- Thiazolidinedione "magic Bullets" Simultaneously Targeting PPARγand HDACs: Design, Synthesis, and Investigations of their in Vitro and in Vivo Antitumor Effects
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Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγagonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγand HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγEC50 = 0.245 μM and HDAC4 IC50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 μM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.
- Tilekar, Kalpana,Hess, Jessica D.,Upadhyay, Neha,Bianco, Alessandra Lo,Schweipert, Markus,Laghezza, Antonio,Loiodice, Fulvio,Meyer-Almes, Franz-Josef,Aguilera, Renato J.,Lavecchia, Antonio,Ramaa
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p. 6949 - 6971
(2021/06/25)
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- Mechanistic insights into binding of ligands with thiazolidinedione warhead to human histone deacetylase 4
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Recently, we have reported that non-hydroxamate thiazolidinedione (TZD) analogs are capable of inhibiting human deacetylase 4 (HDAC4). This study aims at the dissection of the molecular determinants and kinetics of the molecular recognition of TZD ligands by HDAC4. For this purpose, a structure activity relationship analysis of 225 analogs was combined with a comprehensive study of the enzyme and binding kinetics of a variety of HDAC4 mutant variants. The experimental data were rationalized by docking to the two major conformations of HDAC4. TZD ligands are competitive inhibitors and bind via a two-step mechanism involving principal molecular recognition and induced fit. The residence time of 24 g is (34 ± 3) min and thus much larger than that of the canonical pan-HDAC inhibitor SAHA ((5 ± 2) min). Importantly, the binding kinetics can be tuned by varying the structure of the CAP group.
- Basheer, Sidra,J?nsch, Niklas,Müller, Marlene,Meyer-Almes, Franz-Josef,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha,Wozny, Ewelina,Wurster, Eva
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- Biological evaluation of a series of benzothiazole derivatives as mosquitocidal agents
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Aedes aegypti is associated with the transmission of numerous human and animal diseases, such as yellow fever, dengue fever, chikungunya, and more recently Zika virus. Emerging insecticide resistance has created a need to develop new mosquitocidal agents for effective control operations. A series of benzothiazole-piperidine derivatives (1-24) were investigated for their larvicidal and adulticidal effects on Ae. aegypti It was observed that compounds 2, 4, 6, 7, 8, 11 and 13 showed notable larvicidal activity. Furthermore, compounds 6 and 10 showed promising adulticidal activity. Based on the mosquitocidal properties of these compounds, docking studies were also carried out in the active site of the AeSCP2 enzyme to explore any insights into further in vitro enzyme studies. Docking results indicated that all these active compounds showed reasonable interactions with critical residues in the active site of this enzyme. This outcome suggested that these compounds might show their larvicidal and adulticidal effects via the inhibition of AeSCP2. According to in vitro and in silico studies, compounds 2, 4, 6, 7, 8, 10, 11 and 13 stand out as candidates for further studies.
- Sever, Belgin,Altlntop, Mehlika Dilek,?zdemir, Ahmet,Tabanca, Nurhayat,Estep, Alden S.,Becnel, James J.,Bloomquist, Jeffrey R.
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p. 288 - 294
(2019/07/04)
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- Design, synthesis, and biological evaluation of novel 1,3,4-thiadiazole derivatives as potential antitumor agents against chronic myelogenous leukemia: Striking effect of nitrothiazole moiety
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In an attempt to develop potent antitumor agents, new 1,3,4-thiadiazole derivatives were synthesized and evaluated for their cytotoxic effects on multiple human cancer cell lines, including the K562 chronic myelogenous leukemia cell line that expresses the Bcr-Abl tyrosine kinase. N-(5-Nitrothiazol-2-yl)-2-((5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide (2) inhibited the Abl protein kinase with an IC50 value of 7.4 μM and showed selective activity against the Bcr-Abl positive K562 cell line. Furthermore, a Bcr-Abl-compound 2 molecular modelling simulation highlighted the anchoring role of the nitrothiazole moiety in bonding and hydrophobic interaction with the key amino acid residues. These results provide promising starting points for further development of novel kinase inhibitors.
- Alt?ntop, Mehlika Dilek,Ciftci, Halil Ibrahim,Radwan, Mohamed O.,Sever, Belgin,Kaplanc?kl?, Zafer As?m,Ali, Taha F. S.,Koga, Ryoko,Fujita, Mikako,Otsuka, Masami,Zdemir, Ahmet
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- Fighting against alzheimer’s disease: Synthesis of new pyrazoline and benzothiazole derivatives as new acetylcholinesterase and MAO inhibitors
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Background: Alzheimer’s Disease (AD) is a complicated neurodegenerative disorder with a multifaceted pathogenesis.AD, characterized by gradual memory loss, falling in language ability and other cognitive deterioration, and has been a prominent risk to ageing population. This means that there is an urgent need to find new lead compounds for controlling and fighting against (AD). In this way, a new thiophene-2-pyrazoline derivatives (A1-A5) and benzothiazole derivatives (A6-A13) have been synthesized to give beneficial compounds to controlling and battling against (AD). Results: Compounds A5 and A13 showed the most remarkable activity with an 18.53 μM and 15.26 μM IC50 values against AChE enzyme. In like manner, compound A4 was active with a 20.34 μM IC50 value against MAO-A. These active compounds are in fact non-toxic making them very attractive for additional future studies. Enzyme kinetic was analyzed and the Lineweaver-Burk plot reveals that compound A13 was typically mixed AChE inhibitors, which showed significant similarity to donepezil. In addition, the best docking pose was done by analyzing the docking pattern of the most active compound A13 which was very compatible with the gorge and in interaction with both CAS and PAS. Conclusion: The synthesis of new thiophene-2-pyrazoline and benzothiazole derivatives targeting AChE/(MAO-A)/(MAO-B) enzymes was described. The selection of enzyme-kinetic analysis, molecular docking and toxicity test was led to good understanding to the therapeutic potential for the active derivatives. Therefore, these compounds may be accepted as promising leads for future research efforts in fighting against AD.
- Turan-Zitouni, Gülhan,Hussein, Weiam,Sa?l?k, Begüm Nurpelin,Baysal, Merve,Kaplanc?kl?, Zafer As?m
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p. 414 - 427
(2018/04/20)
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- Design, synthesis, in vitro and in silico evaluation of a new series of oxadiazole-based anticancer agents as potential Akt and FAK inhibitors
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In the current work, new 1,3,4-oxadiazole derivatives were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cell lines. Compounds 2, 6 and 9 were found to be the most potent anticancer agents against A549 and C6 cell lines and therefore their effects on apoptosis, caspase-3 activation, Akt, FAK, mitochondrial membrane potential and ultrastructural morphological changes were evaluated. N-(5-Nitrothiazol-2-yl)-2-[[5-[((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl]-1,3,4-oxadiazol-2-yl]thio]acetamide (9) increased early and late apoptotic cell population in A549 and C6 cells more than cisplatin and caused more mitochondrial membrane depolarization in both cell lines than cisplatin. On the other hand, N-(6-methoxybenzothiazol-2-yl)-2-[[5-[((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl]-1,3,4-oxadiazol-2-yl]thio]acetamide (6) caused higher caspase-3 activation than cisplatin in both cell lines. Compound 6 showed significant Akt inhibitory activity in both cell lines. Moreover, compound 6 significantly inhibited FAK (Phospho-Tyr397) activity in C6 cell line. Molecular docking simulations demonstrated that compound 6 fitted into the active sites of Akt and FAK with high affinity and substrate-specific interactions. Furthermore, compounds 2, 6 and 9 caused apoptotic morphological changes in both cell lines obtained from micrographs by transmission electron microscopy. A computational study for the prediction of ADME properties of all compounds was also performed. These compounds did not violate Lipinski's rule, making them potential orally bioavailable anticancer agents.
- Alt?ntop, Mehlika Dilek,Sever, Belgin,Akal?n ?ift?i, Gül?en,Turan-Zitouni, Gülhan,Kaplanc?kl?, Zafer As?m,?zdemir, Ahmet
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p. 905 - 924
(2018/07/06)
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- Aminothiazoles as Potent and Selective Sirt2 Inhibitors: A Structure-Activity Relationship Study
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Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl but also other acyl groups from the ε-amino group of lysines in histones and other substrate proteins. Dysregulation of human Sirt2 (hSirt2) activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, which makes the modulation of hSirt2 activity a promising strategy for pharmaceutical intervention. The sirtuin rearranging ligands (SirReals) have recently been discovered by us as highly potent and isotype-selective hSirt2 inhibitors. Here, we present a well-defined structure-activity relationship study, which rationalizes the unique features of the SirReals and probes the limits of modifications on this scaffold regarding inhibitor potency. Moreover, we present a crystal structure of hSirt2 in complex with an optimized SirReal derivative that exhibits an improved in vitro activity. Lastly, we show cellular hyperacetylation of the hSirt2 targeted tubulin caused by our improved lead structure.
- Schiedel, Matthias,Rumpf, Tobias,Karaman, Berin,Lehotzky, Attila,Oláh, Judit,Gerhardt, Stefan,Ovádi, Judit,Sippl, Wolfgang,Einsle, Oliver,Jung, Manfred
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p. 1599 - 1612
(2016/03/05)
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- Synthesis and antimicrobial activity evaluation of new dithiocarbamate derivatives bearing thiazole/benzothiazole rings
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The synthesis of 2-(substituted phenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A1-A24) derivatives and 2-(4-substituted thiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B1-B14) derivatives was undertaken starting from the potassium salt of 4-(2-pyrimidinyl)piperazine dithiocarbamate. The structures of the obtained compounds were elucidated by1H NMR,13C NMR, MS spectral data, and elemental analysis. The antimicrobial activity of the thirty eight newly synthesized compounds were tested against 12 microorganism strains using the microdilution technique. Compounds 2-(4-ethoxycarbonylthiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B12), 2-(3-fluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A18) and 2-(3,4-difluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A21) were determined to possess high antimicrobial activity.
- Yurtta?, Leyla,?zkay, Yusuf,Duran, Murat,Turan-Zitouni, Gülhan,?zdemir, Ahmet,Cantürk, Zerrin,Kü?üko?lu, Kaan,Kaplanc?kl?, Zafer As?m
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p. 1166 - 1173
(2016/07/27)
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- Catalytic N-formylation for synthesis of 6-substituted-2-benzothiazolylimino-5-piperazinyl-4-thiazolidinone antimicrobial agents
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A new class of piperazine-based 2-benzothiazolylimino-4-thiazolidinones has been efficiently prepared via highly accelerated N-formylation of N-isopropylpiperazine by the use of a mild heterogeneous catalyst, sulfated tungstate. Heterocyclization of N-(benzo[d]thiazol-2-yl)-2-chloroacetamides (3a-j) by use of NH4SCN in ethanol under reflux efficiently furnished the intermediates 2-benzothiazolyliminothiazolidin-4-ones (4a-j). These were treated with 4-isopropylpiperazine-1-carbaldehyde (2) to prepare the final products 5a-j. The structures of the new derivatives were confirmed by elemental analysis and use of spectroscopic data (FTIR and 1H NMR). Their pharmacological potential as promising antimicrobial agents was determined in vitro against bacteria and a fungus; the lowest minimum inhibitory concentrations (MIC) observed were in the range 4-8 μg/mL.
- Patel, Rahul V.,Park, Se Won
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p. 5599 - 5609
(2015/07/08)
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- Cytotoxic activities of some benzothiazole-piperazine derivatives
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Synthesis, characterization and cytotoxic activities of ten benzothiazole-piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell li
- Gurdal, Enise Ece,Durmaz, Irem,Cetin-Atalay, Rengul,Yarim, Mine
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p. 649 - 654
(2015/07/27)
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- In vitro biological investigations of novel piperazine based heterocycles
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Eleven N.phenyl- and 11 N.benzothiazolyl-2-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)acetamides have been synthesised by a simple and efficient method. The 22 novel compounds were tested for their in vitro biological efficacy against two Grampositive bacteria, three Gram-negative bacteria, two fungi and Mycobacterium tuberculosis H37Rv. The bioassay results revealed that the majority of the N.benzothiazole-substituted piperazine derivatives exhibited moderate to good bioefficacies with encouraging MICs. The influence of the presence or absence of various electron-withdrawing or -donating functional groups on the aryl acetamide moiety on the different bioassay results is discussed.
- Chhatriwala, Nirmal M.,Patel, Amit B.,Patel, Rahul V.,Kumari, Premlata
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p. 611 - 616
(2015/02/02)
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- Access to a new class of biologically active quinoline based 1,2,4-triazoles
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As an aspect of our ongoing research in search of new antimicrobial armamentarium, a series of 1,2,4-triazol-3-ylthio-acetamides was constructed and in vitro analyzed for their antimicrobial activity against several bacteria and fungi. Aiming to establish an increased potency, the bioassay results were matched to those of 1,3,4-oxadiazoles, utilized previously. Remarkably, 1,2,4-triazoles were found to possess a good spectrum of antifungal potency, which eventually suggested the azole template as an essential pharmacophore to diversify the biological occupations of the attendant molecules. However, it was noticed that the potency of final analogs against each strain placed reliance on the type of substituent present on benzothiazole ring. The structures of final compounds were confirmed with the aid of IR, 1H NMR, 13C NMR spectroscopy and CHN analysis.
- Patel, Rahul V.,Park, Se Won
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- Synthesis of coumarin-based 1,3,4-oxadiazol-2ylthio-N-phenyl/benzothiazolyl acetamides as antimicrobial and antituberculosis agents
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In an attempt to find new agents to fight against microbial infections, a series of coumarin-based 1,3,4-oxadiazol-2ylthio-N-phenyl/benzothiazolyl acetamides was synthesized starting from coumarin-3-carboxylic acid ethyl ester obtained through Knoevenagel and Pinner reaction. In vitro antimicrobial activity against several bacteria (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain was assessed. This study shows to what extent the presence of various electron withdrawing/donating substituents on the phenyl or benzothiazole ring affects the activity profiles of the newer molecules. The relationship between activity profiles (MICs, 3.12-25 μg/mL) and the lipophilic character (LogP) of the prepared products is also discussed and the MIC values of the active conjugates seem to correlate to some extent with the lipophilicity profiles. Two (5e and 6c) of the final analogues displayed promising antimycobacterial activity at 12.5 μg/mL of MIC, half fold potent to the standard drug pyrazinamide (6.25 μg/mL). Compounds were characterized by IR, 1H NMR, 13C NMR spectroscopy and elemental analysis.
- Patel, Rahul V.,Kumari, Premlata,Rajani, Dhanji P.,Chikhalia, Kishor H.
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p. 195 - 210
(2013/03/13)
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- New quinolinyl-1,3,4-oxadiazoles: Synthesis, in vitro antibacterial, antifungal and antituberculosis studies
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In order to generate hybrid antimicrobial remedies with novel mode of action, two series of quinoline based 1,3,4-oxadiazole derivatives condensed with N-aryl/benzothiazolyl acetamides were synthesized and the MIC values of the compounds towards eight reference bacterial strains (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), four fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and Mycobacterium tuberculosis H37Rv were assayed in vitro. Quinoline-6-carboxlic acid was treated with thionyl chloride in refluxing methanol to obtain the corresponding ester derivative to be hydrazinolyzed by 99% hydrazine hydrate in ethanol to produce carbohydrazide intermediate. The carbohydrazide precursor underwent cyclization by carbon disulfide and ethanolic KOH to construct 5-quinolinyl-6-yl-1,3,4- oxadiazol-2-thiol. Substituted 2-chloro-N-phenyl(benzothiazolyl)aceta-mide derivatives were then condensed to 1,3,4-oxadiazole nucleus via sulphur linkage to yield the desired products. Target products bearing N-benzothiazolyl-2- chloroacetamides displayed good inhibitory potential. The biological screening identified that many final analogues exhibited a significant inhibition of the growth of microorganisms at 3.12-25 μg/mL of MIC, which were comparable to control drugs. The influence of the presence of various functional groups to the phenyl/benzothiazolyl ring on activity profiles was investigated. The proposed structures of the newly prepared products were confirmed with the aid of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. These results may provide new insights in the design of a novel pool of bioactive templates.
- Patel, Rahul V.,Kumari, Premlata,Chikhalia, Kishor H.
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p. 596 - 607
(2013/07/28)
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- Synthesis and biological evaluation of some amide derivatives bearing benzothiazole and piperidine moieties as antimicrobial agents
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In this study, N-(benzothiazol-2-yl)-2-(piperidin-1-yl)acetamide derivatives (1-24) were obtained by the reaction of 2-chloro-N-(benzothiazole-2- yl)acetamides with piperidine derivatives. The structures of the compounds were elucidated by 1H-NMR and mass spectral data and elemental analysis. The compounds were screened for their antimicrobial activities against pathogenic bacteria and Candida species. The compounds were also investigated for their cytotoxic properties using MTT assay. The microbiological results revealed that the compounds were more effective against fungi than bacteria. Among Candida species, C. utilis was the most susceptible fungus to compounds 7 and 11. It is apparent that 2,6-dimethylpiperidine group and chloro and methyl substituents on benzothiazole ring have an important impact on anticandidal activity. MTT assay indicated that the effective doses of these derivatives were lower than their cytotoxic doses.
- Altintop, Mehlika Dilek,Oezdemir, Ahmet,Kaplancikli, Zafer Asim,Turan-Zitouni, Guelhan,Iscan, Goekalp,Ciftci, Guelsen Akalin
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p. 453 - 461
(2013/07/26)
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- Biological evaluation of some antimicrobial nano-materials
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N-(benzothiazol-2-yl)-2-(piperidin-1-yl)acetamide derivatives (1-24) were obtained by the reaction of 2-chloro-N-(benzothiazole-2-yl)acetamides with piperidine derivatives. The structures of the compounds were elucidated by 1H-NMR and mass spectral data and elemental analysis. The compounds were screened for their antimicrobial activities against pathogenic bacteria and Candida species. The compounds were also investigated for their cytotoxic properties usingMTT assay. The microbiological results revealed that the compounds were more effective against fungi than bacteria. Among Candida species C. utilis was the most susceptible fungus to compounds 7 and 11. It is apparent that 2,6-dimethylpiperidine group and chloro and methyl substituents on benzothiazole ring have an important impact on anticandidal activity. MTT assay indicated that the effective doses of these derivatives were lower than their cytotoxic doses.
- Mokhtari, Bahram,Pourabdollah, Kobra
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p. 663 - 670
(2013/10/22)
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- Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as antibacterial, antifungal and antituberculosis agents
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To affiliate multiple bioactivities in a compact heteronuclei, two series of benzimidazole based 1,3,4-oxadiazoles were synthesized and assessed in vitro for their efficacy as antimicrobial agents against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv and best results were observed amongst the N-benzothiazolyl aetamide series. The lipophilicity (LogP) influence on the biological profile (MICs) of the prepared products was also discussed. Upon biological screening, it was observed that the majority of the compounds were found to possess a significant broad spectrum antimicrobial (3.12-25 μg/mL of MIC) and antitubercular (6.25-25 μg/mL of MIC) potential. The structural assignments of the new products were done on the basis of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis.
- Patel, Rahul V.,Patel, Paresh K.,Kumari, Premlata,Rajani, Dhanji P.,Chikhalia, Kishor H.
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- Combination of bioactive moieties with different heteroatom(s): Application of the Suzuki cross-coupling reaction
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Two series of thiophene/benzothiophene-linked quinolinyl oxadiazoles condensed to the substituted N-benzothiazolyl acetamides have been synthesized via the Suzuki cross-coupling reaction. The ester derivative of 6-bromo-substituted quinoline was reacted via the Suzuki cross-coupling reaction with commercially available (benzo)thiophen-2-ylboronic acid at optimized temperature in 1,2-dimethoxy ethane and water in the presence of potassium carbonate and palladium tetrakis. The resulting derivatives were then hydrazinolized using 99% hydrazine hydrate followed by cyclization using carbon disulfide in ethanolic KOH to furnish the corresponding oxadiazoles, which were then condensed with various substituted 2-chloro-N-benzothiazolyl acetamides to produce the final scaffolds involving a unique combination of four heterocycles to be examined for their antimicrobial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus), three Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae), and two fungal species (Aspergillus niger and Candida albicans). The investigation of biological screening data revealed that the majority of the compounds tested have demonstrated excellent activity (minimum inhibitory concentrations; 6.25-50 μg/mL) against most of the microorganisms as compared with the standard and hence they warrant more consideration as prospective antimicrobial agents. New products (9a-10i) were characterized by physicochemical, elemental, and spectral (IR, 1H NMR, and 13C NMR) data.
- Patel, Rahul V.,Patel, Jigar K.,Kumari, Premlata,Chikhalia, Kishor H.
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p. 399 - 410
(2012/08/28)
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- Synthesis, antimicrobial activity and cytotoxicity of novel oxadiazole derivatives
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In the present study, 5-substituted-1,3,4-oxadiazolin-2-thiones (1ab) were synthesized via the ring closure reactions of appropriate acid hydrazides with carbon disulphide. N-(Benzothiazol-2-yl)-2-[[5-substituted-1,3,4-oxadiazol-2-yl] sulfanyl]acetamide d
- Kaplancikli, Zafer Asim,Altintop, Mehlika Dilek,Turan-Zitouni, Gulhan,Ozdemir, Ahmet,Ozic, Rasime,Akaliin, Guelsen
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experimental part
p. 51 - 57
(2012/04/05)
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- Synthesis and analgesic activity of some acetamide derivatives
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In the present study, some acetamide derivatives were synthesized and their potential analgesic activities were investigated. N-(benzothiazol-2-yl)-2-[(1- substituted-1H-tetrazol-5-yl)thio]acetamide derivatives were obtained by the nucleophilic substitution reaction of 2-chloro-N-(benzothiazole-2-yl)acetamides with appropriate tetrazol-5-thioles. The chemical structures of the compounds were elucidated by IR, 1H-NMR, 13C-NMR and FAB +-MS spectral data and elemental analyses. The prepared compounds were investigated for their potential analgesic properties against thermal, mechanical and chemical nociceptive stimuli using hot-plate, tail-clip and acetic acid-induced writhing tests, respectively. The assessment of motor coordination was carried out using Rota-Rod test. Tested compounds applied at 100mg/kg doses caused significant decrease in acetic acid-induced writhing responses and increase in hot-plate and tail-clip latencies. None of the compounds exhibited destructive effect on motor coordination of the mice in Rota-Rod performance.
- Kaplancikli, Zafer Asim,Altintop, Mehlika Dilek,Turan-Zitouni, Gulhan,Ozdemir, Ahmet,Can, Ozgur Devrim
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experimental part
p. 275 - 280
(2012/07/13)
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- Synthesis and anticholinesterase activity and cytotoxicity of novel amide derivatives
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In the present study, some amide derivatives were synthesized and their potential anticholinesterase properties were investigated. N-(Benzothiazol-2-yl) -2-[(5-amino/methyl-1,3,4-thiadiazol-2-yl)thio]acetamide derivatives were obtained by nucleophilic substitution of 2-chloro-N-(benzothiazole-2-yl) acetamide derivatives with appropriate 1,3,4-thiadiazole-2-thioles. The chemical structures of the compounds were elucidated by 1H-NMR, 13C-NMR and FAB+-MS spectral data and elemental analyses. Each amide derivative was evaluated for its ability to inhibit AChE and BuChE using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. 2-(5-Amino-1,3,4-thiadiazol-2-yl)thio-N-(benzothiazol-2-yl)acetamide derivatives have anticholinesterase activity, whereas 2-(5-methyl-1,3,4-thiadiazol-2-yl) thio-N-(benzothiazol-2-yl)acetamide derivatives have no inhibitory effect on enzyme activity. Among these compounds, it is clear that compound IIh is the most potent derivative. Among these new compounds, compound IIh is the most potent inhibitor of AChE and BuChE with an IC50 value of 66±0.71μg/mL and 48.75±2.48μg/mL, respectively.
- Altintop, Mehlika Dilek,Kaplancikli, Zafer Asim,Ozdemir, Ahmet,Turan-Zitouni, Guelhan,Temel, Halide Edip,Akalin, Guelsen
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experimental part
p. 112 - 116
(2012/04/10)
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- Synthesis of some thiazolyl aminobenzothiazole derivatives as potential antibacterial, antifungal and anthelmintic agents
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A series of 4-(6-substituted-1,3-benzothiazol-2-yl)amino-2-(4- substitutedphenyl)-amino-1,3-thiazoles, 9-24 have been synthesised from 2-chloro-N-(6-substituted-1,3-benzothiazol-2-yl)acetamides, 5-8. The structures of these compounds have been elucidated by spectral (IR, 1H NMR, Mass) and elemental (C, H, N) analysis data. All the newly synthesised compounds (9-24) were screened for their antibacterial, antifungal and anthelmintic activities. Almost all of these compounds showed moderate to good antimicrobial activity against two gram negative bacteria (E. coli, P. aeruginosa), two gram positive bacteria (S. aureus, B. subtilis), pathogenic fungal strains (C. albicans, A. niger) and good anthelmintic activity against earthworm species (P. corethruses). Compounds 18 and 20 exhibited good antibacterial and antifungal activities, while compound 22 displayed the most significant anthelmintic activity.
- Amnerkar, Nikhil D.,Bhusari, Kishore P.
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scheme or table
p. 22 - 28
(2011/10/13)
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- Synthesis and biological evaluation of new thiazolyl/benzothiazolyl-amides, derivatives of 4-phenyl-piperazine
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A series of thiazolyl-N-phenyl piperazines has been synthesised and tested for anti-inflammatory activity. Their RM values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and logPsk also performed. The effect of the synthesised compounds on inflammation, using the carrageenin induced mouse paw oedema model was studied. In general, the studied compounds were found to be potent anti-inflammatory agents (44-74.1%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesised compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure-activity relationship approach (QSAR).
- Papadopoulou, Christina,Geronikaki, Athina,Hadjipavlou-Litina, Dimitra
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p. 969 - 973
(2008/09/18)
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