ADME (adsorption, distribution, metabolism and excretion) analysis and found good agreement with in vitro activity.
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http://dx.doi.org/10.3390/molecules23112788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278665PMC
October 2018

Microwave-Assisted Synthesis of Some Potential Bioactive Imidazolium-Based Room-Temperature Ionic Liquids.

Molecules 2018 Jul 15;23(7). Epub 2018 Jul 15.

Department of Chemistry, Taibah University, Al-Madina Al-Mounawara 30002, Saudi Arabia.

An environmentally-friendly and easy synthesis of a series of novel functionalized imidazolium-based ionic liquids (ILs) is described under both the conventional procedure and microwave irradiation. The structures of newly synthesized room-temperature ionic liquids (RTILs) were established by different spectral analyses. All ILs (⁻) were screened for their in vitro antimicrobial activity against a panel of clinically isolated bacteria. The results of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) showed that some of the tested ILs are very promising anti-bacterial agents especially those containing an alkyl chain with a phenyl group (most notably , , , and ).
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http://dx.doi.org/10.3390/molecules23071727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099736PMC
July 2018

Design, synthesis, in silico and in vitro antimicrobial screenings of novel 1,2,4-triazoles carrying 1,2,3-triazole scaffold with lipophilic side chain tether.

Chem Cent J 2017 Nov 21;11(1):117. Epub 2017 Nov 21.

Department of Chemistry, Faculty of Science, Taibah University, Al-Madinah Al-Munawarah, 30002, Saudi Arabia.

Background: 1,2,4-Triazoles and 1,2,3-triazoles have gained significant importance in medicinal chemistry.

Results: This study describes a green, efficient and quick solvent free click synthesis of new 1,2,3-triazole-4,5-diesters carrying a lipophilic side chain via 1,3-dipolar cycloaddition of diethylacetylene dicarboxylate with different surfactant azides. Further structural modifications of the resulting 1,2,3-triazole diesters to their corresponding 1,2,4-triazole-3-thiones via multi-step synthesis has been also investigated. The structures of the newly designed triazoles have been elucidated based on their analytical and spectral data. These compounds were evaluated for their antimicrobial activities. Relative to the standard antimicrobial agents, derivatives of 1,2,3-triazole-bis-4-amino-1,2,4-triazole-3-thiones were the most potent antimicrobial agents with compound 7d demonstrating comparable antibacterial and antifungal activities against all tested microorganisms. Further, the selected compounds were studied for docking using the enzyme, Glucosamine-6-phosphate synthase.

Conclusions: The in silico study reveals that all the synthesized compounds had shown good binding energy toward the target protein ranging from - 10.49 to - 5.72 kJ mol and have good affinity toward the active pocket, thus, they may be considered as good inhibitors of GlcN-6-P synthase.
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http://dx.doi.org/10.1186/s13065-017-0347-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696273PMC
November 2017

Green Ultrasound versus Conventional Synthesis and Characterization of Specific Task Pyridinium Ionic Liquid Hydrazones Tethering Fluorinated Counter Anions: Novel Inhibitors of Fungal Ergosterol Biosynthesis.

Molecules 2017 Nov 7;22(11). Epub 2017 Nov 7.

Department of Chemistry, Faculty of Sciences, Taibah University, P.O. Box 344, Al-Madinah Al-Munawarah 30002, Saudi Arabia.

A series of specific task ionic liquids (ILs) based on a pyridiniumhydrazone scaffold in combination with hexafluorophosphate (PF₆), tetrafluoroboron (BF₄) and/or trifluoroacetate (CF₃COO) counter anion, were designed and characterized by IR, NMR and mass spectrometry. The reactions were conducted under both conventional and green ultrasound procedures. The antifungal potential of the synthesized compounds - was investigated against 40 strains of (four standard and 36 clinical isolates). Minimum inhibitory concentrations (MIC) of the synthesized compounds were in the range of 62.5-2000 μg/mL for both standard and oral isolates. MIC results showed that the synthesized 1-(2-(4-chlorophenyl)-2-oxoethyl)-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-pyridin-1-ium hexafluorophosphate () was found to be most effective, followed by 4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)-1-(2-(4-nitrophenyl)-2-oxoethyl)-pyridin-1-ium hexafluorophosphate () and 1-(2-ethoxy-2-oxoethyl)-4-(2-(4-fluorobenzylidene)hydrazinecarbonyl)pyridin-1-ium hexafluorophosphate (). All the isolates showed marked sensitivity towards the synthesized compounds. Ergosterol content was drastically reduced by more active synthesized compounds, and agreed well with MIC values. Confocal scanning laser microscopy (CLSM) results showed that the red colored fluorescent dye enters the test agent treated cells, which confirms cell wall and cell membrane damage. The microscopy results obtained suggested membrane-located targets for the action of these synthesized compounds. It appears that the test compounds might be interacting with ergosterol in the fungal cell membranes, decreasing the membrane ergosterol content and ultimately leading to membrane disruption as visible in confocal results. The present study indicates that these synthesized compounds show significant antifungal activity against which forms the basis to carry out further in vivo experiments before their clinical use.
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http://dx.doi.org/10.3390/molecules22111532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150352PMC
November 2017

Green ultrasound-assisted three-component click synthesis of novel 1H-1,2,3-triazole carrying benzothiazoles and fluorinated-1,2,4-triazole conjugates and their antimicrobial evaluation.

Acta Pharm 2017 Sep;67(3):309-324

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The present study describes an efficient and ecofriendly, ultrasound, one-pot click cycloaddition approach for the construction of a novel series of 1,4-disubstituted-1,2,3-triazoles tethered with fluorinated 1,2,4-triazole-benzothiazole molecular conjugates. It involved three-component condensation of the appropriate bromoacetamide benzothiazole, sodium azide and 4-alkyl/aryl-5-(2-fluorophenyl)-3-(prop-2-ynylthio)-1,2,4-triazoles 4a-e through a Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction. This approach involves in situ generation of azidoacetamide benzothiazole, followed by condensation with terminal alkynes in the presence of CuSO4/Na-ascorbate in aqueous DMSO under both conventional and ultrasound conditions. Some of the designed 1,2,3-triazole conjugates 6a-o were recognized for their antimicrobial activity against some bacterial and fungal pathogenic strains.
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http://dx.doi.org/10.1515/acph-2017-0024DOI Listing
September 2017

An Eco-Friendly Ultrasound-Assisted Synthesis of Novel Fluorinated Pyridinium Salts-Based Hydrazones and Antimicrobial and Antitumor Screening.

Int J Mol Sci 2016 May 21;17(5). Epub 2016 May 21.

Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21500, Egypt.

The present work reports an efficient synthesis of fluorinated pyridinium salts-based hydrazones under both conventional and eco-friendly ultrasound procedures. The synthetic approach first involves the preparation of halogenated pyridinium salts through the condensation of isonicotinic acid hydrazide (1) with p-fluorobenzaldehyde (2) followed by the nucleophilic alkylation of the resulting N-(4-fluorobenzylidene)isonicotinohydrazide (3) with a different alkyl iodide. The iodide counteranion of 5-10 was subjected to an anion exchange metathesis reaction in the presence of an excess of the appropriate metal salts to afford a new series of fluorinated pyridinium salts tethering a hydrazone linkage 11-40. Ultrasound irradiation led to higher yields in considerably less time than the conventional methods. The newly synthesized ILs were well-characterized with FT-IR, ¹H NMR, (13)C NMR, (11)B, (19)F, (31)P and mass spectral analyses. The ILs were also screened for their antimicrobial and antitumor activities. Within the series, the salts tethering fluorinated counter anions 11-13, 21-23, 31-33 and 36-38 were found to be more potent against all bacterial and fungal strains at MIC 4-8 µg/mL. The in vitro antiproliferative activity was also investigated against four tumor cell lines (human ductal breast epithelial tumor T47D, human breast adenocarcinoma MCF-7, human epithelial carcinoma HeLa and human epithelial colorectal adenocarcinoma Caco-2) using the MTT assay, which revealed that promising antitumor activity was exhibited by compounds 5, 12 and 14.
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http://dx.doi.org/10.3390/ijms17050766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881586PMC
May 2016

A Green Ultrasound Synthesis, Characterization and Antibacterial Evaluation of 1,4-Disubstituted 1,2,3-Triazoles Tethering Bioactive Benzothiazole Nucleus.

Authors:
Nadjet Rezki

Molecules 2016 Apr 18;21(4):505. Epub 2016 Apr 18.

Department of Chemistry, Faculty of Sciences, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.

The synthesis of N-(benzo[d]thiazol-2-yl)-2-(4-substituted-1H-1,2,3-triazol-1-yl)acetamides 5a-r via the 1,3-dipolar cycloaddition reaction between 2-azido-N-(benzo[d]thiazol-2-yl)acetamide derivatives 3a-c and different alkynes were performed in the presence and absence of ultrasound irradiation. The synthesis was carried out using t-BuOH/H₂O (1:1, v/v) as reaction solvents and CuSO₄·5H₂O/sodium ascorbate as the catalyst. The copper catalyst was implemented to provide the regioselective 1,4-disubstituted 1,2,3-triazoles 5a-r. Significant reductions in reaction times with comparably higher yields were observed when the reactions were carried out under ultrasound irradiation. The structures of the newly synthesized 1,2,3-triazoles were elucidated by IR, NMR, MS, and elemental analyses. They were also screened for their antimicrobial activity against three gram-positive (Streptococcus pneumonia, Bacillus subtilis, and Staphylococcus aureus), three gram-negative (Pseudomonas aeuroginosa, Escherichia coli, and Klebsiella pneumonia), and two fungal strains (Aspergillus fumigates and Candida albicans). Most of the tested compounds displayed promising antimicrobial activities at a Minimum Inhibition Concentration (MIC) of 4-16 μg/mL.
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http://dx.doi.org/10.3390/molecules21040505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273572PMC
April 2016

Synthesis of Novel 2,5-Disubstituted-1,3,4-thiadiazoles Clubbed 1,2,4-Triazole, 1,3,4-Thiadiazole, 1,3,4-Oxadiazole and/or Schiff Base as Potential Antimicrobial and Antiproliferative Agents.

Molecules 2015 Sep 2;20(9):16048-67. Epub 2015 Sep 2.

Department of Chemistry, Faculty of Sciences, Taibah University, P. O. Box 344, Al-Madinah Al-Munawarah 30002, Saudi Arabia.

In the present study, a new series of 2,5-disubstituted-1,3,4-thiadiazole tethered 1,2,4-triazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole and Schiff base derivatives were synthesized and characterized by IR, ¹H-NMR, (13)C-NMR, MS and elemental analyses. All compounds were screened for their antibacterial, antifungal and antiproliferative activity. Some of the synthesized derivatives have displayed promising biological activity.
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http://dx.doi.org/10.3390/molecules200916048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331880PMC
September 2015

Synthesis and characterization of some novel 1,2,4-triazoles, 1,3,4-thiadiazoles and Schiff bases incorporating imidazole moiety as potential antimicrobial agents.

Acta Pharm 2015 Jun;65(2):117-32

(1,4,5-Triphenylimidazol-2-yl-thio)butyric acid hydrazide (3) was obtained via alkylation of 1,4,5-triphenylimidazol-2- thiol (1) with ethylbromobutyrate, followed by addition of hydrazine hydrate. Treatment of acid hydrazide 3 with carbon disulfide in an ethanolic potassium hydroxide solution gave the intermediate potassium dithiocarbazinate salt, which was cyclized to 4-amino-5-[(1,4,5-triphenylimidazol- -2-yl)thiopropyl]-2H-1,2,4-triazole-3-thione (4) in the presence of hydrazine hydrate. Condensation of compound 3 with alkyl/arylisothiocyanate afforded the corresponding 1-[4-(1,4,5-triphenylimidazol-2-ylthio)butanoyl]-4-alkyl/arylthiosemicarbazides (5-7), which upon refluxing with sodium hydroxide, yielded the corresponding 1,2,4-triazole - -3-thiols 8-10. Under acidic conditions, compounds 4-6 were converted to aminothiadiazoles 11-13. Moreover, the series of Schiff bases 14-18 were synthesized from the condensation of compound 3 with different aromatic aldehydes. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and mass spectral analyses. They were also preliminarily screened for their antimicrobial activity.
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http://dx.doi.org/10.1515/acph-2015-0011DOI Listing
June 2015

Synthesis of bis-acyclonucleoside analogues bearing benzothienyl-1,2,4-Triazol-3-Yl-disulfide under conventional and microwave methods.

Nucleosides Nucleotides Nucleic Acids 2013 ;32(1):28-41

Department of Chemistry, Taibah University, Madinah, Saudi Arabia.

The oxidation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (1) with a solution of iodine and potassium iodide at room temperature afforded [5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-yl]disulfide (2). In contrast, when the reaction mixture was heated or irradiated by MW, an unexpected additional product was obtained and identified as 3-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole (3); the ratio of products was 3:1. The preferred conformer of 2 was deduced from the theoretical calculation. The alkylation of compounds 2 and 3 with epichlorohydrin and hydroxyalkylating agents gave the corresponding N,N-bis- and N-acyclonucleosides analogues 8-15.
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http://dx.doi.org/10.1080/15257770.2012.751491DOI Listing
July 2013

Inhibition of α-glucosidase and α-amylase by diaryl derivatives of imidazole-thione and 1,2,4-triazole-thiol.

Eur J Med Chem 2011 Jun 31;46(6):2596-601. Epub 2011 Mar 31.

Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.

The in vivo and in vitro effects of 4,5-diphenylimidazole-2-thione (1), 4,5-diphenyl-1,2,4-triazole-3-thiol (2) and 5-(2-hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thiol (3) on α-glucosidase and α-amylase were investigated. The in vivo inhibition has been found to be dose-dependent and to occur at a value less than LD50. The in vitro treatment of the enzymes by 4,5-diphenylimidazole-2-thione exhibited a reversible inhibition of the non-competitive type with Ki value of 3.5 and 6.5×10(-5) M for α-glucosidase and α-amylase, respectively. 4,5-diphenyl-1,2,4-triazole-3-thione showed a reversible inhibition of the competitive and non-competitive types, with Ki value of 10(-5) M magnitude, for α-glucosidase and α-amylase. On the other hand, 5-(o-hydroxyphenyl)-4-phenyl-1,2,4-triazole-3-thione did not display an inhibitory effect towards α-amylase but showed a potent inhibition of the competitive type for hepatic α-glucosidase with 10(-5) M magnitude of Ki value.
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http://dx.doi.org/10.1016/j.ejmech.2011.03.051DOI Listing
June 2011

Synthesis of thiadiazoles and 1,2,4-triazoles derived from cyclopropane dicarboxylic acid.

Molecules 2005 Sep 30;10(9):1153-60. Epub 2005 Sep 30.

Department of Chemistry, College of Science, Al-Mustansirya University, Baghdad, Iraq.

New heterocyclic derivatives of cyclopropane dicarboxylic acid comprising thiadiazole and 1,2,4-triazole moieties are reported. Reaction of 1,1-cyclopropane dicarboxylic acid (1) with thiosemicarbazide and phosphorous oxychloride resulted in 1,1-bis (2-amino-1,3,4-thiadiazol-5- yl)cyclopropane (2). Cyclopropane dicarboxylic acid thiosemicarbazide (6) was converted into 1,1-bis(3-thio-4H-1,2,4-triazol-5-yl) cyclo- propane (7) by ring closure in an alkaline medium. The thiadiazole 2 and the triazole 7 were converted into a variety of derivatives.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147730PMC
http://dx.doi.org/10.3390/10091153DOI Listing
September 2005