Design, synthesis, and structure-activity relationships of pyrazole derivatives as potential FabH inhibitors

被引：87

作者：

Lv, Peng-Cheng ^{[1
]}

Sun, Juan ^{[1
]}

Luo, Yin ^{[1
]}

Yang, Ying ^{[1
]}

Zhu, Hai-Liang ^{[1
]}

机构：

[1] Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210093, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 15期

基金：

中国国家自然科学基金; 美国国家科学基金会;

关键词：

Design; Synthesis; FabH inhibitors; Antibacterial; Pyrazole derivatives; Structure-activity relationship; ACYL-CARRIER-PROTEIN; SYNTHASE-III; ANTITUMOR-ACTIVITY; ANTIBACTERIAL ACTIVITY; ANTIMICROBIAL AGENTS; CONDENSING ENZYME; ESCHERICHIA-COLI; IDENTIFICATION; NUCLEOSIDES; ETHERS;

D O I：

10.1016/j.bmcl.2010.05.105

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Fatty acid biosynthesis is essential for bacterial survival. FabH, beta-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and - \negative bacteria. Fifty-six 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-(4-fluorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl) ethanone (12) and 1-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl) ethanone (13) were potent inhibitors of E. coli FabH. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：4657 / 4660

页数：4

共 27 条

[1] A combined approach of docking and 3D QSAR study of β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors [J].

Ashek, A ;

Cho, SJ .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (05) :1474-1482

[2] The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice [J].

Bebernitz, GR ;

Argentieri, G ;

Battle, B ;

Brennan, C ;

Balkan, B ;

Burkey, BF ;

Eckhardt, M ;

Gao, JP ;

Kapa, P ;

Strohschein, RJ ;

Schuster, HF ;

Wilson, M ;

Xu, DD .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (16) :2601-2611

[3] Design and synthesis of some substituted 1H-pyrazolyl-thiazolo[4,5-d]pyrimidines as anti-inflammatory-antimicrobial agents [J].

Bekhit, AA ;

Fahmy, HTY ;

Rostom, SAF ;

Baraka, AM .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2003, 38 (01) :27-36

[4]

CLOUGH RC, 1992, J BIOL CHEM, V267, P20992

[5]

COMBER RN, 1991, CARBOHYD RES, V216, P441

[6]

CRONAN JE, 1996, CELLULAR MOL BIOL, P612

[7] First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling [J].

Daines, RA ;

Pendrak, I ;

Sham, K ;

Van Aller, GS ;

Konstantinidis, AK ;

Lonsdale, JT ;

Janson, CA ;

Qiu, XY ;

Brandt, M ;

Khandekar, SS ;

Silverman, C ;

Head, MS .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (01) :5-8

[8] Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis [J].

Genin, MJ ;

Allwine, DA ;

Anderson, DJ ;

Barbachyn, MR ;

Emmert, DE ;

Garmon, SA ;

Graber, DR ;

Grega, KC ;

Hester, JB ;

Hutchinson, DK ;

Morris, J ;

Reischer, RJ ;

Ford, CW ;

Zurenko, GE ;

Hamel, JC ;

Schaadt, RD ;

Stapert, D ;

Yagi, BH .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (05) :953-970

[9] Regulation of fatty acid elongation and initiation by acyl acyl carrier protein in Escherichia coli [J].

Heath, RJ ;

Rock, CO .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (04) :1833-1836

[10] The Claisen condensation in biology [J].

Heath, RJ ;

Rock, CO .

NATURAL PRODUCT REPORTS, 2002, 19 (05) :581-596

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