共查询到20条相似文献,搜索用时 0 毫秒
1.
Yi-Long Yan Melissa T. Miller Yuchen Cao Seth M. Cohen 《Bioorganic & medicinal chemistry letters》2009,19(7):1970-1976
The zinc(II)-dependent matrix metalloproteinases (MMPs) are associated with a variety of diseases. Development of inhibitors to modulate MMP activity has been an active area of investigation for therapeutic development. Hydroxypyrones and hydroxythiopyrones are alternative zinc-binding groups (ZBGs) that, when combined with peptidomimetic backbones, comprise a novel class of MMP inhibitors (MMPi). In this report, a series of hydroxypyrone- and hydroxythiopyrone-based MMPi with aryl backbones at the 2-, 5-, and 6-positions of the hydroxypyrone ring have been synthesized. Synthetic routes for developing inhibitors with substituents at two of these positions (so-called double-handed inhibitors) are also explored. The MMP inhibition profiles and structure–activity relationship of synthesized hydroxypyrones and hydroxythiopyrones have been analyzed. The results here show that the ZBG, the position of the backbone on the ZBG, and the nature of the linker between the ZBG and backbone are critical for MMPi activities. 相似文献
2.
《Bioorganic & medicinal chemistry》2014,22(15):4119-4123
A series of thiobarbituric acid derivatives 1–27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1–27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC50 values 18.1 ± 0.52, 16.0 ± 0.45, 16.0 ± 0.22, 14.3 ± 0.27, 6.7 ± 0.27, 10.6 ± 0.17, 19.2 ± 0.29, 18.2 ± 0.76 and 1.61 ± 0.18 μM, respectively, much better than the standard urease inhibitor thiourea (IC50 = 21 ± 0.11 μM). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC50 values 21.4 ± 1.04 and 21.5 ± 0.61μM, 22.8 ± 0.32, 25.2 ± 0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure–activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and 1H NMR. 相似文献
3.
4.
Kouji Kuramochi Keishi Fukudome Isoko Kuriyama Toshifumi Takeuchi Yoshihiro Sato Shinji Kamisuki Kazunori Tsubaki Fumio Sugawara Hiromi Yoshida Yoshiyuki Mizushina 《Bioorganic & medicinal chemistry》2009,17(20):7227-7238
Herein, we describe the synthesis and structure–activity relationships of dehydroaltenusin derivatives as inhibitors of a mammalian DNA polymerase α. We have newly synthesized nine dehydroaltenusin derivatives modified at the side chains or benzoquinone moiety. We also achieved the first synthesis of desmethylaltenusin and desmethyldehydroaltenusin, metabolites of Alternaria sp. or Talaromyces flavus, respectively. Among all synthesized derivatives, demethoxydehydroaltenusin was the most selective inhibitor of DNA polymerase α. The o-hydroxy-p-benzoquinone (2-hydroxycyclohexa-2,5-dienone) moiety is essential for the inhibition of DNA polymerases. Substitution at the 5-position of dehydroaltenusin is important for the inhibitory potency. Because dehydroaltenusin is conjugated with N-acetylcysteine methyl ester at the o-hydroxy-p-benzoquinone moiety, one or more cysteine residues of DNA polymerase α may act as a target for this compound. 相似文献
5.
Guolin Wu Haixia Wang Wenhui Zhou Bihua Zeng Wenhui Mo Kejie Zhu Rong Liu Jia Zhou Ceshi Chen Haijun Chen 《Bioorganic & medicinal chemistry》2018,26(12):3321-3344
Recent studies revealed that MALT1 is a promising therapeutic target for the treatment of ABC-DLBCL. Among several reported MALT1 inhibitors, MI-2 as an irreversible inhibitor represents a new class of ABC-DLBCL therapeutics. Due to its inherent potential cross-reactivity, further structure–activity relationship (SAR) study is imperative. In this work, five focused compound libraries based on the chemical structure of MI-2 are designed and synthesized. The systematic SARs revealed that the side chain of 2-methoxyethoxy has little impact on the activity and can be replaced by other functionalized groups, providing new MI-2 analogues with retained or enhanced potency. Compounds 81–83 with terminal hydroxyl group as side chain displayed enhanced activities against MALT1. Replacement of triazole core with pyrazole is also tolerant, while structural modifications on other sites are detrimental. These findings will facilitate further development of small-molecule MALT1 inhibitors. 相似文献
6.
Martina Hrast Kaja Rožman Marko Jukič Delphine Patin Stanislav Gobec Matej Sova 《Bioorganic & medicinal chemistry letters》2017,27(15):3529-3533
MurA is an intracellular bacterial enzyme that is essential for peptidoglycan biosynthesis, and is therefore an important target for antibacterial drug discovery. We report the synthesis, in silico studies and extensive structure–activity relationships of a series of quinazolinone-based inhibitors of MurA from Escherichia coli. 3-Benzyloxyphenylquinazolinones showed promising inhibitory potencies against MurA, in the low micromolar range, with an IC50 of 8 µM for the most potent derivative (58). Furthermore, furan-substituted quinazolinones (38, 46) showed promising antibacterial activities, with MICs from 1 µg/mL to 8 µg/mL, concomitant with their MurA inhibitory potencies. These data represent an important step towards the development of novel antimicrobial agents to combat increasing bacterial resistance. 相似文献
7.
Hongcai Li Chao Wang Tino Sanchez Yanmei Tan Chunying Jiang Nouri Neamati Guisen Zhao 《Bioorganic & medicinal chemistry》2009,17(7):2913-2919
HIV-1 integrase, which catalyzes the integration of the viral genome into the cellular chromosome, is an essential enzyme for retroviral replication, and represents an attractive and validated target in the development of therapeutics against AIDS. In this paper, 17 amide-containing novel diketoacids were designed and synthesized, and their ability to inhibit HIV-1 integrase was tested. The structure–activity relationships were also analyzed. 相似文献
8.
Stevan Pecic Svetlana Pakhomova Marcia E. Newcomer Christophe Morisseau Bruce D. Hammock Zhengxiang Zhu Alison Rinderspacher Shi-Xian Deng 《Bioorganic & medicinal chemistry letters》2013,23(2):417-421
A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure–activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development. 相似文献
9.
Haofan Wang Youngjoo Byun Cyril Barinka Mrudula Pullambhatla Hyo-eun C. Bhang James J. Fox Jacek Lubkowski Ronnie C. Mease Martin G. Pomper 《Bioorganic & medicinal chemistry letters》2010,20(1):392-397
We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure–activity relationship studies of the P1′ site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with Ki values below 20 nM. Among them, compound 32d (Ki = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1′ pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d. 相似文献
10.
Discovery and structure–activity relationship analysis of Staphylococcus aureus sortase A inhibitors
Nuttee Suree Sung Wook Yi William Thieu Melanie Marohn Robert Damoiseaux Albert Chan Michael E. Jung Robert T. Clubb 《Bioorganic & medicinal chemistry》2009,17(20):7174-7185
Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structure–activity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC50 values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors. 相似文献
11.
Lydia P.P. Liew Marcel Kaiser Brent R. Copp 《Bioorganic & medicinal chemistry letters》2013,23(2):452-454
Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC50 0.89 μM). Preliminary structure–activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC50 8.6 nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics. 相似文献
12.
Lloyd J. Simons Bradley W. Caprathe Michael Callahan James M. Graham Takenori Kimura Yingjie Lai Harry LeVine William Lipinski Annette T. Sakkab Yoshikazu Tasaki Lary C. Walker Tomoyuki Yasunaga Yuyang Ye Nian Zhuang Corinne E. Augelli-Szafran 《Bioorganic & medicinal chemistry letters》2009,19(3):654-657
It is believed that β-amyloid aggregation is an important event in the development of Alzheimer’s disease. In the course of our studies to identify β-amyloid aggregation inhibitors, a series of N-phenyl anthranilic acid analogs were synthesized and studied for β-amyloid inhibition activity. The synthesis, structure–activity relationship, and in vivo activity of these analogs are discussed. 相似文献
13.
Marietta Tóth Sándor Kun Éva Bokor Mahmoud Benltifa Gaylord Tallec Sébastien Vidal Tibor Docsa Pál Gergely László Somsák Jean-Pierre Praly 《Bioorganic & medicinal chemistry》2009,17(13):4773-4785
A series of per-O-benzoylated 5-β-d-glucopyranosyl-2-substituted-1,3,4-oxadiazoles was prepared by acylation of the corresponding 5-(β-d-glucopyranosyl)tetrazole. As an alternative, oxidation of 2,6-anhydro-aldose benzoylhydrazones by iodobenzene I,I-diacetate afforded the same oxadiazoles. 1,3-Dipolar cycloaddition of nitrile oxides to per-O-benzoylated β-d-glucopyranosyl cyanide gave the corresponding 5-β-d-glucopyranosyl-3-substituted-1,2,4-oxadiazoles. The O-benzoyl protecting groups were removed by base-catalyzed transesterification. The 1,3,4-oxadiazoles were practically inefficient as inhibitors of rabbit muscle glycogen phosphorylase b while the 1,2,4-oxadiazoles displayed inhibitory activities in the micromolar range. The best inhibitors were the 5-β-d-glucopyranosyl-3-(4-methylphenyl- and -2-naphthyl)-1,2,4-oxadiazoles (Ki = 8.8 and 11.6 μM, respectively). A detailed analysis of the structure–activity relationships is presented. 相似文献
14.
Sheeba Wajid Asma Khatoon Maria Aqeel Khan Humaira Zafar Shama Kanwal M. Iqbal Choudhary Fatima Z. Basha 《Bioorganic & medicinal chemistry》2019,27(18):4030-4040
A series of benzamide derivatives 1–12 with various functional groups (–H, –Br, –F, –OCH3, –OC2H5, and –NO2) was synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) activity in vitro. Structure–activity relationship showed that the substitution of –Br group influenced the inhibitory activity against BCHE enzyme. Synthesized compounds were found to be selective inhibitors of BCHE. In addition, all compounds 1–12 were found to be non-cytotoxic, as compared to the standard cycloheximide (IC50 = 0.8 ± 0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ± 0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Enzyme kinetic studies indicated that compounds 1, 3–4, and 7–8 showed a mixed mode of inhibition against BCHE, while compounds 2, 5–6 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329, and many others. 相似文献
15.
Faten Sliman Mélina Blairvacq Emilie Durieu Laurent Meijer Jordi Rodrigo Didier Desmaële 《Bioorganic & medicinal chemistry letters》2010,20(9):2801-2805
Pim-1 kinase is a cytoplasmic serine/threonine kinase that controls programmed cell death by phosphorylating substrates that regulate both apotosis and cellular metabolism. A series of 2-styrylquinolines and quinoline-2-carboxamides has been identified as potent inhibitors of the Pim-1 kinase. The 8-hydroxy-quinoline 7-carboxylic acid moiety appeared to be a crucial pharmacophore for activity. Molecular modeling indicated that interaction of this scaffold with Asp186 and Lys67 residues within the ATP-binding pocket might be responsible for the kinase inhibitory potency. 相似文献
16.
Yan Lu Zhao Wang Chien-Ming Li Jianjun Chen James T. Dalton Wei Li Duane D. Miller 《Bioorganic & medicinal chemistry》2010,18(2):477-495
A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure–activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10 mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60 mg/kg. 相似文献
17.
T.K. Sasikumar Li Qiang Duane A. Burnett David Cole Ruo Xu Hongmei Li William J. Greenlee John Clader Lili Zhang Lynn Hyde 《Bioorganic & medicinal chemistry letters》2010,20(12):3632-3635
Tricyclic sulfones were designed as γ-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency. 相似文献
18.
Ehsan Ullah Mughal Amina Sadiq Shahzad Murtaza Hummera Rafique Muhammad Naveed Zafar Tauqeer Riaz Bilal Ahmad Khan Abdul Hameed Khalid Mohammed Khan 《Bioorganic & medicinal chemistry》2017,25(1):100-106
The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawesson’s reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE. 相似文献
19.
Jun Pu Anthony F. Kreft Suzan H. Aschmies Kevin P. Atchison Joshua Berkowitz Thomas J. Caggiano Micheal Chlenov George Diamantidis Boyd L. Harrison Yun Hu Donna Huryn J. Steven Jacobsen Mei Jin Kerri Lipinski Peimin Lu Robert L. Martone Koi Morris June Sonnenberg-Reines Dave R. Riddell Joan Sabalski Lynn Resnick 《Bioorganic & medicinal chemistry》2009,17(13):4708-4717
γ-Secretase inhibitors have been shown to reduce the production of β-amyloid, a component of the plaques that are found in brains of patients with Alzheimer’s disease. A novel series of heterocyclic sulfonamide γ-secretase inhibitors that reduce β-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative γ-secretase substrate. 相似文献
20.
Hyeju Jo Minho Choi Jaeuk Sim Mayavan Viji Siyuan Li Young Hee Lee Youngsoo Kim Seung-Yong Seo Yuanyuan Zhou Kiho Lee Wun-Jae Kim Jin Tae Hong Heesoon Lee Jae-Kyung Jung 《Bioorganic & medicinal chemistry letters》2017,27(15):3374-3377
We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities. 相似文献