- Design, synthesis, molecular docking and antiproliferative activity of some novel benzothiazole derivatives targeting EGFR/HER2 and TS
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Multi-targeted anticancer drugs are in focus as a promising research topic. A new series of benzothiazoles hybridized with pyrimidine moiety was designed and synthesized using the lead compound 4a. Various chemical modifications on the pyrimidine ring of 4a at four different positions were done in a trial to get new multi-targeted anticancer agents. The structures of the newly synthesized compounds were established on their elemental analyses and spectral data. All final synthesized derivatives were submitted to the National Cancer Institute (NCI), USA, to be screened for their in vitro anticancer activity. Further evaluation for the cytotoxic activity of the most active compounds was performed using the MTT assay method. Compounds 4d, 8d, 8h, 8i and 17 were then selected for examining their in vitro enzyme inhibitory activities against EGFR, HER2 and TS enzymes using lapatinib and 5FU as standards. Furthermore, cell cycle analysis and apoptosis induction detection were also evaluated. Finally, molecular docking studies were carried out for compounds 4d, 8d, 8h, 8i and 17 to interpret their observed enzymatic activities based on the ligand–protein interactions.
- Abdellatif, Khaled R. A.,Amin, Noha H.,Belal, Amany,El-Saadi, Mohamed T.,Hemeda, Loah R.,Said, Eman G.
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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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- Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety
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Antitumor screening of several novel 4-thiazolidinones with benzothiazole moiety has been performed. Reactions of (benzothiazole-2-yl)hydrazine with trithiocarbonyl diglycolic acid or 6-methyl-2-aminobenzothiazole with 2-carbethoxymethylthio-2-thiazoline-4-one have yielded starting 3- (1) or 2-substituted (11) 4-thiazolidinones which have been subsequently utilized in a Knoevenagel condensation for obtaining a series of 5-arylidene derivatives 2-10, 12-16. Compound 11 has been obtained alternatively by a counter synthesis method based on the reaction of 2-chloro-N-(6-methylbenzothiazol-2-yl)-acetamide and ammonium thiocyanate. The structures of compounds have been determined by 1H, 13C NMR, IR and X-ray analysis. In vitro anticancer activity of the synthesized compounds was tested by the National Cancer Institute and two (6, 16) of them has revealed the anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancers cell lines. Among tested compounds, 2-{2-[3-(benzothiazol-2-ylamino)-4- oxo-2-thioxothiazolidin-5-ylidenemethyl]-4-chlorophenoxy}-N-(4-methoxyphenyl) -acetamide (6) was found to be the most active candidate with average logGI 50 and logTGI values -5.38 and -4.45 respectively.
- Havrylyuk, Dmytro,Mosula, Ludmyla,Zimenkovsky, Borys,Vasylenko, Olexandr,Gzella, Andrzej,Lesyk, Roman
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- An extensive research on aldose reductase inhibitory effects of new 4H-1,2,4-triazole derivatives
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Aldose reductase (AR) is a key enzyme, which triggers the excessive accumulation of sorbitol in insulin independent tissues leading to severe diabetes-induced microvascular complications. Substantial evidence has proven that AR inhibition is a well-establ
- Sever, Belgin,Alt?ntop, Mehlika Dilek,Demir, Yeliz,Pekdo?an, Muhammed,Akal?n ?ift?i, Gül?en,Beydemir, ?ükrü,?zdemir, Ahmet
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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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- Targeting EGFR tyrosine kinase: Synthesis, in vitro antitumor evaluation, and molecular modeling studies of benzothiazole-based derivatives
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New benzothiazole-based derivatives were synthesized in the present work with the aim of evaluating their antitumor activity. They were in vitro tested against hepatocellular carcinoma (HepG2), colorectal carcinoma (HCT-116), mammary gland cancer (MCF-7), prostate cancer (PC-3), and epithelioid carcinoma (HeLa). The results of the in vitro antitumor evaluation revealed that the most active compounds were 39, 40, 51, 56, and 61 exhibiting IC50 values comparable to the reference drug lapatinib. The most active compounds were further subjected to EGFR inhibitory activity assay to rationalize their potency mode. Notably, the most active antitumor compounds 39 and 40 represented the most potent inhibitors to EGFR with IC50 values of 24.58 and 30.42 nM respectively in comparison with 17.38 nM for lapatinib as a standard drug. Molecular modeling studies were also conducted for the synthesized compounds, including docking into EGFR active site and surface mapping. Results proved the superior binding of the hydrazone derivatives 39 and 40 with EGFR suggesting them as good candidates for targeted antitumor therapy through EGFR kinase inhibition.
- Mokhtar, Amal M.,El-Messery, Shahenda M.,Ghaly, Mariam A.,Hassan, Ghada S.
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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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- Design, synthesis, and screening of hybrid benzothiazolyl-oxadiazoles as anticonvulsant agents
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Background: Epilepsy affects approximately 50 million people globally. It is generally characterized by periodic seizures of unpredictable nature, though a variety of anticonvulsant drugs are available but the major drawback is undesirable side effects. Here an effort is being made to utilise the beneficial effect of benzothiazoles and oxadiazoles as potent anticonvulsants and there is an anticipation of synergistic effect from the hybrid molecule. Methods: Here a series of new hybrid molecules containing oxadiazole and benzothiazole pharmacophore were synthesised using appropriate synthetic route and characterised by IR, 1H NMR, 13C NMR, mass and elemental analysis. The synthesised compounds were examined for their maximal electroshock seizure (MES) and subcutaneous pentylene tetrazole (Sc PTZ) induced seizure and neurotoxicity screens. Those found potent were also evaluated for their CNS depressant effect. Results: Among the compounds tested 4m N-(6-fluro-1,3-benzothiazol-2-yl)-2-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamide and 4n N-(6-Chloro-1,3-benzothiazol-2-yl)-2-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]sulfanyl} acetamide showed protection from seizures in both the animal models at dose level of 30 mg/kg after 0.5 hr and at 100 mg/kg after 4 hr period indicating that the compound is potent and long acting. These compounds also exhibited lesser CNS depression and neurotoxicity. Conclusion: Among the synthesized compounds 4m and 4n possessed significant anticonvulsant activity without any neurotoxicity and CNS depressant effects. Thus the hybrid benzothiazolyl acetamide derivatives containing oxadizole scaffold provided a new opportunity for possible modification and future exploitation to get the safer and effective anticvulsant agents.
- Murtuja, Sheikh,Shaquiquzzaman, Mohammad,Amir, Mohammad
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p. 398 - 405
(2018/04/20)
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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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- Identification of biologically active pyrimido[5, 4-b]indoles that prolong NF-κB activation without intrinsic activity
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Most vaccine adjuvants directly stimulate and activate antigen presenting cells but do not sustain immunostimulation of these cells. A high throughput screening (HTS) strategy was designed to identify compounds that would sustain NF-κB activation by a stimulus from the Tolllike receptor (TLR)4 ligand, lipopolysaccharide (LPS). Several pilot studies optimized the parameters and conditions for a cell based NF-κB reporter assay in human monocytic THP-1 cells. The final assay evaluated prolongation of LPS induced NF-κB activation at 12 h. The dynamic range of the assay was confirmed in a pilot screen of 14 631 compounds and subsequently in a main extensive screen with 166 304 compounds. Hit compounds were identified using an enrichment strategy based on unsupervised chemoinformatic clustering, and also by a na?ve "Top X" approach. A total of 2011 compounds were then rescreened for levels of coactivation with LPS at 5 h and 12 h, which provided kinetic profiles. Of the 407 confirmed hits, compounds that showed correlation of the kinetic profiles with the structural similarities led to identification of four chemotypes: pyrimido[5, 4-b]indoles, 4H-chromene-3-carbonitriles, benzo[d][1, 3]dioxol- 2-ylureas, and tetrahydrothieno[2, 3-c]pyridines, which were segregated by 5 h and 12 h kinetic characteristics. Unlike the TLR4 agonistic pyrimidoindoles identified in previous studies, the revealed pyrimidoindoles in the present work did not intrinsically stimulate TLR4 nor induce NF-κB but rather prolonged NF-κB signaling induced by LPS. A 42-member combinatorial library was synthesized which led to identification of potent N3-alkyl substituted pyrimidoindoles that were not only active in vitro but also enhanced antibody responses in vivo when used as a coadjuvant. The novel HTS strategy led to identification of compounds that are intrinsically quiescent but functionally prolong stimulation by a TLR4 ligand and thereby potentiate vaccine efficacy.
- Chan, Michael,Ahmadi, Alast,Yao, Shiyin,Sato-Kaneko, Fumi,Messer, Karen,Pu, Minya,Nguyen, Brandon,Hayashi, Tomoko,Corr, Maripat,Carson, Dennis A.,Cottam, Howard B.,Shukla, Nikunj M.
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supporting information
p. 533 - 543
(2017/10/13)
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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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- Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes
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Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1–38) were elucidated by IR,1H NMR,13C NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 26–29 indicated important inhibitory activity on AChE enzyme. Kinetic studies were performed in order to observe the effects of the most active compounds on substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the compounds. The compounds 26–29 were found to be nontoxic at their effective concentrations against AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were performed for the most active compounds 26–29 and interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds.
- Sa?l?k, Begüm Nurpelin,Ilg?n, Sinem,?zkay, Yusuf
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p. 1026 - 1040
(2016/11/09)
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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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- 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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- Synthesis and biological evaluation of novel benzothiazole clubbed fluoroquinolone derivatives
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In the present investigation, synthesis and anti-bacterial, analgesic and anthelmintic evaluation of a novel series of fluoroquinolone derivatives clubbed with benzothiazole moeity has been described. The synthesized compounds were characterised by spectral analysis (IR and H NMR). Preliminary results indicated that the most of the synthesized compounds demonstrated good activities against gram negative and gram positive bacterial strains. Compounds 5a, 5b, 5f and 5k demonstrated potent anti-bacterial activities. Compound 5a exhibited most potent anti-bacterial activity with MIC values of 04, 03, 08 and 15 μg/ mL against B. subtilis, S. aureus, E. coli and P. aeruginosa. Analogs 5a, 5c, 5g and 5h showed promising anthelmintic activity against Eisemia foetida in a low concentration as compared to standard drug piperazine citrate with mean paralysis time ranging 22.60 ± 2.46 to 31.60 ± 3.07 min. All synthesized compounds depicted good in vivo analgesic activity with compound 5a exhibiting the most potent activity of 55.19% inhibition of writhing in comparison to the standard drug.
- Sharma, Prabodh Chander,Kumar, Ravinder,Chaudhary, Monika,Sharma, Archana,Rajak, Harish
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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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- Analgesic and antiinflammatory activity of derivatives of 2-aminobenzothiazole
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A series of 5-(4-substituted benzylidene-2-(substituted benzo[d]thiazol-2-ylimino)thiazolidin-4-one (5a-r) have been synthesized from 2-aminobenzothiazole as starting material. Condensation of thiazolidin-4-one with different substituted aromatic benzaldehyde occurred at reactive methylene group present at C-5 position of thiazolidin-4-one ring and resulted in the formation of compounds (5a-r). These were characterized using physical and spectral methods. The compounds (5a-r) were evaluated for analgesic and antiinflammatory activity using in vivo models.
- Deodhar, Meenakshi N.,Dongre, Ashishkumar C.,Kudale, Sayali D.
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p. 2747 - 2752
(2012/09/22)
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- Novel 3-nitro-1 H -1,2,4-triazole-based amides and sulfonamides as potential antitrypanosomal agents
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A series of novel 3-nitro-1H-1,2,4-triazole-based (and in some cases 2-nitro-1H-imidazole-based) amides and sulfonamides were characterized for their in vitro antitrypanosomal and antileishmanial activities as well as mammalian toxicity. Out of 36 compounds tested, 29 (mostly 3-nitro-1H-1,2,4-triazoles) displayed significant activity against Trypanosoma cruzi intracellular amastigotes (IC50 ranging from 28 nM to 3.72 μM) without concomitant toxicity to L6 host cells (selectivity 66-2782). Twenty-three of these active compounds were more potent (up to 58-fold) than the reference drug benznidazole, tested in parallel. In addition, nine nitrotriazoles which were moderately active (0.5 μM ≥ IC50 6.0 μM) against Trypanosoma brucei rhodesiense trypomastigotes were 5-31-fold more active against bloodstream-form Trypanosoma brucei brucei trypomastigotes engineered to overexpress reduced nicotinamide adenine dinucleotide dependent nitroreductase. Finally, three nitrotriazoles displayed a moderate activity against the axenic form of Leishmania donovani. Therefore, 3-nitro-1H-1,2,4-triazole-based amides and sulfonamides are potent antitrypanosomal agents.
- Papadopoulou, Maria V.,Bloomer, William D.,Rosenzweig, Howard S.,Chatelain, Eric,Kaiser, Marcel,Wilkinson, Shane R.,McKenzie, Caroline,Ioset, Jean-Robert
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experimental part
p. 5554 - 5565
(2012/08/29)
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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 and pharmacological screening of novel (2-(4-Methyl-2-oxo-2H- chromen-7-yloxy)-N-(benzo[d]thiazol-2-yl))acetamide derivatives
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A new series of 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)-N-(benzo[d]thiazol-2- yl)acetamide derivatives (4a-k) was synthesized and evaluated for their D 2 and 5HT2 antagonistic activity as a measure of atypical antipsychotic property. Compounds (4a-k) were synthesized by refluxing various N-(benzothiazol-2-yl)-2-chloroacetamides substituted derivatives (3a-k) with 7-hydroxy-4 methyl-2H-chromen-2-one (1) in acetonitrile and anhydrous K 2CO3. N-(Benzothiazol-2-yl)-2-chloroacetamides substituted derivatives (3a-k) were prepared from the chloroacetyl chloride with various 2-amino benzothiazole substituted derivatives (2a-k). The synthesized compounds were characterized with the help of spectral and analytical data. Most of these compounds showed dopamine D2 receptor antagonistic activity from moderate to high affinity along with serotonin 5-HT2 receptor blockage activity: a property that has been suggested as necessary for atypicality. The D 2 and 5-HT2 receptor blockage activity was evaluated by inhibition of apomorphine-induced climbing behaviour and 5HTP induced head twitches in mice, respectively.
- Gawai, Ashish,Das, Sanjib,Nemade, Mahesh,Wathore, Sandeep
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p. 3969 - 3974
(2012/01/13)
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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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- AZOLE DERIVATIVES AS WTN PATHWAY INHIBITORS
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The present invention relates to new compounds of formula I, to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy. Such compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the Wnt pathway. For example, these may be used in preventing and/or retarding proliferation of tumor cells, for example carcinomas such as colon carcinomas.
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Page/Page column 117-118
(2010/12/29)
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- Thiazole and benzothiazole derivatives of cytisine
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Several new derivatives were prepared by reacting N-1(5-R-thiazol-2-yl)-2- chloroacetamides and N-1(6-R-benzothiazol-2-yl)chloroacetamides with cytisine.
- Saprykina,Vinogradova,Ambartsumova,Ibragimov,Shakhidoyatov
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p. 470 - 472
(2008/02/07)
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