- Design, synthesis, docking study and urease inhibitory activity evaluation of novel 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-N-arylacetamide derivatives
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In this paper, novel 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-N-arylacetamide derivatives (7a–l) are designed, synthesized, and evaluated in vitro for their urease inhibitor activities. The compounds are synthesized efficiently in three steps in high isolated yields from amines, 2-chloroacetyl chloride, hydrazinecarbothioamide, and carbon disulfide. The molecular docking simulation were performed using AutoDock4 by docking all synthesized compound and standard inhibitors into the crystal structure of Jack bean urease. Comparison between the urease inhibitory activity of compounds 7a–l with the IC50 of (2.85–5.83 μM) and thiourea and hydroxyurea as standards inhibitors with the IC50 of (22.00 and 100.00 μM, respectively) proved the high activity of the synthesized compounds against the mentioned enzyme. Docking results were in good agreement with experimental results and indicate that synthesized compounds could interact well with the active site of the urease enzyme and among all; compound 7j shows more favorable interactions with the active site which confirm its great inhibitory activity with IC50 of 2.85 μM. Therefore, compound 7j might be a promising candidate for further evaluation.
- Nazari Montazer, Mohammad,Asadi, Mehdi,Bahadorikhalili, Saeed,Hosseini, Faezeh Sadat,Amanlou, Arash,Biglar, Mahmood,Amanlou, Massoud
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- Synthesis and Biological Evaluation of Endocannabinoid Uptake Inhibitors Derived from WOBE437
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WOBE437 ((2E,4E)-N-(3,4-dimethoxyphenethyl)dodeca-2,4-dienamide, 1) is a natural product-derived, highly potent inhibitor of endocannabinoid reuptake. In this study, we synthesized almost 80 analogues of 1 with different types of modifications in the dodecadienoyl domain as well as the dimethoxyphenylethyl head group, and we investigated their effects on anandamide uptake into U937 cells. Intriguingly, none of these analogues was a more potent inhibitor of anandamide uptake than WOBE437 (1). At the same time, a number of WOBE437 variants exhibited potencies in the sub-100 nM range, with high selectivity over inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase; two compounds were virtually equipotent with 1. Interestingly, profound activity differences were observed between analogues in which either of the two methoxy substituents in the head group had been replaced by the same bulkier alkoxy group. Some of the compounds described here could be interesting departure points for the development of potent endocannabinoid uptake inhibitors with more drug-like properties.
- M?der, Patrick,Bartholom?us, Ruben,Nicolussi, Simon,Baumann, Alice,Weis, Melanie,Chicca, Andrea,Rau, Mark,Sim?o, Ana Catarina,Gertsch, Jürg,Altmann, Karl-Heinz
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supporting information
p. 145 - 154
(2020/06/02)
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- Novel chromenyl-based 2-iminothiazolidin-4-one derivatives as tubulin polymerization inhibitors: Design, synthesis, biological evaluation and molecular modelling studies
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Here-in, we present molecular design, chemical synthesis and evaluation of novel chromenyl-based 2-iminothiazolidin-4-one derivatives as tubulin polymerization inhibitors. The newly synthesized compounds were evaluated for their in vitro cytotoxicities against A549 (lung cancer), MDA-MB-231 and BT-471 (breast cancer), HepG2 (liver cancer) and HCT-116 (colon cancer) cell lines by MTT assay. Among the synthesized compounds, compound 12b showed excellent anticancer activity on MDA-MB-231 cell line with IC50 value of 0.95 ± 1.88 μM and was verified to be safe in normal human bronchial epithelial cells (Beas-2B). Apoptosis induced by the lead 12b was observed using morphological observations, AO/EB and DAPI staining procedures. Further, dose-dependent increase in the depolarization of mitochondrial membrane was also observed through JC-1 staining. Annexin V-FITC/PI assay confirmed that 12b induced early apoptosis. Additionally, cell cycle analysis indicated that the MDA-MB-231 cells were arrested at sub-G2/M phase and also inhibited tubulin polymerization with IC50 value of 3.54 ± 0.2 μM. Molecular docking simulations were employed to identify the important binding modes responsible for the tubulin inhibitory activity, thus supporting their effective anticancer potential.
- Bathini, Nagendra Babu,Godugu, Chandraiah,Guggilapu, Sravanthi Devi,Kadagathur, Manasa,Pooladanda, Venkatesh,Sigalapalli, Dilep Kumar,Tangellamudi, Neelima D.,Uppu, Jaya Lakshmi
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- Discovery of Dihydropyrrolo[1,2- a]pyrazin-3(4 H)-one-Based Second-Generation GluN2C- And GluN2D-Selective Positive Allosteric Modulators (PAMs) of the N-Methyl- d -Aspartate (NMDA) Receptor
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The N-methyl-d-aspartate receptor (NMDAR) is an ion channel that mediates the slow, Ca2+-permeable component of glutamatergic synaptic transmission in the central nervous system (CNS). NMDARs are known to play a significant role in basic neurological functions, and their dysfunction has been implicated in several CNS disorders. Herein, we report the discovery of second-generation GluN2C/D-selective NMDAR-positive allosteric modulators (PAMs) with a dihydropyrrolo[1,2-a]pyrazin-3(4H)-one core. The prototype, R-(+)-EU-1180-453, exhibits log unit improvements in the concentration needed to double receptor response, lipophilic efficiency, and aqueous solubility, and lowers cLogP by one log unit compared to the first-generation prototype CIQ. Additionally, R-(+)-EU-1180-453 was found to increase glutamate potency 2-fold, increase the response to maximally effective concentration of agonist 4-fold, and the racemate is brain-penetrant. These compounds are useful second-generation in vitro tools and a promising step toward in vivo tools for the study of positive modulation of GluN2C- and GluN2D-containing NMDA receptors.
- Epplin, Matthew P.,Mohan, Ayush,Harris, Lynnea D.,Zhu, Zongjian,Strong, Katie L.,Bacsa, John,Le, Phuong,Menaldino, David S.,Traynelis, Stephen F.,Liotta, Dennis C.,Liotta, Dennis C.
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p. 7569 - 7600
(2020/08/21)
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- Effective Synthesis of 3,4-Diaryl-isoxazole-5-carboxamides and their Antiproliferative Properties
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A simple scalable procedure for the synthesis of 3,4-diaryl-isoxazole-5-carboxamides 6 under mild conditions from readily available material was developed. The targeted compounds 6, structural analogues of heat shock protein inhibitors, were obtained by the rearrangement of intermediate 3,4-diaryl-5-carboxamido-isoxazoline N-oxides 5. In contrast to carboxamido-isoxazoline oxides 5, base-catalyzed recyclization of 3,4-diaryl-5-(ethoxycarbonyl)isoxazoline N-oxides 9c unexpectedly yielded 5-hydroxy-1,2-oxazin-6-ones 17c instead of ethyl 3,4-diaryl-isoxazole-5-carboxylates 10. Crystal and molecular structure of 4-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-5-hydroxy-3-phenyl-6H-1,2-oxazin-6-one 17c was established by single-crystal X-ray diffraction study. In a phenotypic sea urchin embryo assay, carboxamide 6f showed moderate antimitotic antitubulin activity compared to 5-unsubstituted 3,4-diarylisoxazoles 15, which featured strong microtubule destabilizing effect.
- Maksimenko, Anna S.,Kislyi, Victor P.,Chernysheva, Natalia B.,Strelenko, Yuri A.,Zubavichus, Yan V.,Khrustalev, Victor N.,Semenova, Marina N.,Semenov, Victor V.
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p. 4260 - 4270
(2019/07/12)
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- Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study
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A series of certain benzyl/phenethyl thiazolidinone-indole hybrids were synthesized for the study of anti-proliferative activity against A549, NCI-H460 (lung cancer), MDA-MB-231 (breast cancer), HCT-29 and HCT-15 (colon cancer) cell lines by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We found that compound G37 displayed highest cytotoxicity with IC50 value of 0.92 ± 0.12 μM towards HCT-15 cancer cell line among all the synthesized compounds. Moreover, compound G37 was also tested on normal human lung epithelial cells (L132) and was found to be safe in contrast to HCT-15 cells. The lead compound G37 showed significant G2/M phase arrest in HCT-15 cells. Additionally, compound G37 significantly inhibited tubulin polymerization with IC50 value of 2.92 ± 0.23 μM. Mechanistic studies such as acridine orange/ethidium bromide (AO/EB) dual staining, DAPI nuclear staining, annexinV/propidium iodide dual staining, clonogenic growth inhibition assays inferred that compound G37 induced apoptotic cell death in HCT-15 cells. Moreover, loss of mitochondrial membrane potential with elevated intracellular ROS levels was observed by compound G37. These compounds bind at the active pocket of the α/β-tubulin with higher number of stable hydrogen bonds, hydrophobic and arene-cation interactions confirmed by molecular modeling studies.
- Sigalapalli, Dilep Kumar,Pooladanda, Venkatesh,Singh, Priti,Kadagathur, Manasa,Guggilapu, Sravanthi Devi,Uppu, Jaya Lakshmi,Tangellamudi, Neelima D.,Gangireddy, Pavan Kumar,Godugu, Chandraiah,Bathini, Nagendra Babu
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supporting information
(2019/08/26)
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- Synthesis and structure activity relationship of tetrahydroisoquinoline- based potentiators of GluN2C and GluN2D containing N-Methyl-D-aspartate receptors
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We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the
- Santangelo Freel, Rose M.,Ogden, Kevin K.,Strong, Katie L.,Khatri, Alpa,Chepiga, Kathryn M.,Jensen, Henrik S.,Traynelis, Stephen F.,Liotta, Dennis C.
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supporting information
p. 5351 - 5381
(2013/07/26)
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- 3-aroylmethylene-2,3,6,7-tetrahydro-1 H -pyrazino[2,1- a ]isoquinolin-4(11b H)-ones as potent Nrf2/ARE inducers in human cancer cells and AOM-DSS treated mice
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Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation, and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house data
- Xi, Mei-Yang,Jia, Jian-Min,Sun, Hao-Peng,Sun, Zhong-Ying,Jiang, Jie-Wei,Wang, Ya-Jing,Zhang, Min-Ye,Zhu, Jun-Feng,Xu, Li-Li,Jiang, Zheng-Yu,Xue, Xin,Ye, Ming,Yang, Xi,Gao, Yuan,Tao, Lei,Guo, Xiao-Ke,Xu, Xiao-Li,Guo, Qing-Long,Zhang, Xiao-Jin,Hu, Rong,You, Qi-Dong
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p. 7925 - 7938
(2013/11/06)
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- Synthesis of bioactive 2-aza-analogues of ipecac and alangium alkaloids
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License to kill: Substitution of the methine carbon C2 in the ipecac or alangium alkaloids by nitrogen yields functional mimetics with low micromolar to high naonomolar IC50 values against Trypanosoma brucei, the parasite that causes African tr
- Koelzer, Michael,Weitzel, Kerstin,Goeringer, H. Ulrich,Thines, Eckhard,Opatz, Till
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experimental part
p. 1456 - 1464
(2011/11/29)
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- Design and synthesis of novel pyrazino[2,1-a]isoquinoline derivatives with potent antifungal activity
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A series of novel pyrazino[2,1-a]isoquinoline compounds were designed, synthesized, and their antifungal activities in vitro were evaluated. The results showed that all of the title compounds exhibited antifungal activities. Most of them exhibited stronge
- Tang, Hui,Zheng, Can-Hui,Zhu, Ju,Fu, Bing-Yue,Zhou, You-Jun,Lv, Jia-Guo
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experimental part
p. 360 - 366
(2011/07/09)
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- Synthesis and antifungal activities in vitro of novel pyrazino [2,1-a] isoquinolin derivatives
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A series of novel pyrazino[2,1-a]isoquinolin compounds were designed and synthesized, and their antifungal activities in vitro were evaluated. The results showed that all of the compounds exhibited antifungal activities. Some of them exhibited stronger an
- Tang, Hui,Zheng, Canhui,Lv, Jiaguo,Wu, Juan,Li, Yanan,Yang, Hui,Fu, Bingyue,Li, Chuntong,Zhou, Youjun,Zhu, Ju
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scheme or table
p. 979 - 982
(2010/06/12)
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- TETRAHYDRO ISOQUINOLINE DERIVATIVES, PREPARATION METHODS AND MEDICINAL USES THEREOF
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A kind of tetrahydro isoquinoline derivatives (I), their preparation methods, medicine compositions and medicinal uses thereof, especially their uses as κ-opioid receptor excitant in pain relieving, which belongs to the medicine chemistry. The substituents R1, R2, R3, R4 of general formula (I) are defined as the description.
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Page/Page column 13
(2009/04/23)
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- General and efficient strategy for erythrinan and homoerythrinan alkaloids: Syntheses of (±)-3-demethoxyerythratidinone and (±)- erysotramidine
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A general and efficient strategy to both aromatic-type and nonaromatic-type erythrinan and homoerythrinan alkaloids has been developed. This approach involves a key two-step sequence, an alkylation of a ketone with various N-substituted iodoacetamides fol
- Gao, Shuanhu,Tu, Yong Qiang,Hu, Xiangdong,Wang, Shaohua,Hua, Rongbao,Jiang, Yijun,Zhao, Yuming,Fan, Xiaohui,Zhang, Shuyu
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p. 2373 - 2376
(2007/10/03)
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- Novel formation of 1,3-oxazepine heterocycles via palladium-catalyzed intramolecular coupling reaction
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The oxazepine ring systems containing pyridazinone moiety were constructed via palladium-catalyzed intramolecular coupling reaction. The best conditions for this reaction were Pd(OAc)2 as a palladium source, 1,1′-bis(diphenylphosphino)-ferrocene (DPPF) as the ligand, and K2CO3 as base at 80 °C in toluene. The products have potential applications as biological and medicinal relevant compounds.
- Ma, Chen,Liu, Shao-Jie,Xin, Liang,Falck,Shin, Dong-Soo
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p. 9002 - 9009
(2007/10/03)
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- Synthesis of heterocyclic and non-heterocyclic entities as antibacterial and anti-HIV agents
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3,4-dimethoxy-1-[{(2-aryl/alkyl amino)-2-oxoethyl} amino]-ethylbenzene 4a-o and 2-[{2-(3,4-dimethoxy phenyl ethyl amino)-2-oxo ethyl}amino]-4,6-diaryl pyrimidines 5a-o have been synthesized and tested for their antibacterial and anti-HIV activities against different microorganisms. The structures of novel synthesized compounds have been established on the basis of elemental analyses, 1H NMR, IR and mass spectral data.
- Patel,Chikhalia
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p. 1871 - 1879
(2007/10/03)
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- Synthesis and biological evaluation of pyridooxazine-tetrahydroisoquinoline derivatives as MDR modulators
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Pyridooxazine-tetrahydroisoquinoline derivatives were designed and synthesized for MDR modulating activity. Pyridooxazin-2-one scaffolds were constructed in a one-pot annulation of N-substituted-2-chloroacetamides with 2-bromo-3-hydroxy pyridine via Smile
- Ma, Chen,Liu, Shao-Jie,Xin, Liang,Zhang, Qun,Ding, Kai,Falck,Shin, Dong-Soo
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p. 1010 - 1011
(2007/10/03)
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- Synthesis of 2-, 4- And 5-(2-alkylcarbamoyl-l-methylvinyl)-7- alkyloxybenzo[b]furans and their leukotriene 64 receptor antagonistic activity
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Variable benzo[6]furan derivatives having (E)- and (Z)-2-alkylcarbamoyl-l- methylvinyl groups at the 2-, 4- and 5-positions and a carboxylpropoxy or (1-phenyl)ethoxy group at the 7-position were prepared to find novel and selective leukotriene B4 (LTB4) receptor antagonists. (E)-2-(2-Diethylcarbamoyl- l-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (4v) showed selective inhibition to the human BLT2 receptor (hBLT2). On the other hand, (E)-2-acetyl-4-(2-diethylcarbamoyl-l-methylvinyl)-7-(l-phenylethoxy)benzo[b] furan (7v) inhibited both human BLTi receptor (hBLT1) and hBLT 2. The (E)-2-(2-diethylcarbamoyl-l-methylvinyl) group lay on approximately the same plane as the benzo[e]furan ring, whereas the (E)-4-(2-diethylcarbamoyl-l-methylvinyl) group had the torsion angle (45.7°) from the benzo[e]furan ring plane. However, the (Z)-(2-alkylcarbamoyl-l- methylvinyl)benzo[b]furans were inactive. The inhibitory activity depended on the conformation of the 2-diethylcarbamoyl-l-methylvinyl group. The Royal Society of Chemistry 2005.
- Ando, Kumiko,Tsuji, Eriko,Ando, Yuko,Kunitomo, Jun-Ichi,Kobayashi, Reina,Yokomizo, Takehiko,Shimizu, Takao,Yamashita, Masayuki,Ohta, Shunsaku,Nabe, Takeshi,Kohno, Shigekatsu,Ohishi, Yoshitaka
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p. 2129 - 2139
(2007/10/03)
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- One-pot synthesis of pyridazino[1,4]oxazin-3-ones
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Pyridazino[1,4]oxazin-3-ones were conveniently prepared in a one-pot condensation of N-substituted 2-chloroacetamides with various 5-chloro-pyridazin-6-ones via rearrangement of a spiro-aminoketal intermediate.
- Ma, Chen,Cho, Su-Dong,Falck,Shin, Dong-Soo
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p. 1399 - 1405
(2007/10/03)
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- Synthetic studies on isoquinoline derivatives with multidrug resistance (MDR) modulating activity
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Tetrahydropyridazino-1,4-oxazinoisoquinoline derivatives with multidrug Resist. (MDR) modulating activity were designed and synthesized. A key step for cyclization of 1,4-oxazine ring was developed using K2CO3 and CH3CN in one-pot. Among prepared compounds, 2-(4-fluorobenzyl)-9,10-dimethoxy-12-methyl-6,7,11b,12-tetrahydropyridazino[4', 5',5,6] [1,4]oxazine-[3,4,-a]isoquinolin-1(2H)-one (1f) exhibited significant MDR reversing activity and low toxicity, which might be as potential MDR agent.
- Ma, Chen,Cho, Su-Dong,Falck,Shin, Dong-Soo
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- Novel synthesis of pyridazino[4,5-b][1,4]oxazin-3,8-diones
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A novel and effective synthesis of pyridazino[4,5-b][1,4]oxazin-3,8-diones via Smiles rearrangement is presented. Treatment of N-substituted 2-chloro(or hydroxy)acetamide, 2-tetrahydropyranyl-4-chloro-5-hydroxy(or chloro)pyridazin-3-one and cesium carbonate in refluxing acetonitrile was afforded the corresponding pyridazino[4,5-b][1,4]oxazin-3,8-diones in excellent yield.
- Cho, Su-Dong,Song, Sang-Yong,Park, Yong-Dae,Kim, Jeum-Jong,Joo, Woo-Hong,Shiro, Motoo,Falck,Shin, Dong-Soo,Yoon, Yong-Jin
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p. 8995 - 8998
(2007/10/03)
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- A one-pot synthesis of pyrido[2,3.b][1,4]oxazin-2-ones
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Pyrido[2,3-b][1,4]oxazin-2-ones are conveniently prepared in excellent yields by a one-pot annulation of N-substituted-2-chloroacetamides with 2-halo-3-hydroxypyridines with use of cesium carbonate in refluxing acetonitrile. The key transformation features a Smiles rearrangement of the initial O-alkylation product and subsequent cyclization.
- Cho, Su-Dong,Park, Yong-Dae,Kim, Jeum-Jong,Lee, Sang-Gyeong,Ma, Chen,Song, Sang-Yong,Joo, Woo-Hong,Falck,Shiro, Motoo,Shin, Dong-Soo,Yoon, Yong-Jin
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p. 7918 - 7920
(2007/10/03)
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- An efficient synthesis of γ-substituted α,β-unsaturated-δ-lactams. Formal synthesis of (±)-protoemetinol
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γ-Substituted α,β-unsaturated δ-lactams 1 was synthesized from α-sulfinyl acetamides 3 in three steps. Formal synthesis of (±)-protoemetinol was also reported.
- Huang, Chang-Gin,Chang, Bo-Rui,Chang, Nein-Chen
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p. 2721 - 2723
(2007/10/03)
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- Synthesis of a small library of phenylalkylamide derivatives as melatoninergic ligands for human mt1 and MT2 receptors
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Focused small libraries of melatonin receptor ligands from arylalkylamine derivatives were synthesised by combinatorial chemistry using the mix and split method in the solid phase. A library of 108 compounds was then synthesised from 12 arylalkyl amines and nine carboxylic acids. The compound mixtures were evaluated on chicken brain melatonin and recombinant human mt1 and MT2 receptors. Deconvolution of the most potent mixture demonstrated the superiority of 3-methoxy and 2,5-dimethoxy substitution on the phenyl ring with isopropyl, propyl and ethyl amido chains. Several compounds with nanomolar affinity for human melatonin receptors were obtained. (C) 2000 Elsevier Science Ltd.
- Pegurier, C.Ecile,Curtet, Sophie,Nicolas, Jean-Paul,Boutin, Jean A.,Delagrange, Philippe,Renard, Pierre,Langlois, Michel
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p. 163 - 171
(2007/10/03)
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- Synthesis of some azeto[2,1-a]isoquinolin-2-ones
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Some azeto[2,1-a]isoquinolin-2-ones were synthesized from 2-(3,4- dimethoxyphenyl)ethylamine in three steps in good yield.
- Cho, Su-Dong,Kim, Sung-Kyu,Yoon, Yong-Jin
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- STUDIES ON m-CYCLOPHANE FORMATION FROM THE PHOTOLYSIS OF CHLOROACETAMIDE DERIVATIVES
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The synthesis of 12-hydroxy-2-oxa-6-azabicyclotrideca-1(13),9,11-trien-5-one (4) is described.Two routes to (4) based on the photolysis of N-chloroacetamide (2b) and N-chloroacetamide (2c) followed by O-demethylation or O-desilylation, were developed.Extension of the work has given the new m-cyclophane ester derivative (9), whose structure has been confirmed by X-ray crystallography.
- Rezaie, Robert,Bremner, John B.,Blanch, Gregory K.,Skelton, Brian W.,White, Allan H.
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p. 959 - 972
(2007/10/02)
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- 1,2,4-triazinone derivatives, their preparation and use
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Compounds of formula (I): STR1 (in which: R1 is hydrogen or alkl; R2 is a variety of groups or atoms; R3 is optionally substituted hydroxy or --(NH)n --NR5 R6, wherein R5 and R6 are a variety of groups or atoms, preferably alkyl substituted by heterocyclic, and n is 0 or 1; Q is oxygen or sulfur; and A is a C1 -C6 alkylene group) have valuable cardiotionic activity and may be used for the treatment of cardiac disorders. They may be prepared from corresponding compounds containing a benzene ring with a group --QH at the 1-position and a group --CO--CHR1 --NH--COOR7 at the 4-position by ring closure and introduction of the group of formula --A--CO--R3 in any order.
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