- Design, synthesis and biological evaluation of novel thienylpyridyl-and thioether-containing acetamides and their derivatives as pesticidal agents
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Referring to the structural information of the “hit” compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl-and thioether/sulfoxide/ sulfone-containing acetamide derivatives have been designed and synthesized.
- Li, Huan,Wang, Baolei,Xiong, Lixia,Yang, Na
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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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- Thiazolidinedione "magic Bullets" Simultaneously Targeting PPARγand HDACs: Design, Synthesis, and Investigations of their in Vitro and in Vivo Antitumor Effects
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Monotargeting anticancer agents suffer from resistance and target nonspecificity concerns, which can be tackled with a multitargeting approach. The combined treatment with HDAC inhibitors and PPARγagonists has displayed potential antitumor effects. Based on these observations, this work involves design and synthesis of molecules that can simultaneously target PPARγand HDAC. Several out of 25 compounds inhibited HDAC4, and six compounds acted as dual-targeting agents. Compound 7i was the most potent, with activity toward PPARγEC50 = 0.245 μM and HDAC4 IC50 = 1.1 μM. Additionally, compounds 7c and 7i were cytotoxic to CCRF-CEM cells (CC50 = 2.8 and 9.6 μM, respectively), induced apoptosis, and caused DNA fragmentation. Furthermore, compound 7c modulated the expression of c-Myc, cleaved caspase-3, and caused in vivo tumor regression in CCRF-CEM tumor xenografts. Thus, this study provides a basis for the rational design of dual/multitargeting agents that could be developed further as anticancer therapeutics.
- Tilekar, Kalpana,Hess, Jessica D.,Upadhyay, Neha,Bianco, Alessandra Lo,Schweipert, Markus,Laghezza, Antonio,Loiodice, Fulvio,Meyer-Almes, Franz-Josef,Aguilera, Renato J.,Lavecchia, Antonio,Ramaa
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p. 6949 - 6971
(2021/06/25)
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- PIPERIDINE-2,6-DIONES AS SMALL MOLECULE DEGRADERS OF HELIOS AND METHODS OF USE
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Disclosed are compounds and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof that may cause degradation of various proteins e.g., IKZF2 (Helios). Also disclosed are pharmaceutical compositions containin
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Paragraph 00344-00346
(2021/11/26)
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- Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
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In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.
- Chittiboyina, Amar G.,Doerksen, Robert J.,Modi, Gyan,Nayak, Prasanta Kumar,Pandey, Amruta,Pandey, Pankaj,Priya, Khushbu,Rai, Geeta,Shankar, Gauri,Singh, Yash Pal,Tej, Gullanki Naga Venkata Charan,Vishwakarma, Swati
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- Hydrophobic substituents on isatin derivatives enhance their inhibition against bacterial peptidoglycan glycosyltransferase activity
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Moenomycin A, the well-known natural product inhibitor of peptidoglycan glycosyltransferase (PGT), is a large amphiphilic molecule of molecular mass of 1583 g/mol and its bioavailablity as a drug is relatively poor. In searching for small-molecule ligands
- Chan, Kin-Fai,Chen, Yu Wai,Cheong, Wing-Lam,Liang, Zhiguang,So, Lok-Yan,So, Pui-Kin,Wang, Yong,Wong, Kwok-Yin,Wong, Wing-Leung
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- Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation
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Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 – 9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 – 28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 – 104.2 μM) and human fibroblasts (HS27) (CC50 – 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.
- Aguilera, Renato J.,Choe, Jun-yong,Henze Macias, Luca,Hess, Jessica D.,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha,J?nsch, Niklas
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- Structure guided design and synthesis of furyl thiazolidinedione derivatives as inhibitors of GLUT 1 and GLUT 4, and evaluation of their anti-leukemic potential
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Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital ro
- Aguilera, Renato J.,Choe, Jun-yong,Hess, Jessica D.,Iancu, Cristina V.,Macias, Lucasantiago Henze,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Tilekar, Kalpana,Upadhyay, Neha
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- Permuted 2,4-thiazolidinedione (TZD) analogs as GLUT inhibitors and their in-vitro evaluation in leukemic cells
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Cancer is a heterogeneous disease, and its treatment requires the identification of new ways to thwart tumor cells. Amongst such emerging targets are glucose transporters (GLUTs, SLC2 family), which are overexpressed by almost all types of cancer cells; t
- Aguilera, Renato J.,Choe, Jun-yong,Hess, Jessica D.,Iancu, Cristina V.,Macias, Lucasantiago Henze,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha
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- Benzylidene thiazolidinediones: Synthesis, in vitro investigations of antiproliferative mechanisms and in vivo efficacy determination in combination with Imatinib
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Thiazolidinedione (TZD) has been an interesting scaffold due to its proven antidiabetic activity and encouraging findings in anticancer drug discovery. We synthesised benzylidene thiazolidinedione derivatives which exhibited excellent antiproliferative effects in chronic myeloid leukemic cells K562 and the most active compounds 3t and 3x had GI50 value of 0.9 and 0.23 μM respectively. Both the compound was found to arrest the growth of K562 cells in G0/G1 phase in a time and dose dependent manner. Further, western blot analysis revealed that 3t and 3x could also inhibit the expression of cell proliferation markers, PCNA and Cyclin D1 and compound 3x up-regulated apoptosis markers, cleaved PARP1 and activated caspase 3, which could be a possible mechanism for the excellent antiproliferative effects exhibited by these compounds. In vitro combination studies of 3t and 3x with Imatinib found to potentiate the antitumor effects of Imatinib. Further in vivo efficacy in K562 xenografts, of 3t and 3x alone and in combination with Imatinib was found to be promising and far better than control group and combination treatment was found to be more effective as compared to only Imatinib treated or test compound treated animals. Thus, our findings suggest that these compounds are promising antitumor agents and could help to enhance the anticancer effects of Imatinib and other tyrosine kinase inhibitors, when used in combination.
- Joshi, Hardik,Patil, Vijay,Tilekar, Kalpana,Upadhyay, Neha,Gota, Vikram,Ramaa
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supporting information
(2020/10/02)
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- Antidiabetic compounds
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Compounds for the treatment of hyperglycemia and/or diabetes are provided. The compounds, which inhibit the enzyme dipeptidyl peptidase (DPP-4), are based on the structure where X may be present or absent an may be OH, Ar is an aryl group; and n ranges from 0 to 5.
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Page/Page column 13-14
(2020/06/16)
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- Design, synthesis, and biological evaluation of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives as androgen receptor antagonists
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Androgen receptor (AR) signaling is often activated in prostate cancer (PCa) cells, and blockage of this signaling by AR antagonists is an important strategy in PCa therapy. In this study, we designed and synthesized a series of 2-(5-methyl-1H-pyrazol-1-y
- Dong, Junze,Zhang, Jingya,Li, Zilu,Asnake, Solomon,Zhang, Daoguang,Olsson, Per-Erik,Zhao, Guisen
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p. 380 - 386
(2019/01/30)
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- Substituted phenyl[(5-benzyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetates/acetamides as alkaline phosphatase inhibitors: Synthesis, computational studies, enzyme inhibitory kinetics and DNA binding studies
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Substituted phenyl[(5-benzyl-1,3,4-oxadiazol-2-yl)sulfanyl]acetates/acetamides 9a-j were synthesized as alkaline phosphatase inhibitors. Phenyl acetic acid 1 through a series of reactions was converted into 5-benzyl-1,3,4-oxadiazole-2-thione 4. The intermediate oxadiazole 4 was then reacted with chloroacetyl derivatives of phenols 6a-f and anilines derivatives 8a-d to afford the title oxadiazole derivatives 9a-j. All of the title compounds 9a-j were evaluated for their inhibitory activity against human alkaline phosphatise (ALP). It was found that compounds 9a-j exhibited good to excellent alkaline phosphatase inhibitory activity especially 9h displayed potent activity with IC50 value 0.420 ± 0.012 μM while IC50 value of standard (KH2PO4) was 2.80 μM. The enzyme inhibitory kinetics of most potent inhibitor 9h was determined by Line-weaever Burk plots showing non-competitive mode of binding with enzyme. Molecular docking studies were performed against alkaline phosphatase enzyme (1EW2) to check the binding affinity of the synthesized compounds 9a-j against target protein. The compound 9h exhibited excellent binding affinity having binding energy value (?7.90 kcal/mol) compared to other derivatives. The brine shrimp viability assay results proved that derivative 9h was non-toxic at concentration used for enzyme assay. The lead compound 9h showed LD50 106.71 μM while the standard potassium dichromate showed LD50 0.891 μM. The DNA binding interactions of the synthesized compound 9h was also determined experimentally by spectrophotometric and electrochemical methods. The compound 9h was found to bind with grooves of DNA as depicted by both UV–Vis spectroscopy and cyclic voltammetry with binding constant values 7.83 × 103 and 7.95 × 103 M?1 respectively revealing significant strength of 9h-DNA complex. As dry lab and wet lab results concise each other it was concluded that synthesized compounds, especially compound 9h may serve as lead compound to design most potent inhibitors of human ALP.
- Iqbal,Ashraf,Hassan, Mubashir,Abbas,Jabeen, Erum
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- Design, synthesis, and SAR of novel 2-glycinamide cyclohexyl sulfonamide derivatives against botrytis cinerea
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N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring more novel structures, 33 new compounds were synthesized by N-alkylation and acid–amine coupling reactions with chesulfamide as the core moiety, and their structures were characterized and established by 1H-NMR, 13C-NMR, MS, and elemental analysis. The structure of (1R,2S)-2-(2-(N-(4-chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl) acetamide (II-19) was defined by X-ray single crystal diffraction. The in vivo and in vitro fungicidal activities against B. cinerea were evaluated. The bioassay results of mycelial growth demonstrated that most compounds exhibited excellent inhibitory activity against B. cinerea at 50 μg mL?1, and 7 compounds showed lower EC50 values than boscalid (EC50 = 4.46 μg mL?1) against B. cinerea (CY-09). In cucumber pot experiment, the inhibitory rates of four compounds (II-4, II-5, II-12, and II-13) against B. cinerea were 90.48, 93.45, 92.86, and 91.07, which were better than cyprodinil (88.69%), the best performing of all controls. In tomato pot experiment, the control efficacy of two analogs (II-8 and II-15) were 87.98 and 87.97% at 200 μg mL?1, which were significantly higher than boscalid (78.10%). Most compounds have an excellent fungicidal effect on B. cinerea, with potential as a lead compound for developing new pesticides.
- Cai, Nan,Liu, Caixiu,Feng, Zhihui,Li, Xinghai,Qi, Zhiqiu,Ji, Mingshan,Qin, Peiwen,Ahmed, Wasim,Cui, Zining
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- Anti-proliferative activity, molecular modeling studies and interaction with calf thymus DNA of novel ciprofloxacin analogues
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Abstract: In our pursuit to expand new potential anticancer leads, a series of eighteen novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substituted piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues have been synthesized, characterized and evaluated anti-proliferative activity against five human cancer cell lines such as A549 (lung cancer), Mia Paca (pancreatic cancer), HeLa (cervical cancer), MDA MB-231 (breast cancer), MCF-7 (breast cancer) and normal embryonic kidney?cell line (HEK) were carried out using MTT assay. Few of the synthesized analogues exhibited potent anticancer activity against the cancer cell lines at a lower concentration. The synthesized compounds showed the less toxic effect on normal human embryonic kidney?cell line (HEK) compared with doxorubicin. Noticeably, compound 3o exhibited potent activity against all five cancer cell lines compared with ciprofloxacin. Further study exposed that compound 3o could competently intercalate into calf thymus DNA to form 3o-DNA complex which might block DNA replication to apply anti-proliferative activity. Docking simulation studies supported by molecular interactions with DNA type II topoisomerase. These derivates can become lead structures for the development of potential anticancer drugs. Graphical Abstract: Eighteen CP analogues were synthesized and evaluated for anti-proliferative activity. The interactions with DNA topoisomerase II were supported by molecular docking studies. 3o showed promising anticancer activity than CP against MCF7 cell line and interaction with calf thymus DNA was studied by fluorescence spectroscopy.[Figure not available: see fulltext.].
- Suresh, Narva,Suresh, Amaroju,Yerramsetty, Suresh,Bhadra, Manika Pal,Alvala, Mallika,Sekhar, Kondapalli Venkata Gowri Chandra
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- Synthesis, in?vitro evaluation and molecular docking studies of novel triazine-triazole derivatives as potential α-glucosidase inhibitors
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A novel series of triazine-triazole derivatives 7a–7m were synthesized, characterized by1H NMR and evaluated for their α-glucosidase inhibitory activity. All the synthesized compounds displayed potent α-glucosidase inhibitory activity with IC50range of 11.63?±?0.15 to 37.44?±?0.35?μM, when compared to the standard drug acarbose (IC50?=?817.38?±?6.27?μM). Among the series, compound 7i (IC50?=?11.63?±?0.15?μM) bearing 2,5-dichloro substitution at phenyl ring, represented the most potent α-glucosidase inhibitory activity. Molecular docking studies of the most active compounds with the homology modelled α-glucosidase were also performed to explore the possible inhibitory mechanism. Our studies shown that these triazine-triazole derivatives are a new class of α-glucosidase inhibitors.
- Wang, Guangcheng,Peng, Zhiyun,Wang, Jing,Li, Xin,Li, Juan
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p. 423 - 429
(2016/10/03)
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- Synthesis, molecular docking and α-glucosidase inhibition of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides
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A novel series of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides 5a–5q have been synthesized and evaluated for their α-glucosidase inhibitory activity. All newly synthesized compounds exhibited potent α-glucosidase inhibitory activity in the range of IC50?=?12.46?±?0.13–72.68?±?0.20?μM, when compared to the standard drug acarbose (IC50?=?817.38?±?6.27?μM). Among the series, compound 5j (12.46?±?0.13?μM) with strong electron-withdrawing nitro group on the arylacetamide moiety was identified as the most potent inhibitor of α-glucosidase. Molecular docking study was carried out to explore the binding interactions of these compounds with α-glucosidase. Our study identifies a novel series of potent α-glucosidase inhibitors for further investigation.
- Wang, Guangcheng,Li, Xin,Wang, Jing,Xie, Zhenzhen,Li, Luyao,Chen, Ming,Chen, Shan,Peng, Yaping
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p. 1115 - 1118
(2017/06/19)
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- 1,3-disubstituted pyrazole derivative as well as preparation method and application thereof
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The invention discloses a 1,3-disubstituted pyrazole derivative as well as a preparation method and application thereof. The compound has a structure shown as a general formula (I). The invention further provides a preparation method of the compounds and
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Paragraph 0078; 0079; 0080; 0081; 0084
(2018/03/24)
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- 5-Benzylidene-2,4-thiazolidenedione derivatives: Design, synthesis and evaluation as inhibitors of angiogenesis targeting VEGR-2
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A series of novel 5-benzylidene-2,4-thiazolidinediones were designed as inhibitors of angiogenesis targeting VEGFR-2. In docking study, molecules showed similar way of binding with VEGFR-2 as that of the co-crystallized ligand. Compounds were then synthes
- Bhanushali, Umesh,Rajendran, Saranya,Sarma, Keerthana,Kulkarni, Pushkar,Chatti, Kiranam,Chatterjee, Suvro,Ramaa
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p. 139 - 147
(2016/07/12)
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- 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation
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In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode.
- Abou-Seri, Sahar M.,Eldehna, Wagdy M.,Ali, Mamdouh M.,Abou El Ella, Dalal A.
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p. 165 - 179
(2015/11/25)
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- Synthesis and anti-leishmanial evaluation of 1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline derivatives against Leishmania infantum
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In the present study, antileishmanial activity of sixteen novel series of tetrahydro-β-carboline derivatives against transgenic infrared fluorescent Leishmania infantum strain has been reported. Among these reported analogues, most of the compounds exhibited potent inhibition against both promastigote (IC50from 1.99?±?1.40 to 20.69?±?0.95?μM) and amastigote (IC50from 0.67?±?0.05 to 4.16?±?0.008?μM) forms of L.?infantum. Moreover, compound 7l, displayed most potent and selective inhibition of parasite amastigote form with IC500.67?±?0.05?μM, selectivity index >298.5 and was comparable with standard drug amphotericin B. From this study, a new class of tetrahydro-β-carboline derivatives with potent antileishmanial activity was identified and it needs further extensive study to optimize the lead molecules to win the battle against severe and neglected disease leishmaniasis.
- Ashok, Penta,Chander, Subhash,Tejería, Ana,García-Calvo, Laura,Bala?a-Fouce, Rafael,Murugesan, Sankaranarayanan
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p. 814 - 821
(2016/08/23)
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- Synthesis and biological evaluation of N-(substituted phenyl)-2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylsulfanyl)acetamides as antimicrobial, antidepressant, and anticonvulsant agents
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A new series of N-Aryl-2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylsulfanyl)acetamides were synthesized by condensation of tricyclic compound 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione with chloro N-phenylacetamides. The tricyclic compound was obtaine
- Shruthi,Poojary, Boja,Kumar, Vasantha,Prathibha,Hussain, Mumtaz Mohammed,Revanasiddappa,Joshi, Himanshu
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p. 223 - 230
(2015/04/14)
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- Discovery of novel AHLs as potent antiproliferative agents
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Three series of novel AHL analogs were synthesized and evaluated for their in vitro cytotoxic activity against four human cancer cell lines. The SARs investigation indicated that AHLs with a terminal phenyl group, especially those with the chalcone scaffold had remarkably enhanced cytotoxicity than those with the hydrophobic side chains. Besides, some of these compounds were much more potent than 5-Fu and natural OdDHL. Through the detailed SARs discussions, we found that compounds 10a-k and 14 with the 4-amino chalcone scaffold showed excellent inhibition against all the tested cancer cell lines and were much more potent than 5-Fu and AHLs. Such scaffold may act as a template for further lead optimization. Compound 10i with a 3, 4, 5-trimethoxy group was the most potent one against all the tested cancer cell lines. Flow cytometry analysis indicated that analog 11e induced the cellular apoptosis and cell cycle arrest of MCF-7 cells at G2/M phase in a concentration-and time-dependent manner.
- Ren, Jing-Li,Zhang, Xu-Yao,Yu, Bin,Wang, Xi-Xin,Shao, Kun-Peng,Zhu, Xiao-Ge,Liu, Hong-Min
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p. 321 - 329
(2015/03/04)
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- Design, Synthesis, and Biological Evaluation of Chalcone Derivatives as Novel Anticandidal Agents
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Twenty chalcone derivatives were designed and synthesized with a view to developing novel anticandidal agents. All the compounds were evaluated for their antifungal activity against Candida albicans (ATCC 10231 and ten clinical isolates). Most of them exhibited moderate anticandidal potency with MIC values ranging from 2.0 to 32.0 μg/mL. Four compounds (T4, T6, T19, T20) displayed potent anticandidal activity with MIC values of 2.0 μg/mL. Compound T6 showed the most potent activity against Candida albicans (ATCC 10231 and four clinical isolates). In addition, attempts have also been made to correlate anticandidal activity to physicochemical properties. The results indicated that incorporation of halogen on the benzene ring is beneficial for anticandidal activity.
- Shan, Yuanyuan,Lei, Jine,Zhang, Li,Fan, Te,Wang, Maoyi,Ma, Ying
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p. 620 - 625
(2015/08/24)
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- Synthesis and anticonvulsant activity of new N-phenyl-2-(4-phenylpiperazin-1-yl)acetamide derivatives
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Twenty-two new N-phenyl-2-(4-phenylpiperazin-1-yl)acetamide derivatives have been synthesized and evaluated for their anticonvulsant activity in animal models of epilepsy. These molecules have been designed as analogs of previously obtained anticonvulsant
- Kamiński, Krzysztof,Wiklik, Beata,Obniska, Jolanta
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p. 3047 - 3061
(2015/03/18)
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- 6-bromo-2,3-dioxoindolin phenylacetamide derivatives: Synthesis, potent CDC25B, PTP1B inhibitors and anticancer activity
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A series of 6-bromo-2,3-dioxoindolin phenylacetamide derivatives was synthesized and evaluated for inhibitory activity against CDC25B and PTP1B. Most of the synthesized compounds showed potential inhibitory activities for CDC25B and PTP1B with compound 12 being the most potent (IC50=3.87μmol/L and 2.98 μmol/L, respectively). Compound 12 also exhibited higher cytotoxic activity against three cancer cell lines (HeLa, A549 and HCT116). In addition, compound 12 delayed the potent tumor inhibitory activity in a colo205 xenograft model in vivo.
- Zhao, Shui-Lian,Peng, Zhou,Zhen, Xing-Hua,Han, Yan,Jiang, Hai-Ying,Qu, You-Le,Guan, Li-Ping
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p. 529 - 536
(2016/03/22)
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- Synthesis and evaluation of 2-(5-(aryl)-1,3,4-oxadiazol-2-ylthio)-N-(3- (trifluoromethyl)phenyl)acetamides and N-(4-chloro-3-fluorophenyl)-2-(5-(aryl)- 1,3,4-oxadiazol-2-ylthio)acetamides as antimicrobial agents
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A series of 2-mercapto-5-phenyl-1,3,4-oxadiazole derivatives have been condensed with different phenyl acetamide derivatives possessing fluorine atom at meta position; resulting in the formation of 2-(5-aryl-1,3,4-oxadiazol-2- ylthio)-N-(3-(trifluoromethyl)phenyl)acetamide (5a-j) and N-(4-chloro-3- fluorophenyl)-2-(5-aryl-1,3,4-oxadiazol-2-ylthio)acetamide (5k-t) derivatives. The antimicrobial properties of the synthesized entities (5a-t) measured as their MIC (Minimum Inhibitory Concentration) values were evaluated by using the broth dilution method against Gram-positive bacteria (S. aureus and E. faecalis), Gram-negative bacteria (E. coli and P. aeruginosa) and fungi (C. albicans and A. niger). The results of antimicrobial activities (in μg/ml) revealed the fact that the compounds 5a and g bearing a maximum number of fluorine atoms showed the highest potency among the synthesized compounds against the broad panel of bacterial and fungal strains. The presence of fluorine atom at the meta position in the phenyl ring of final derivatives (5a-t) brought about an enhancement of their antimicrobial properties to a notable extent.
- Parikh, Kalpesh,Joshi, Deepkumar
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p. 827 - 835
(2014/07/07)
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- Synthesis, cytotoxic study and docking based multidrug resistance modulator potential analysis of 2-(9-oxoacridin-10(9H)-yl)-N-phenyl acetamides
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The present study describes the synthesis of fifteen 2-(9-oxoacridin-10(9H) -yl)-N-phenyl acetamide derivatives (13a-o) through condensation of 2-chloro-N-phenyl acetamides (12a-o) with acridone molecule (10). All the synthesized compounds were screened f
- Kumar, Rajesh,Kaur, Maninder,Bahia, Malkeet Singh,Silakari, Om
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- Synthesis and anticancer activities of novel 1,2,4-triazolo[3,4-a] phthalazine derivatives
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Trying to develop potent and selective anticancer agents, two series of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives were designed and synthesized. Their antitumor activities were evaluated by MTT method against four selected human cancer cell lines (MGC-803, EC-9706, HeLa and MCF-7). Our results showed that compound 11h exhibited good anticancer activities compared to 5-fluorouracil against the four tested cell lines, with IC50 values ranging from 2.0 to 4.5 μM. Flow cytometry analysis indicated that compound 11h induced the cellular early apoptosis and cell cycle arrest at G2/M phase in EC-9706.
- Xue, Deng-Qi,Zhang, Xu-Yao,Wang, Chao-Jie,Ma, Li-Ying,Zhu, Nan,He, Peng,Shao, Kun-Peng,Chen, Peng-Ju,Gu, Yi-Fei,Zhang, Xiao-Song,Wang, Cai-Feng,Ji, Cong-Hui,Zhang, Qiu-Rong,Liu, Hong-Min
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p. 235 - 244
(2014/08/18)
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- Synthesis and evaluation of novel benzimidazole derivatives as antimicrobial agents
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Benzimidazole analogs bearing electron-withdrawing as well as electron-donating substituent were synthesized to achieve bioactive molecules with significant antimicrobial property. The desired compounds were prepared by multi-step synthesis process. The formation of intermediates and their corresponding derivatives (III 1-13 ) was confirmed by spectral characterization such as 1H NMR, 13C NMR, mass spectra, IR, and elemental analysis. The compounds were screened for their antimicrobial properties against a broad panel of Gram-positive and Gram-negative bacteria as well as fungi. From the SAR study data, it was observed that the derivatives with electron-withdrawing functional groups were more bioactive than that with electron-donating functional groups.
- Joshi, Deepkumar,Parikh, Kalpesh
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p. 1290 - 1299
(2014/03/21)
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- Design, synthesis and antibacterial evaluation of novel AHL analogues
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Two series of novel AHL analogues were designed, synthesized and evaluated for antibacterial activity under cell membrane conditions in vitro. Analogues 4a-c and 4g-m presented potent activity against Gram-positive bacteria. Especially the analogue 4l exe
- Ren, Jing-Li,Zhang, En,Ye, Xian-Wei,Wang, Meng-Meng,Yu, Bin,Wang, Wen-Hua,Guo, Ya-Zhuo,Liu, Hong-Min
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supporting information
p. 4154 - 4156
(2013/07/25)
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- Design, synthesis and in-vivo hypoglycemic evaluation of novel non - TZD'S in a type - 2 diabetic model
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With a view to develop novel non-TZD anti-diabetic compounds, series of isoxazolidinediones were designed to target the PPAR-γ receptors. Docking studies were performed on co-crystallized protein structure of rosiglitazone with PPAR-γ receptor obtained from Protein Data Bank (2PRG). Interactions similar to that of rosiglitazone were observed for three molecules; 3a, 3b and 3c which were further synthesized and subjected to in vivo hypoglycemic, total cholesterol (CHL) and triglyceride (TG) evaluation. 14 days treatment revealed significant reduction in blood glucose levels but did not portray desirable results in terms of total CHL and TG lowering effect. The blood glucose reduction observed for 3a, 3b and 3c at 20 mg/kg/day was 53.96 %, 61.35%, 61.32% respectively as against 59.95% of the standard pioglitazone at 10mg/kg/day.
- Jadhav, Rupali,Gupta-Rajoria, Ranu,Pal, Tanushree,Subramanian, Ramaa Chelakara
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p. 104 - 111
(2013/04/24)
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- Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors
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Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC50 values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization.
- Wang, Fang,Lu, Wen,Zhang, Tao,Dong, Jinyun,Gao, Hongping,Li, Pengfei,Wang, Sicen,Zhang, Jie
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p. 6973 - 6980
(2013/11/06)
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- Discovery of novel N -phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
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In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
- Flipo, Marion,Willand, Nicolas,Lecat-Guillet, Nathalie,Hounsou, Candide,Desroses, Matthieu,Leroux, Florence,Lens, Zoé,Villeret, Vincent,Wohlk?nig, Alexandre,Wintjens, René,Christophe, Thierry,Kyoung Jeon, Hee,Locht, Camille,Brodin, Priscille,Baulard, Alain R,Déprez, Benoit
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supporting information; experimental part
p. 6391 - 6402
(2012/10/07)
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- Hydrazones derived from thiooxamohydrazides and 3-formyl-4-hydroxycoumarin: Synthesis, structures, and fragmentation
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Novel hydrazones were obtained from thiooxamohydrazides and 3-3-formyl-4-hydroxycoumarin. According to data from NMR spectroscopy and X-ray diffraction, the coumarin fragment in the compounds obtained exists as 4-hydroxycoumarin or chromane-2,4-dione. When dissolved in dimethyl sulfoxide, these hydrazones undergo fragmentation into derivatives of 1,3,4-thiadiazole and 4-hydroxycoumarin.
- Milevsky,Solov'Eva,Chibisova,Yarovenko,Zayakin,Chernyshev,Krayushkin,Traven
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p. 2311 - 2321
(2013/10/01)
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- MODIFIED FLUOROQUINOLONE COMPOUNDS AND METHODS OF USING THE SAME
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Embodiments of the invention relate to modified fluoroquinolone (MFQ) compounds and methods of using the same in treatment of an infection in a subject.
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Page/Page column 30-31
(2011/04/19)
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- An efficient and scalable synthesis of the spirocyclic glycine transporter inhibitor GSK2137305
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An efficient and scalable synthesis of a glycine transporter inhibitor is presented. The key steps in the synthetic sequence are the formation of a spirocyclic imidazolidinone from an -amino nitrile and a cyclic ketone and an arylation of 4-methyl imidazo
- Graham, Jonathan P.,Langlade, Nathalie,Northall, John M.,Roberts, Alastair J.,Whitehead, Andrew J.
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experimental part
p. 44 - 48
(2011/09/15)
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- QUINUCLIDINE DERIVATIVES AS MUSCARINIC M3 RECEPTOR ANTAGONISTS
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The invention provides named compounds of formula (I), wherein R4 is a N-substituted quinuclidine (I) pharmaceutical compositions containing them and a process for preparing the pharmaceutical compositions. Their use in therapy for’ the treatment of conditions mediated by M3 muscarinic receptors, such as chronic obstructive pulmonary disease is also disclosed.
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Page/Page column 35
(2011/08/02)
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- Synthesis and primary cytotoxicity evaluation of new 5-benzylidene-2,4- thiazolidinedione derivatives
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In the present work, ten novel derivatives (3a-3j) of 5-benzylidene-2,4- thiazolidinediones were synthesized and their structures were determined by analytical and spectral (FTIR, 1H NMR, 13C NMR) methods. The newly synthesized compounds were evaluated for their antiproliferative activity at Tata Memorial's Advanced Center for Treatment, Research and Education in Cancer (ACTREC), India, in a panel of 7 cancer cell lines using four concentrations at 10-fold dilutions. Sulforhodamine B (SRB) protein assay was used to estimate cell stability or growth. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most marked effect was observed by compound 3e in MCF7 (breast cancer), K562 (leukemia) and GURAV (nasopharyngeal cancer) cell lines with log10 GI50 values of -6.7, -6.72 and -6.73 respectively.
- Patil, Vijay,Tilekar, Kalpana,Mehendale-Munj, Sonali,Mohan, Rhea,Ramaa
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experimental part
p. 4539 - 4544
(2010/10/19)
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- Synthesis and biological evaluation of 1,4-diazepane derivatives as T-type calcium channel blockers
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We have synthesized and biologically evaluated 1,4-diazepane derivatives as T-type calcium channel blockers. In this study, we discovered compound 4s, a potential T-type calcium channel blocker with good selectivity over hERG and N-type calcium channels. In addition, it exhibited favorable pharmacokinetic characteristics for further investigation of T-type calcium channel related diseases.
- Gu, Su Jin,Lee, Jae Kyun,Pae, Ae Nim,Chung, Hye Jin,Rhim, Hyewon,Han, So Yeob,Min, Sun-Joon,Cho, Yong Seo
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scheme or table
p. 2705 - 2708
(2010/07/15)
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- Synthesis and in vitro trichomonicidal, giardicidal and amebicidal activity of N-acetamide(sulfonamide)-2-methyl-4-nitro-1H-imidazoles
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Two new series of imidazole derivatives (acetamides: 1-8 and sulfonamides: 9-15) were synthesized using a short synthetic route. Compound 1 as well as the intermediate 16g were characterized by X-ray crystallography. Imidazole derivatives 1-15 were tested in vitro against three unicellular parasites (Giardia intestinalis, Trichomonas vaginalis and Entamoeba histolytica) in comparison with benznidazole (Bzn) and metronidazole. Compound 1 [N-benzyl-2-(2-methyl-4-nitro-1H-imidazol-1-yl)acetamide] was 2 times more active than Bzn against T. vaginalis and G. intestinalis and it was as active as Bzn against E. histolytica. Sulfonamides showed selective toxicity against E. histolytica over the other parasites. Toxicity assay showed that all compounds are non-cytotoxic against MDCK cell line. The results revealed that compounds 1-15 have antiparasitic bioactivity in the micromolar range against the parasites tested, and could be considered as benznidazole bioisosteres.
- Hernandez-Nunez, Emanuel,Tlahuext, Hugo,Moo-Puc, Rosa,Torres-Gomez, Hector,Reyes-Martinez, Reyna,Cedillo-Rivera, Roberto,Nava-Zuazo, Carlos,Navarrete-Vazquez, Gabriel
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experimental part
p. 2975 - 2984
(2009/10/02)
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- Benzamide derivatives as dual-action hypoglycemic agents that inhibit glycogen phosphorylase and activate glucokinase
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A series of benzamide derivatives which can simultaneously inhibit glycogen phosphorylase (GP) and activate glucokinase (GK) were prepared and evaluated. The structure-activity relationships (SAR) of these compounds were also presented. Among these, compo
- Zhang, Lei,Li, Honglin,Zhu, Qingzhang,Liu, Jun,Chen, Ling,Leng, Ying,Jiang, Hualiang,Liu, Hong
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scheme or table
p. 7301 - 7312
(2010/03/04)
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- Synthesis and antispasmodic activity of lidocaine derivatives endowed with reduced local anesthetic action
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The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.
- Costa, Jorge C.S.,Neves, Josiane S.,de Souza, Marcus V.N.,Siqueira, Rodrigo A.,Romeiro, Nelilma C.,Boechat, Nubia,Silva, Patricia M.R.e,Martins, Marco A.
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p. 1162 - 1166
(2008/09/20)
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- Discovering benzamide derivatives as glycogen phosphorylase inhibitors and their binding site at the enzyme
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A series of novel benzamide derivatives was designed, synthesized, and their inhibitory activities against glycogen phosphorylase (GP) in the direction of glycogen synthesis by the release of phosphate from glucose-1-phosphate were evaluated. The structur
- Chen, Ling,Li, Honglin,Liu, Jun,Zhang, Luyong,Liu, Hong,Jiang, Hualiang
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p. 6763 - 6774
(2008/04/12)
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- Synthesis of 1-[N-(aryl)methylcarbamoyl]-1, 10-phenanthrolinium iodides with potential biological activity
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1-[N-(aryl)methylcarbamoyl]-1,10-phenanthrolinium iodides 10b-g were obtained by the reaction between N-aryl-2-iodoacetamides 9b-g and 1,10-phenanthroline. Also, the primary amide 10a was prepared by quaternization of 1,10-phenanthroline with iodoacetamid
- Dumitra?cu, Florea,Drǎghici, Constantin,Caira, Mino R.,Bǎdoiu, Andrei,Barbu, Loredana
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