- Synthesis, Evaluation and Molecular Docking of Thiazolopyrimidine Derivatives as Dipeptidyl Peptidase IV Inhibitors
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A series of thiazolopyrimidine derivatives was designed, synthesized and screened for in-vitro inhibition of Dipeptidyl Peptidase IV (DPP IV). The SAR study indicated the influence of substituted chemical modifications on thiazolopyrimidine scaffold. Comp
- Sharma, Mani,Gupta, Monica,Singh, Divya,Kumar, Manoj,Kaur, Punit
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- Conventional and microwave-assisted synthesis of new 1H-benzimidazole-thiazolidinedione derivatives: A potential anticancer scaffold
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A series of new benzimidazole bearing thiazolidinedione derivatives has been designed, synthesized by using conventional as well as microwave-assisted methods. Microwave-assisted synthesis caused a significant reduction in the reaction times and improvement in the yields of all the derivatives. All the new synthesized compounds were evaluated for their in vitro cytotoxic potential against selected human cancer cell lines of breast (MDAMB-231), prostate (PC-3), cervical (HeLa), lung (A549) and bone (HT1080) along with a normal kidney cells (HeK-293T). The compounds 17n, 17p and 17q were found to be potent cytotoxic with IC50 values in the range of 0.096–0.63 μM on PC-3, HeLa, A549 and HT1080 cancer cells. Most of the compounds have found to be safe on normal HeK-293T kidney cells in comparison to cancer cells. The treatment of cells with 17p and 17q showed the typical apoptotic morphological features like fragmentation and shrinkage of nuclei. Further, test compounds resulted in inhibition of cell migration through disruption of F-actin protein assembly. Hoechst, DCFH-DA staining, mitochondrial membrane and annexin binding assays revealed that the cancer cell proliferation was inhibited through induction of apoptosis in A549 cells.
- Sharma, Pankaj,Reddy, T. Srinivasa,Kumar, Niggula Praveen,Senwar, Kishna Ram,Bhargava, Suresh K.,Shankaraiah, Nagula
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- A C-3-Selective Direct Alkylation of Coumarins by Using a Microwave-Assisted Xanthate-Based Radical Reaction
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A xanthate-based oxidative radical process for the direct alkylation of the coumarin ring system is presented. In the reaction, a vinylic and unactivated C-H bond of the coumarin system is replaced by an α-acyl functionality under neutral conditions. This reaction has a high reaction site selectivity, which can realize alkylation at the C-3 position. A vinylic and unactivated C-H bond of the coumarin system is replaced by an alkyl functionality trough a xanthate-based radical reaction (DLP = dilauroyl peroxide).
- Miranda, Luis D.,Icelo-ávila, Estefanía,Rentería-G?mez, ángel,Pila, Michell,Marrero, Joaquín G.
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- Synthesis of 3-(aminooxoethyl)-6-methyl-1-(thiethan-3-yl)-pyrimidine-2,4-(1H,3H)-diones
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A new approach to prepare 2-chloroacetamides has been developed, based on the reaction of chloroacetyl chloride with excess of secondary amines. Alkylation of 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione with the synthesized 2-chloroacetamides in the presence of potassium carbonate has afforded N 3-acetamido-substituted 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-diones.
- Meshcheryakova
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- Asymmetric synthesis of pochonin e and F, revision of their proposed structure, and their conversion to potent Hsp90 inhibitors
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A concise and modular synthesis of pochonin E and F, and their epimers at C-6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C-6 position. Molecular dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.
- Karthikeyan, Ganesan,Zambaldo, Claudio,Barluenga, Sofia,Zoete, Vincent,Karplus, Martin,Winssinger, Nicolas
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- Design, synthesis, and biological evaluation of 2,6,7-substituted pyrrolo[2,3-d]pyrimidines as cyclin dependent kinase inhibitor in pancreatic cancer cells
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Pancreatic cancer is a highly malignant tumor, and more effective treatment is urgently needed to lengthen the life of patients. In this paper a class of new 2,6,7-substituted pyrrolo[2,3-d]pyrimidine derivatives of CDK 4/6 inhibitor ribociclib (1) was de
- Shi, Xingpeng,Quan, Yanni,Wang, Yixuan,Wang, Ying,Li, Yanping
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- Structure–activity relationship investigation of coumarin–chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors
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Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin–chalcone hybrids (5d–7j, 9d–11f, 12k–13m) against AChE and BChE. The nature and position of the chalcone substituents had major effects on inhibitory activity as well as selectivity for AChE over BChE. Compounds with para-substituted chalcone fragments in which the substituents were choline-like had potent activity against AChE and poor activity against BChE, while ortho-substituted analogs exhibited an opposite effect. Replacement of the terminal amine groups by amide, alkyl or alkenyl groups abrogated activity. Compound 5e showed potent inhibitory activity (IC50=0.15±0.01μmol/L) and good selectivity for AChE over BChE (ratio 27.4), and a kinetic study showed that 5e exhibited mixed-type inhibition against AChE. Computational docking results indicate that 5e binds to Trp 279, Tyr334 and Trp 84 in AChE, but only to Trp 82 in BChE. Overall, the results show that coumarin–chalcone hybrids with choline-like side-chains have promising activity and selectivity against AChE and be promising therapeutic leads for Alzheimer’s disease.
- Kang, Lu,Gao, Xiao-Hui,Liu, Hao-Ran,Men, Xue,Wu, Hong-Nian,Cui, Pei-Wu,Oldfield, Eric,Yan, Jian-Ye
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- Design and Synthesis of New Aryloxy-linked Dimeric 1,2,3-Triazoles via Click Chemistry Approach: Biological Evaluation and Molecular Docking Study
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A quest for more potent new antitubercular agents has prompted to design and synthesize aryloxy-linked dimeric 1,2,3-triazoles (4a–j), from azides (2a-e) and bis(prop-2-yn-1-yloxy)benzene (3a–b) on 1,3-dipolar cycloaddition reaction via copper (I)-catalyzed click chemistry approach with good to better yields. The titled compounds (4a–j) were designed using molecular hybridization approach by assembling various bioactive pharmacophoric fragments in a single molecular framework. All the synthesized compounds have been screened for their in vitro antitubercular, antifungal, and antioxidant activities against their respective strains. Among them, 4h and 4i show the highest antifungal activity, whereas compounds 4h, 4i, and 4j have revealed promising antitubercular activity against their respective strains. In addition to this, most of the synthesized compounds were found as potent antifungal and antioxidant agents. A significant network of bonded and non-bonded interactions stabilized these molecules into the active site of fungal CYP51 that is realized from the obtained well-placed docking poses and the associated thermodynamic interactions with the enzyme. The synthesized compounds have also been analyzed for absorption, distribution, metabolism, and excretion properties.
- Deshmukh, Tejshri R.,Khare, Smita P.,Krishna, Vagolu S.,Sriram, Dharmarajan,Sangshetti, Jaiprakash N.,Bhusnure, Omprakash,Khedkar, Vijay M.,Shingate, Bapurao B.
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- Synthesis, evaluation and molecular docking of prolyl-fluoropyrrolidine derivatives as dipeptidyl peptidase IV inhibitors
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A series of prolyl-fluoropyrrolidine derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study revealed the influence of substituted chemical modifications on dipeptidyl peptidase IV inhibitory activity. Among all the compounds screened, compound 9 (IC50 = 0.83 μm) and 10 (IC50 = 0.43 μm) possessing aryl substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors. Both the compounds 9 and 10 resulted significant reduction in glucose excursion during oral glucose tolerance test in streptozotocin-induced diabetic rat model at single dose of 10 mg/kg. Molecular docking studies were performed to illustrate the probable binding mode and interactions of prolyl-fluoropyrrolidine nucleus and its derivatives at binding site of receptor. The fluoropyrrolidine moiety of prolyl-fluoropyrrolidine derivatives occupied S1 pocket as observed in the crystal structure (PDB id: 2FJP). The compounds 9 and 10 were observed to occupy S2 binding pocket and were observed to have interaction with Arg125, Tyr547 and Ser630 acquired through hydrogen bond. The aryl moiety at piperazine ring was found to extend into the cavity and interacted with Arg358. The observed interactions signalled that occupancy of the highly hydrophobic S2 pocket is very crucial for dipeptidyl peptidase IV inhibitory activity. A series of prolyl-fluoropyrrolidine derivatives were synthesized and evaluated for inhibition of dipeptidyl peptidase IV (DPP IV) for treatment of Type 2 diabetes. The binding position of docked compounds (stick rendering) in the binding pocket of DPP IV.
- Sharma, Mani,Gupta, Monica,Singh, Divya,Kumar, Manoj,Kaur, Punit
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- Access to newly functionalized imidazole derivatives: Efficient synthesis of novel 5-amino-2-thioimidazoles using propylphosphonic anhydride (T3P)
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We describe here an efficient method to synthesize 5-amino-2-thioimidazole compounds by T3P-mediated cyclization of N-acetamidoisothiourea intermediates. The newly functionalized 5-amino-2-thioimidazole compounds are finally obtained in 5 steps from an amine as starting block.
- Lasalle, Manuel,Picon, Sylvain,Boulahjar, Rajaa,Hoguet, Vanessa,Van Obbergen, Jolien,Roussel, Pascal,Deprez, Benoit,Charton, Julie
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- Indoles and 1-(3-(benzyloxy)benzyl)piperazines: Reversible and selective monoamine oxidase B inhibitors identified by screening an in-house compound library
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The therapeutic indications for monoamine oxidases A and B (MAO-A and MAO-B) inhibitors that have emerged from biological studies on animal and cellular models of neurological and oncological diseases have focused drug discovery projects upon identifying
- ?akelj, Simon,Frlan, Rok,Gobec, Stanislav,Hrast, Martina,Knez, Damijan,Kos, Janko,Pi?lar, Anja
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- Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer
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1,2,3-triazoles have continuously shown effectiveness as biologically active systems towards various cancers, and when used in combination with steroid skeletons as a carrier, which can act as a drug delivery system, allows for a creation of a novel set of analogs that may be useful as a pharmacophore leading to a potential treatment option for cancer. A common molecular target for cancer inhibition is that of the Epidermal Growth Factor Receptor/Mitogen Activated Protein Kinase pathways, as inhibition of these proteins is associated with a decrease in cell viability. Estradiol-Triazole analogs were thus designed using a molecular modeling approach. Thirteen of the high scoring analogs were then synthesized and tested in-vitro on an ovarian cancer cell line (A2780) and colorectal cancer cell line (HT-29). The most active compound, Fz25, shows low micromolar activity in both the ovarian (15.29 ± 2.19 μM) and colorectal lines (15.98 ± 0.39 μM). Mechanism of action studies proved that Fz25 moderately arrests cells in the G1 phase of the cell cycle, specifically inhibiting STAT3 in both cell lines. Additionally, Fz57 shows activity in the colorectal line (24.19 ± 1.37 μM). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR, STAT3, ERK, and mTOR. To further study their effects as therapeutics, Fz25 and Fz57 were studied against drug efflux proteins, which are associated with drug resistance, and were found to inhibit the ABC transporter P-glycoprotein. We can conclude that these estradiol-triazole analogs provide a key for future studies targeting protein inhibition and drug resistance in cancer.
- Alotaibi, Faez,Halaweish, Fathi,Halaweish, Hossam,Iram, Surtaj,Kasten, Abigail,Kyeremateng, Jennifer,Ostlund, Trevor
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- Synthesis and Evaluation of Bakuchiol Derivatives as Potent Anti-inflammatory Agents in Vitro and in Vivo
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Bakuchiol, a prenylated phenolic monoterpene derived from the fruit of Psoralen corylifolia L. (Buguzhi), is widely used to treat tumors, viruses, inflammation, and bacterial infections. In this study, we designed and synthesized 30 bakuchiol derivatives
- Bai, Chunmei,Bian, Ming,Du, Huan-Huan,Gong, Guohua,Liu, Chunyan,Ma, Qianqian,Quan, Zhe-Shan,Wei, Chengxi
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supporting information
p. 15 - 24
(2022/01/27)
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- Microwave-assisted synthesis, structural characterization and assessment of the antibacterial activity of some new aminopyridine, pyrrolidine, piperidine and morpholine acetamides
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A series of new acetamide derivatives 22–28 of primary and secondary amines and para-toluene sulphinate sodium salt have been synthesized under microwave irradiation and assessed in vitro for their antibacterial activity against one Gram-positive and two Gram-negative bacterial species such as S. pyogenes, E. coli, and P. mirabilis using the Mueller-Hinton Agar diffusion (well diffusion) method. The synthesized compounds with significant differences in inhibition diameters and MICs were compared with those of amoxicillin, ampicillin, cephalothin, azithromycin and doxycycline. All of the evaluated acetamide derivatives were used with varying inhibition concentrations of 6.25, 12.5, 37.5, 62.5, 87.5, 112.5 and 125 μg/mL. The results show that the most important antibacterial properties were displayed by the synthetic compounds 22 and 24, both of bear a para-chlorophenyl moiety incorporated into the 2-position moiety of acetamide 1. The molecular structures of the new compounds were determined using the FT-IR and1H-NMR techniques.
- Abdulghani, Saba S.,Alsamarrai, Abdulmajeed S. H.
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- Novel selective ido1 inhibitors with isoxazolo[5,4-d]pyrimidin-4(5h)-one scaffold
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Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6-or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC50 values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demon-strate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.
- ?vajger, Urban,Bratkovi?, Toma?,Dol?ak, Ana,Gobec, Stanislav,Mlinari?, Larisa,Ogorevc, Eva,Sova, Matej
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- Design and synthesis of some barbituric and 1,3-dimethylbarbituric acid derivatives: A non-classical scaffold for potential PARP1 inhibitors
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Six series based on barbituric acid 5a-e, 10a-d; thiobarbituric acid 6a-e, 11a-d and 1,3-dimethylbarbituric acid 7a-e, 12a-d were prepared and screened for their in vitro PARP1 inhibition. They revealed promising inhibition at nanomolar level especially compounds 5c, 7b, 7d and 7e (IC50 = 30.51, 41.60, 41.53 and 36.33 nM) with higher potency than olaparib (IC50 = 43.59 nM). Moreover, compounds 5b, 5d, 7a, 12a and 12c exhibited good comparable activity (IC50 = 65.93, 58.90, 66.57, 45.40 and 50.62 nM, respectively). Furthermore, the most active compounds 5c, 7b, 7d, 7e, 12a and 12c against PARP1 in vitro were evaluated in the BRCA1 mutated triple negative breast cancer cell line MDA-MB-436 where 5c and 12c showed higher potency compared to olaparib and result in cell cycle arrest at G2/M phase. 5c and 12c showed apoptotic effects in MDA-MB-436 and potentiated the cytotoxicity of temozolomide in A549 human lung epithelial cancer cell line. Compounds 5c and 12c represent interesting starting points towards PARP1 inhibitors.
- Eldin A. Osman, Essam,Hanafy, Noura S.,George, Riham F.,El-Moghazy, Samir M.
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- Design, synthesis and biological evaluation of novel osthole-based derivatives as potential neuroprotective agents
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A total of 26 compounds based on osthole skeleton were designed, synthesized. Their cytoprotective abilities of antioxidation, anti-inflammation and Aβ42(Amyloid β-protein 42)-induced neurotoxicity were evaluated by MTT assays. Mechanism of the action of selected compounds were investigated by molecular docking. AlogP, logS and blood–brain barrier (BBB) permeability of all these compounds were simulated by admetSAR. Most of the compounds showed better antioxidative and anti-inflammatory activities compared with osthole, especially OST7 and OST17. The compound OST7 showed relative high activity in neuroprotection against H2O2 (45.7 ± 5.5%), oxygen glucose deprivation (64.6 ± 4.8%) and Aβ42 (61.4 ± 5.2%) at a low concentration of 10 μM. EC50 of selected compounds were measured in both H2O2 and OGD induced cytotoxicity models. Moreover, NO inhibiting ability of OST17(50.4 ± 7.1%) already surpassed the positive drug indomethacin. The structure activity relationship study indicated that introduction of piperazine group, tetrahydropyrrole group and aromatic amine group might be beneficial for enhancement of osthole neuroprotective properties. Molecular docking explained that the reason OST7 exhibited relatively stronger neuroprotection against Aβ because of the greater area of interactions between molecule and target protein. OST7 and OST17 both provided novel methods to investigate osthole as anti-AD drugs.
- Zhang, Li,Wu, Yuhang,Yang, Guixiang,Gan, Haixian,Sang, Dayong,Zhou, Jiye,Su, Lin,Wang, Rui,Ma, Lei
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supporting information
(2020/11/03)
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- Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells
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Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.
- Roberti, Marinella,Schipani, Fabrizio,Bagnolini, Greta,Milano, Domenico,Giacomini, Elisa,Falchi, Federico,Balboni, Andrea,Manerba, Marcella,Farabegoli, Fulvia,De Franco, Francesca,Robertson, Janet,Minucci, Saverio,Pallavicini, Isabella,Di Stefano, Giuseppina,Girotto, Stefania,Pellicciari, Roberto,Cavalli, Andrea
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- Substituted Aminoacetamides as Novel Leads for Malaria Treatment
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Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.
- Norcross, Neil R.,Wilson, Caroline,Baraga?a, Beatriz,Hallyburton, Irene,Osuna-Cabello, Maria,Norval, Suzanne,Riley, Jennifer,Fletcher, Daniel,Sinden, Robert,Delves, Michael,Ruecker, Andrea,Duffy, Sandra,Meister, Stephan,Antonova-Koch, Yevgeniya,Crespo, Benigno,de Cózar, Cristina,Sanz, Laura M.,Gamo, Francisco Javier,Avery, Vicky M.,Frearson, Julie A.,Gray, David W.,Fairlamb, Alan H.,Winzeler, Elizabeth A.,Waterson, David,Campbell, Simon F.,Willis, Paul A.,Read, Kevin D.,Gilbert, Ian H.
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supporting information
p. 1329 - 1335
(2019/07/17)
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- BENZOTHIOPHENE ESTROGEN RECEPTOR MODULATORS
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This invention is a benzothiophene estrogen receptor modulator or its pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof to treat an estrogen-related medical disorder.
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Paragraph 0629-0630
(2018/08/29)
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- NOVEL DIHYDROPYRANOPYRIMIDINONE DERIVATIVES, AND USE THEREOF
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The present invention relates to a novel dihydropyranopyrimidinone derivative, a tautomer thereof, a stereoisomer thereof and their mixture, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating a tankyrase-related disease, which contains the same as an active ingredient.
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Paragraph 183; 184
(2017/07/01)
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- Discovery of novel isoflavone derivatives as AChE/BuChE dual-targeted inhibitors: synthesis, biological evaluation and molecular modelling
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AChE and BuChE are druggable targets for the discovery of anti-Alzheimer’s disease drugs, while dual-inhibition of these two targets seems to be more effective. In this study, we synthesised a series of novel isoflavone derivatives based on our hit compound G from in silico high-throughput screening and then tested their activities by in vitro AChE and BuChE bioassays. Most of the isoflavone derivatives displayed moderate inhibition against both AChE and BuChE. Among them, compound 16 was identified as a potent AChE/BuChE dual-targeted inhibitor (IC50: 4.60 μM for AChE; 5.92 μM for BuChE). Molecular modelling study indicated compound 16 may possess better pharmacokinetic properties, e.g. absorption, blood–brain barrier penetration and CYP2D6 binding. Taken together, our study has identified compound 16 as an excellent lead compound for the treatment of Alzheimer’s disease.
- Feng, Bo,Li, Xinpeng,Xia, Jie,Wu, Song
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p. 968 - 977
(2017/07/24)
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- Design, synthesis and apoptosis inducing effect of novel (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)-benzylidene)indolin-2-ones as potential antitumour agents
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A series of new (Z)-3-(3′-methoxy-4′-(2-amino-2-oxoethoxy)benzylidene)indolin-2-one derivatives has been synthesized and evaluated for their cytotoxic activity against selected human cancer cell lines of prostate (PC-3 and DU-145), breast (BT-549 and MDA-MB-231) and non-tumorigenic prostate epithelial cells (RWPE-1). Among the tested, one of the compounds 4p exhibited potent cytotoxicity selectively on prostate cancer cell lines (PC-3 and DU-145; IC50: 1.89 ± 0.6 and 1.94 ± 0.2 μM, respectively). Further experiments were conducted with 4p on PC-3 cancer cells to study the mechanisms of growth inhibition and apoptosis inducing effect. Treatment of PC-3 cells with test compound 4p resulted in inhibition of cell migration through disorganization of F-actin protein. The flow-cytometry analysis results showed that the compound arrested PC-3 cancer cells in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining and annexin-V binding assay revealed that the compound 4p inhibited tumor cell proliferation through induction of apoptosis. Western blot studies demonstrated that the compound 4p treatment led to activation of caspase-3, increased expression of pro-apoptotic Bax and significantly decreased expression of anti-apoptotic Bcl-2 in human prostate cancer PC-3 cells. In addition, the mitochondrial membrane potential (ΔΦm) was also affected and the levels of intracellular Ca2+ were raised.
- Senwar, Kishna Ram,Reddy, T. Srinivasa,Thummuri, Dinesh,Sharma, Pankaj,Naidu,Srinivasulu, Gannoju,Shankaraiah, Nagula
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- Synthesis and biological evaluation of new benzimidazole-thiazolidinedione hybrids as potential cytotoxic and apoptosis inducing agents
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A series of new benzimidazole-thiazolidinedione hybrids has been synthesized and evaluated for their cytotoxic potential against a selected human cancer cell lines of prostate (PC-3 and DU-145), breast (MDA-MB-231), lung (A549) and a normal breast epithelial cells (MCF10A). Among the tested compounds, 11p exhibited promising cytotoxicity with IC50value of 11.46?±?1.46?μM on A549 lung cancer cell line and did not show significant toxicity on normal MCF10A cells. Lung cancer cells (A549) have been used to know the mechanism of cell growth inhibition and apoptosis inducing effect with compound 11p. The treatment of A549?cells with 11p showed typical apoptotic morphology like cell shrinkage, chromatin condensation and horseshoe shaped nuclei formation. Flow-cytometry analysis revealed the G2/M phase of cell cycle arrest in a dose dependent manner. Preliminary mechanistic studies suggested that the cell migration was inhibited through the disruption of F-actin protein. Acridine orange-ethidium bromide (AO-EB), DAPI, annexin V-FITC/propidium iodide, rhodamine-123 and MitoSOX assays suggested the induction of apoptosis in A549 cells by compound 11p.
- Sharma, Pankaj,Srinivasa Reddy,Thummuri, Dinesh,Senwar, Kishna Ram,Praveen Kumar, Niggula,Naidu,Bhargava, Suresh K.,Shankaraiah, Nagula
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supporting information
p. 608 - 621
(2016/09/14)
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- Novel imidazotriazinone or imidazopyrazinone derivatives, and use thereof
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The present invention relates to a novel imidazotriazinone or imidazopyrazinone derivatives, a tautomer thereof, a stereomer and a mixture thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition for preventing or treating tankyrase-related diseases comprising the same as active components.COPYRIGHT KIPO 2016
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Paragraph 0311; 0312; 0318; 0319; 0320
(2016/10/07)
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- 1 - (cinnamoyl) - 4-piperidyl amide piperazine compound and its preparation method
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The invention discloses a 1-(cinnamoyl)-4-piperidyl amide piperazidine compound and a preparation method thereof. The 1-(cinnamoyl)-4-piperidyl amide piperazidine compound is a compound shown as the formula (I) and pharmaceutically acceptable salt. The co
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Paragraph 0024-0026
(2016/10/08)
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- 6-amino-4(3H)-quinazolinone derivatives and their synthesis method and use
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The invention discloses 6-amino-4(3H)-quinazolinone derivatives and their synthesis method and use and belongs to the technical field of drug synthesis. The invention also relates to a use of the 6-amino-4(3H)-quinazolinone derivatives with a general formula (I) and its synthesis method in medical science, wherein in the general formula (I), X represents (CH2)n-1, n=1 to 10 and R1, R2 and R3 represent different substituents. The invention discloses the compound structures and their synthesis method and external acetylcholinesterase inhibition activity. The 6-amino-4(3H)-quinazolinone derivatives can be further studied and developed to form novel drugs for treating Alzheimer disease.
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Paragraph 0126; 0127
(2016/12/22)
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- Efficient syntheses of 1,2,3-triazoloamide derivatives using solid- and solution-phase synthetic approaches
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Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on amide formation with secondary amines and chloro-acid chlorides; SN2 reaction with sodium azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes. The target secondary and tertiary 1,2,3-triazoloamide derivatives were obtained with three-diversity points in excellent overall yields and purities using the reported solid- and solution-phase synthetic routes, respectively.
- Lee, Doohyun,Kim, Daehun,Lee, Seungyeon,Kim, Taegeum,Kim, Joobin,Kim, Sohee,Liu, Kwang-Hyeon,Lee, Sangkyu,Bae, Jong-Sup,Song, Kyung-Sik,Cho, Chang-Woo,Son, Youn Kyung,Baek, Dong Jae,Lee, Taeho
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p. 19984 - 20013
(2015/12/23)
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- Facile synthesis and antifungal activity of dithiocarbamate derivatives bearing an amide moiety
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Two series of novel dithiocarbamate derivatives bearing an amide moiety, 3a-i and 4a-i, were synthesized by a facile method, and the structures of the derivatives were confirmed by elemental analysis and 1H-NMR, 13C- -NMR and high-resolution mass spectrometry (HRMS). Their antifungal activity against five phytopathogenic fungi were evaluated, and the results showed that most of the target compounds displayed low antifungal activity in vitro against Gibberella zeae, Cytospora sp., Colletotrichum gloeosporioides, Alternaria solani, and Fusarium solani at a concentration of 100 mg L-1. However, two compounds, 4f and 4g, exhibited significant activity against A. solani and C. gloeosporioides, respectively.
- Li, Yu-Wen,Li, Shu-Tao
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p. 1367 - 1374
(2016/02/18)
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- Selectivities in acylation of primary and secondary amine with diacylaminoquinazolinones and diacylanilines
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The diacylaminoquinazolinones are highly selective acylating agents for primary amines in the presence of secondary amines. The chemoselective N-acetylation reagents have been investigated using 2-substituted N,Ndiacylaminoquinazolinones (DAQs) and 2-substitued-N-diacylanilines (DAAs). Determination of the selectivity ratios have been made by comparison of the crude product in each case with authentic samples of the amide products using NMR spectroscopy. The control experiments in which pairs of amines compete for acetyl chloride show some selectivity but not comparable with that of DAQs and DAAs selectivity. When the DAQs, DAAs and acetyl chloride react with mixtures of pyrrolidine and piperidine, they give amides in the corresponding ratios. The DAQs 1 and 2 react entirely with diethylamine without any competitive reaction with diphenylamine. The high level of chemoselectivity has also been observed when the 1 and 2 react exclusively with the ethanolamine without any competitive reaction with diethanolamine. Moreover, 1 and 2 react with succinimide without any competitive reaction with phthalimide.
- Al-Sehemi, Abdullah G.,Al-Amri, Reem S. Abdul-Aziz,Irfan, Ahmad
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p. 1115 - 1121
(2014/10/15)
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- Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents
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A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC50) of 0.08 mmol/L, while polyoxin B as positive drug had IC50 of 0.18 mmol/L. These IC 50 values of compounds 5i, 5m, 5n, and 5s were greater than 0.75 mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition- concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC50 values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.
- Ji, Qinggang,Yang, Dan,Wang, Xin,Chen, Chunyan,Deng, Qiao,Ge, Zhiqiang,Yuan, Lvjiang,Yang, Xiaolan,Liao, Fei
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p. 3405 - 3413
(2014/06/23)
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- In vitro antimalarial activity, β-haematin inhibition and structure-activity relationships in a series of quinoline triazoles
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A novel series of quinoline triazole amide analogues (38-51) has been synthesized. Analogues 38-44 had a Cl substituent at the 7-position of the quinoline ring, while 45-51 had a CN substituent at this position. Compounds 40, 45 and 49 were found to be the most active in the series against the Plasmodium falciparum chloroquine-sensitive D10 strain, with IC50 values in the range of 349-1247 nM, with 40 and 45, but not 49 also exhibiting similar activity against the chloroquine-resistant K1 strain of parasite. Quinoline triazoles 40 and 44 were the most active β-haematin inhibitors, with 50% inhibitory concentrations of 14.7 and 8.9 μM respectively. In vitro antimalarial activity of the 7-Cl bearing analogues 38-44 exhibited a strong linear dependence of log(1/IC50) on log P. Thus, the more lipophilic, the more active it was found be. The 7-CN series 45-51 showed no such dependence. The resistance index (IC50 K1/IC50 D10) also exhibited a linear dependence on log P, with a substantially steeper slope in the case of the 7-Cl series. The findings demonstrate the feasibility of producing hydrophilic analogues with strong activity and low cross-resistance with chloroquine.
- Joshi, Mukesh C.,Wicht, Kathryn J.,Taylor, Dale,Hunter, Roger,Smith, Peter J.,Egan, Timothy J.
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p. 338 - 347
(2013/10/21)
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- Synthesis of berberine bromide analogs containing tertiary amides of acetic acid in the 9-O-position
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9-O-Acetamide analogs of berberine bromide were prepared in 20-87% yields via reaction of the isoquinoline alkaloid berberrubine with tertiary amides of bromoacetic acid. Aminolysis did not occur during reaction of methyl-2-(9-demethoxyberberine bromide-9-yl)hydroxyacetate with secondary amines. The corresponding acid or its ethyl ester was isolated.
- Nechepurenko,Komarova,Vasil'ev,Salakhutdinov
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p. 1047 - 1053
(2013/04/23)
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- POCHOXIME CONJUGATES USEFUL FOR THE TREATMENT OF HSP90 RELATED PATHOLOGIES
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The present invention includes novel derivatives, analogs, and intermediates of the natural products radicicol, pochonins, pochoximes, and their syntheses. The present invention also provides a pharamceutical composition comprising the present compound an
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Page/Page column 73-74
(2012/05/05)
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- Synthesis, Evaluation and Molecular Docking of Thiazolopyrimidine Derivatives as Dipeptidyl Peptidase IV Inhibitors
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A series of thiazolopyrimidine derivatives was designed, synthesized and screened for in-vitro inhibition of Dipeptidyl Peptidase IV (DPP IV). The SAR study indicated the influence of substituted chemical modifications on thiazolopyrimidine scaffold. Comp
- Sharma, Mani,Gupta, Monica,Singh, Divya,Kumar, Manoj,Kaur, Punit
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p. 918 - 928
(2013/01/15)
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- D2 ANTAGONISTS, METHODS OF SYNTHESIS AND METHODS OF USE
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Provided are D2 or D3 antagonist compounds and pharmaceutical compositions of formula I and pharmaceutically acceptable salts thereof, or isomers thereof, wherein R1, R2 and R3 are as defined herein. The invention further comprises methods for making the compounds of the invention and methods for the treatment of conditions mediated by the dopamine D2 or D3 receptor from the compounds of the invention.
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Page/Page column 40
(2012/01/06)
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- Synthesis of pochoxime prodrugs as potent HSP90 inhibitors
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Pochoximes are potent inhibitors of heat shock protein 90 (HSP90) based on the radicicol pharmacophores. Herein we present a pharmacokinetics and pharmacodynamics evaluation of this compound series as well as a phosphate prodrug strategy to facilitate for
- Wang, Cuihua,Barluenga, Sofia,Koripelly, Girish K.,Fontaine, Jean-Gonzague,Chen, Ruihong,Yu, Jin-Chen,Shen, Xiaodong,Chabala, John C.,Heck, James V.,Rubenstein, Allan,Winssinger, Nicolas
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supporting information; experimental part
p. 3836 - 3840
(2010/04/05)
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- Synthesis of substituted 3-arylpiperidines and 3-arylpyrrolidines by radical 1,4 and 1,2-aryl migrations
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A route to 3-arylpiperidines and 3-arylpyrrolidines involving radical 1,4- and 1,2-aryl migrations has been explored. For the piperidines, the first route requires a xanthate addition to an N-allylarylsulfonamide, followed by acetylation and treatment with lauroyl peroxide to give the corresponding 1,4-aryl transfer product. This compound can be converted into the desired piperidine derivative following acidic hydrolysis. For the second approach to piperidines, addition of an α-keto xanthate to olefins of type 14 causes 1,2-aryl migration leading to an α,β-unsaturated ester, which can be converted into a piperidine by the action of ammonia or a primary amine and sodium cyanoborohydride. Substituted 3-arylpyrrolidines can be obtained by simply starting with an α-amido substituted xanthate.
- Gheorghe, Alexandru,Quiclet-Sire, Béatrice,Vila, Xavier,Zard, Samir Z.
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p. 7187 - 7212
(2008/02/07)
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- Synthesis of 3-arylpiperidines by a radical 1,4-aryl migration
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(Chemical Equation Presented) A route to 3-arylpiperidines, 3-arylpyridines, and 5-arylpiperidin-2-ones involving a radical 1,4-aryl migration has been explored. The sequence requires a xanthate addition to an N-allylarylsulfonamide, followed by acetylation and treatment with dilauroyl peroxide to give the 1,4-aryl transfer product, which upon acidic hydrolysis affords the desired piperidine derivative.
- Gheorghe, Alexandra,Quiclet-Sire, Beatrice,Vila, Xavier,Zard, Samir Z.
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p. 1653 - 1656
(2007/10/03)
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- Stereoselective synthesis of naturally occurring unsaturated amide alkaloids by a modified Ramberg-Baecklund reaction
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A convenient and rapid approach for the synthesis of naturally occurring unsaturated amide alkaloids 1a-1n by the recently developed one-flask Ramberg-Baecklund reaction is described. The starting material was alcohol 3, which was transformed into thiolacetate 4 using the Mitsunobu reaction. In situ cleavage of acetyl moiety of 4, followed by alkylation of the resulting thiol with appropriate chloroacetamide 5, provided the sulfide 6. Oxidation of sulfide 6 gave the corresponding sulfone 2. Treatment of the sulfone 2 with the dibromodifluoromethane in the presence of alumina-supported potassium hydroxide in dichloromethane solution afforded unsaturated amide alkaloids 1a-1n. To the best of our knowledge, the synthesis of 1e and 1i was reported for the first time.
- Li, Yang,Zhang, Yu,Huang, Zhi,Cao, Xiaoping,Gao, Kun
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p. 622 - 630
(2007/10/03)
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- Synthesis, spectral studies and anti-inflammatory activity of glycolamide esters of niflumic acid as potential prodrugs
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In order to reduce the gastric irritation caused by direct contract mechanism of the carboxylic acid group, a series of glycolamide esters of niflumic (CAS 4394-00-7) (1) have been prepared as biolabile prodrugs by reacting appropriate 2-chloroacetamides with niflumic acid. The required 2-chloroacetamides were obtained by the condensation of chloroacetyl chloride and corresponding amine. Their structures were confirmed by UV, IR and 1H NMR spectra. Selected compounds were evaluated for anti-inflammatory activity in carrageenan induced paw oedema in rats at the doses of 45, 90 and 150 mg/kg b.w. Prodrugs showed comparable anti-inflammatory activity (67.1-79.4%) at 150 mg/kg b.w. with respect to niflumic acid (70.3%) at 45 mg/kg b.w., indicating moderate release of niflumic acid in vivo. The highest activity was observed with diethylamine (4) and pyrrolidine (9) derivatives.
- Gadad, Andanappa K.,Bhat, Shailija,Tegeli, Varsha S.,Redasani, Vivek V.
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p. 817 - 821
(2007/10/03)
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- Fluorovinloxyacetamides, process for preparing same and herbicidal composition comprising same
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Herbicidal fluorovinyloxyacetamide compounds of formula (I) are useful for protecting crops from weeds: wherein: R1is a phenyl group optionally having one or more substituents selected from the group consisting of C1-6alkyl, halogen-
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- A general method for the synthesis of N,N-dialkylaminobutylamines
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A general method for the synthesis of N,N-dialkylaminobutylamines 4 from readily available chloroacetamides 6 is described.
- Seguin, Helene,Gardette, Daniel,Moreau, Marie-France,Madelmont, Jean-Claude,Gramain, Jean-Claude
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p. 4257 - 4272
(2007/10/03)
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- S4N4SbCl5 complex: a useful reagent for conversion of sterically less hindred α-bromo ketones to α-chloro ketones
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The reactions of sterically less hindered α-bromo alkyl and aryl ketones with tetrasulfur tetranitride antimony pentachloride (S4N4SbCl5) complex in toluene at reflux gave the corresponding α-chloro kerones in good to excellent yields.
- Kim, Kil-Joong,Kim, Kyongtae
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p. 4227 - 4230
(2007/10/03)
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- An efficient synthesis of 6-formyl-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid and some carbonyl derivatives of it and its 6-acetyl homologue
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Starting with 1,1-dimethoxy-2-propanone (1), 6-formyl-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid (5a) has been prepared in large quantities by a highly efficient, 4-step synthesis. This compound, along with its one carbon homologue, 6-acetyl-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid (5b) has been reacted with several carbonyl derivative forming reagents to provide a series of side chains for β-lactams. Among these carbonyl derivatives are styrylamides which were prepared from Wittig and Horner-Emmons reagents. The preparation of the phosphonium salts and phosphonate esters is also described.
- Sanchez,Mich,Huang
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p. 297 - 303
(2007/10/02)
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- Synthesis of Dibenzocrown Ethers with Pendent Amide Groups
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Synthetic routes to twenty six crown ether compounds with pendent amide, N-alkylamide, or N,N-dialkylamide groups are reported.The new crown ether compounds are based on sym-dibenzo-16-crown-5-oxyacetamide and sym-(propyl)-dibenzo-16-crown-5-oxyacetamide and are obtained in high yields.
- Kasprzyk, Stanislaw P.,Bartsch, Richard A.
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p. 119 - 123
(2007/10/02)
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- STEREOSELECTIVE SYNTHESES OF SPICY COMPONENTS IN PEPPERS
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The syntheses of (E)-α,β-unsaturated amides were accomplished from chloroacetamides and alkyl halides via β-elimination of the pyrazinyl-sulfinyl group, and some of the products are spicy components of piperaceous plants.
- Ohta, Akihiro,Tonomura, Yoshiko,Sawaki, Junko,Naohito, Sato,Akiike, Hitomi,et al.
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p. 965 - 973
(2007/10/02)
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- Further Reactions in the Tetrahydroazocin-2(1H)-one Series
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5,6,7,8-Tetrahydroazocin-2(1H)-one and the 3-phenylthio- and 3-phenylthiosulfonyl-substituted derivatives have been converted into the corresponding 2-ethoxy-5,6,7,8-tetrahydroazocines with Meerwin's reagent.Upon irradiation under mercury lamp at longer w
- Ridley, Damon D.,Simpson, Gregory W.
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p. 687 - 698
(2007/10/02)
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- Amide phosphorothiolate herbicides
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The present invention relates to new herbicidal phosphorothioate (phosphorodithioate) derivatives and to preparation thereof.
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