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1.
Iminothiazoline‐Sulfonamide Hybrids as Jack Bean Urease Inhibitors; Synthesis,Kinetic Mechanism and Computational Molecular Modeling 下载免费PDF全文
Aamer Saeed Shams‐ul Mahmood Muhammad Rafiq Zaman Ashraf Farukh Jabeen Sung‐Yum Seo 《Chemical biology & drug design》2016,87(3):434-443
The present work reports the synthesis of several 2‐iminothiazoline derivatives of sulfanilamide ( 3a – j ) as inhibitors of jack bean ureases. The title compounds were synthesized by the heterocyclization of sulfanilamide thioureas with propragyl bromide in dry ethanol in the presence of 1,8‐Diazabicyclo[5.4.0]undec‐7‐ene as a base. All of the compounds showed higher urease inhibitory activity than the standard thiourea. The compounds ( 3h ) and ( 3i ) exhibited excellent enzyme inhibitory activity with IC50 0.064 and 0.058 μ m , respectively, while IC50 of thiourea is 20.9 μ m . The kinetic mechanism analyzed by Dixon plot showed that compound ( 3h ) is a mixed‐type inhibitor while ( 3i ) is a competitive one. Docking studies suggested that Asp633, Ala636, His492, Ala440, Lue523, Asp494 and Arg439 are the major interacting residues in the binding site of the protein and may have an instrumental role in the inhibition of enzyme's function. 2‐iminothiazoline analogues ( 3a – j ) showed good docking score (?10.6466 to ?8.7215 Kcal/mol) and binding energy (London dG ranging from ?14.4825 to ?10.4087 Kcal/mol) which is far better than the standard thiourea (binding score in S field ?4.5790 Kcal/mol London dG ?4.7726 Kcal/mol). Our results inferred compound ( 3i ) may serve as a structural model for the design of most potent urease inhibitors. 相似文献
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Yong Yin Shao Sha Yan‐Ting Wang Xun Wu She‐Feng Wang Fang Qiao Peng‐Cheng Lv Hai‐Liang Zhu 《Chemical biology & drug design》2015,86(5):1323-1329
VEGFR2 has been proved to play a major role in the regulation of tumor angiogenesis. Twenty‐one 4‐alkoxyquinazoline‐based derivatives have been designed and synthesized as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors, and their biological activities were evaluated. Among these compounds, compound 3h exhibited the most potent inhibitory activities against VEGFR2 tyrosine kinase and cell proliferation, with the IC50 values of 2.89 nm (for VEGFR2) and 0.25 μ m (for MCF‐7), which were comparable with the control compound. Docking simulation was performed to position compound 3h into the 4ASE active site, and the result showed that compound 3h could bind well at the 4ASE active site. 相似文献
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Jiaying Sun Shaoxi Cai Hu Mei Jian Li Ning Yan Qin Wang Zhihua Lin Danqun Huo 《Chemical biology & drug design》2010,76(3):245-254
Surflex–Dock was employed to dock 36 thiourea and thiadiazolo [2,3-α] pyrimidine derivatives into neuraminidase 1a4g. Molecular docking results showed that hydrogen bonding, electrostatic, and hydrophobic features were important factors affecting inhibitory activities of these neuraminidase inhibitors. Moreover, there was a significant correlation between the predicted binding affinity (total scores) and experimental pIC50 values with correlation coefficient r = 0.846 and p < 0.0001. Hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis were used to develop quantitative structure–activity relationship models. Squared multiple correlation coefficients (r 2) of hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.899, 0.878, and 0.865, respectively. Squared cross-validated correlation coefficient (q 2) of hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models was in turn 0.628, 0.656, and 0.509. In addition, squared multiple correlation coefficients for test set (r 2test) of hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.558, 0.667, and 0.566, respectively. The most active sample ID 2 was taken as a template molecule to design new molecules. Based on the comparative molecular field analysis model, new compounds were designed by LeapFrog. Seven new compounds with improved binding energy and predicted activities were finally obtained. 相似文献
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Naohisa Ogo Yoshinobu Ishikawa Jun-ichi Sawada Kenji Matsuno Akihiro Hashimoto Akira Asai 《ACS medicinal chemistry letters》2015,6(9):1004-1009
l-cysteine derivatives as selective KSP inhibitors. Here, we
report further optimizations using docking modeling in the L5 allosteric
binding site, which led to the discovery of several high affinity
derivatives with two fused phenyl rings in the trityl group giving
low nanomolar range KSP ATPase inhibition. The representative derivatives
potently inhibited cell growth of HCT116 cells in correlation with
KSP inhibitory activities and significantly suppressed tumor growth
in the xenograft model in vivo. 相似文献
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General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors 下载免费PDF全文
Natalya I. Vasilevich Elena A. Aksenova Denis N. Kazyulkin Ilya I. Afanasyev 《Chemical biology & drug design》2016,88(1):54-65
A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine‐tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3–5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained. 相似文献
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Marc Le Borgne Pascal Marchand Muriel Duflos Bndicte Delevoye-Seiller Sylvie Piessard-Robert Guillaume Le Baut Rolf W. Hartmann M. Palzer 《Archiv der Pharmazie》1997,330(5):141-145
In the challenge to develop potent inhibitors of aromatase for reducing the levels of estrogens, we found that azolyl-substituted indoles inhibit aromatase activity. 3-(1-Azolylmethyl)-1H-indoles 9–15 and 3-(1-azolyl-1-phenylmethyl)-1H-indoles 22–25 were prepared, and tested on their ability to inhibit P450 arom. Analysis of the inhibitory effect exerted by several derivatives ( 11, 12, 22 , and 23 ) on microsomal aromatase in vitro activity indicates that azolyl-substituted indoles containing an imidazole moiety are more potent inhibitors than triazole derivatives. In the first series, the introduction of the N-benzyl moiety has been found to enhance the inhibitory profile of these 3-(1-azolylmethyl)-1H-indole derivatives. The corresponding 4-fluoro derivative 12 displays the highest inhibitory activity (IC50 = 0.0718 μM) of all investigated compounds; thus, 12 is 258 times as potent as aminoglutethimide (AG). The presence of a chloro grouping in para position of the phenyl ring in compounds 22 and 24 exerts a positive effect only in the triazol-1-yl sub-series: compound 25 is 4-fold more potent than 24 . 相似文献
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Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis,Pharmacological Evaluation,and Molecular Modeling of Amino‐Alkyl‐Substituted Fluoro‐Chalcones Derivatives 下载免费PDF全文
Hao‐Ran Liu Chao Zhou Hao‐Qun Fan Jing‐Jing Tang Lin‐Bo Liu Xiao‐Hui Gao Qiu‐An Wang Wu‐Kun Liu 《Chemical biology & drug design》2015,86(4):517-522
A new series of‐fluoro chalcones‐substituted amino‐alkyl derivatives ( 3a?3l ) were designed, synthesized, characterized and evaluated for the inhibitory activity against acetylcholinesterase and butyrylcholinesterase. The results showed that the alteration of fluorine atom position and amino‐alkyl groups markedly influenced the activity and the selectivity of chalcone derivates in inhibiting acetylcholinesterase and butyrylcholinesterase. Among them, compound 3l possesses the most potent inhibitory against acetylcholinesterase (IC50 = 0.21 ± 0.03 μmol/L), and the highest selectivity for acetylcholinesterase over butyrylcholinesterase (IC50 (BuChE)/IC50 (AChE) = 65.0). Molecular modeling and enzyme kinetic study on compound 3l supported its dual acetylcholinesterase inhibitory profile, simultaneously binding at the catalytic active and peripheral anionic site of the enzyme. 相似文献
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Novel potent derivatives of phthalazine are described as an adenosine triphosphate-competitive inhibitors of vascular endothelial growth factor receptors I and II. A number of compounds display vascular endothelial growth factor receptor II inhibitory activity reaching that of Vatalanib A (IC(50): < 50 nm) in an homogenous time-resolved fluorescence enzymatic assay. 相似文献
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Johan J. N. Veerman Yorik B. Bruseker Eddy Damen Erik H. Heijne Wendy van Bruggen Koen F. W. Hekking Rob Winkel Christopher D. Hupp Anthony D. Keefe Julie Liu Heather A. Thomson Ying Zhang John W. Cuozzo Andrew J. McRiner Mark J. Mulvihill Peter van Rijnsbergen Birgit Zech Louis M. Renzetti Lee Babiss Gerhard Müller 《ACS medicinal chemistry letters》2021,12(4):555
Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor β-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1H-dicarboxamide scaffold, showing remarkable kinome selectivity. A scaffold-hop to the corresponding imidazole resulted in increased biochemical potency. Next, X-ray crystallography revealed a distinct binding mode compared to other TAK1 inhibitors. A benzylamide was found in a perpendicular orientation with respect to the core hinge-binding imidazole. Additionally, an unusual amide flip was observed in the kinase hinge region. Using structure-based drug design (SBDD), key substitutions at the pyrrolidine amide and the glycine resulted in a significant increase in biochemical potency. 相似文献
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Matthias Lehr 《Archiv der Pharmazie》1996,329(11):483-488
3-(1,4-Diacylpyrrol-2-yl)propionic acids were designed as inhibitors of cytosolic phospholipase A2. Enzyme inhibition was assayed by evaluation of calcium ionophore A23187-induced arachidonic acid release from bovine platelets. While the synthesized bisacyl compound 3-[3,5-dimethyl-4-octadecanoyl-1-(3-phenylpropionyl)pyrrol-2-yl]propionic acid was inactive at 33 μM, the related monoacylated 3-(3,5-dimethyl-4-octadecanoylpyrrol-2-yl)propionic acid and 3-(1,3,5-trimethyl-4-octadecanoylpyrrol-2-yl)propionic acid proved to be inhibitors of cytosolic phospholipase A2 (IC50: 24 μM and 13 μM, respectively). 相似文献
16.
Synthesis,characterization and biological applications of novel Schiff bases of 2-(trifluoromethoxy) aniline 下载免费PDF全文
Thierry Youmbi Fonkui Monisola Itohan Ikhile Freddy Munyololo Muganza Marthe Carine Djuidje Fotsing Charmaine Arderne Xavier Siwe-Noundou 《中国药学》2018,27(5):307-323
A series of five new Schiff bases (1–5) were synthesized by reacting 2-(trifluoromethoxy) aniline with different aromatic aldehydes. The Schiff base compounds were characterized by spectroscopic and analytical methods. Crystal structure of one new compound was also reported. The pharmacological properties, including antibacterial (14 bacterial species), antifungal (7 strains),antimalarial, anti-trypanosomal and anti-HIV activities of the compounds, were investigated. Cytotoxicity of the tested compounds was evaluated against human cervix adernocarcinoma cells (HeLa). Bacterial minimum inhibitory concentration (MIC) results by broth microdilution method showed that Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Proteus vulgaris, Klebsiella oxytoc and Klebsiella pneumonia were more sensitive in the presence of tested compounds with an MIC value of 15.6 µg/mL. All the tested compounds showed good to moderate activity against fungi. The sensitivity of Aspergillus fumigatus was higher than other strains with aminimum cell death concentration (MFC) of 15.6 µg/mL. Compound 1 showed greater antimalarial and anti-trypanosomal properties with very low to no cytotoxic effects against HeLa cells as compared with compound 5, while other compounds exhibited poor activity. Compounds 1–5 demonstrated good activity against HIV type-1. These Schiff base compounds could be used as good antimicrobial agents. 相似文献
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G B Mullen J T Mitchell S D Allen V St Georgiev 《Journal of pharmaceutical sciences》1988,77(12):1050-1054
The in vitro antifungal activity of a novel series of cis- and trans-5-([aryl or aryloxy (or thio)]methyl)-3-(1H-imidazol-1-ylmethyl)-3- (2-thienyl)-2-methylisoxazolidines (13-24) was evaluated and compared with ketoconazole. The title series of compounds was prepared via a 1,3-dipolar cycloaddition reaction of 1-(2-thienyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxides with appropriate styrenes, allyl phenyl ethers, or allyl phenyl thioether precursors. The resulting products were mixtures of the corresponding cis- and trans-diastereomers which were readily separated by flash chromatography on neutral silica gel. The majority of compounds 13-24, when tested in solid agar cultures, exhibited moderate to potent activity against Trichophyton rubrum, Aspergillus fumigatus, and Candida albicans at concentrations ranging between less than or equal to 2.0 and 70.0 micrograms/mL. 相似文献
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Rajyalakshmi Gudipati Rama Narsimha Reddy Anreddy Sarangapani Manda 《Saudi Pharmaceutical Journal》2011,19(3):153-158
A series of 5- or 7-substituted 3-{4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenylimino}-indolin-2-one derivatives were synthesized by treating 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, 1H NMR, MS) analyses. All the synthesized derivatives were screened for anticancer activity against HeLa cancer cell lines using MTT assay. All the synthetic compounds produced a dose dependant inhibition of growth of the cells. The IC50 values of all the synthetic test compounds were found between 10.64 and 33.62 μM. The potency (IC50 values) of anticancer activity of compounds VIb–d was comparable with that of known anticancer agent, Cisplatin. Among the synthesized 2-indolinones, compounds VIb–d with halogen atom (electron withdrawing groups) at C5 position showed the most potent activity. These results indicate that C5 substituted derivatives may be useful leads for anticancer drug development in the future. 相似文献
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We report the design and synthesis of novel FTPA-triazole compounds as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), through a focus on thioether and isoprenoid mimetics. These mimetics were coupled utilizing a copper-assisted cycloaddition to assemble the potential inhibitors. Using the resulting triazole from the coupling as an isoprenyl mimetic resulted in the biphenyl substituted FTPA triazole 10n. This lipid-modified analog is a potent inhibitor of Icmt (IC(50) = 0.8 ± 0.1 μM; calculated K(i) = 0.4 μM). 相似文献