共查询到20条相似文献,搜索用时 15 毫秒
1.
Fereshteh Shiri Maryam Salahinejad Rahmatollah Dijoor Massoud Nejati-Yazdinejad 《Journal of receptor and signal transduction research》2018,38(2):151-165
Pathogenic Gram-negative bacteria are responsible for nearly half of the serious human infections. Hologram quantitative structure–activity relationships (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) were implemented on a group of 32 of potent Gram-negative LpxC inhibitors. The most effective HQSAR model was obtained using atoms, bonds, donor, and acceptor as fragment distinction. The cross-validated correlation coefficient (q2), non-cross-validated correlation coefficient (r2), and predictive correlation coefficient (r2Pred) for test set of HQSAR model were 0.937, 0.993, and 0.892, respectively. The generated models were found to be statistically significant as the CoMFA model had (r2?=?0.967, q2?=?0.804, r2Pred?=?0.827); the CoMSIA model had (r2?=?0.963, q2?=?0.752, r2Pred?=?0.857). Molecular docking was employed to validate the results of the HQSAR, CoMFA, and CoMSIA models. Based on the obtained information, six new LpxC inhibitors have been designed. 相似文献
2.
Tetsuya Kawai Iwase Kazuhiko Noriko Takaya Yuko Yamaguchi Ryuta Kishii Yasushi Kohno Haruaki Kurasaki 《Bioorganic & medicinal chemistry letters》2017,27(4):1045-1049
We attempted to optimize sulfonamide-based non-alkyne LpxC inhibitors by focusing on improvements in enzyme inhibitory and antibacterial activity. It was discovered that inhibitors possessing 2-aryl benzofuran as a hydrophobe exhibited good activity. In particular, compound 21 displayed impressive antibacterial activity (E. coli MIC = 0.063 μg/mL, K. pneumoniae MIC = 0.5 μg/mL, and P. aeruginosa MIC = 0.5 μg/mL), and is a promising lead for further exploration as an antibacterial agent. 相似文献
3.
Shi Ding Rui-Yang Dai Wen-Ke Wang Qiao Cao Le-Fu Lan Xian-Li Zhou Yu-She Yang 《Bioorganic & medicinal chemistry letters》2018,28(2):94-102
LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To develop novel LpxC inhibitors with good antibacterial activities and biological metabolism, we summarized the basic skeleton of reported LpxC inhibitors, designed and synthesized several series of compounds and tested their antibacterial activities against Escherichial coli and Pseudomonas aeruginosa in vitro. Structure-activity relationships have been discussed in this article. The metabolism stability of YDL-2, YDL-5, YDL-8, YDL-14, YDL-20–YDL-23 have been evaluated in liver microsomes, which indicated that the 2-amino isopropyl group may be a preferred structure than the 2-hydroxy ethyl group in the design of LpxC inhibitors. 相似文献
4.
《Bioorganic & medicinal chemistry》2014,22(3):1016-1028
The inhibition of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represents a promising strategy to combat infections caused by multidrug-resistant Gram-negative bacteria. In order to elucidate the functional groups being important for the inhibition of LpxC, the structure of our previously reported hydroxamic acid 4 should be systematically varied. Therefore, a series of benzyloxyacetohydroxamic acids was prepared, of which the diphenylacetylene derivatives 28 (Ki = 95 nM) and 21 (Ki = 66 nM) were the most potent inhibitors of Escherichia coli LpxC. These compounds could be synthesized in a stereoselective manner employing a Sharpless asymmetric dihydroxylation and a Sonogashira coupling in the key steps. The obtained structure–activity relationships could be rationalized by molecular docking studies. 相似文献
5.
《Bioorganic & medicinal chemistry》2020,28(13):115529
The bacterial deacetylase LpxC is a promising target for the development of antibiotics selectively combating Gram-negative bacteria. To improve the biological activity of the reported benzyloxyacetohydroxamic acid 9 ((S)-N-hydroxy-2-{2-hydroxy-1-[4-(phenylethynyl)phenyl]ethoxy}acetamide), its hydroxy group was replaced by a triazole ring. Therefore, in divergent syntheses, triazole derivatives exhibiting rigid and flexible lipophilic side chains, different configurations at their stereocenter, and various substitution patterns at the triazole ring were synthesized, tested for antibacterial and LpxC inhibitory activity, and structure-activity relationships were deduced based on docking and binding energy calculations. 相似文献
6.
Mochalkin I Knafels JD Lightle S 《Protein science : a publication of the Protein Society》2008,17(3):450-457
The cell wall in Gram-negative bacteria is surrounded by an outer membrane comprised of charged lipopolysaccharide (LPS) molecules that prevent entry of hydrophobic agents into the cell and protect the bacterium from many antibiotics. The hydrophobic anchor of LPS is lipid A, the biosynthesis of which is essential for bacterial growth and viability. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is an essential zinc-dependant enzyme that catalyzes the conversion of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine to UDP-3-O-(R-3-hydroxymyristoyl)glucosamine and acetate in the biosynthesis of lipid A, and for this reason, LpxC is an attractive target for antibacterial drug discovery. Here we disclose a 1.9 A resolution crystal structure of LpxC from Pseudomonas aeruginosa (paLpxC) in a complex with the potent BB-78485 inhibitor. To our knowledge, this is the first crystal structure of LpxC with a small-molecule inhibitor that shows antibacterial activity against a wide range of Gram-negative pathogens. Accordingly, this structure can provide important information for lead optimization and rational design of the effective small-molecule LpxC inhibitors for successful treatment of Gram-negative infections. 相似文献
7.
Laura A. McAllister Justin I. Montgomery Joseph A. Abramite Usa Reilly Matthew F. Brown Jinshan M. Chen Rose A. Barham Ye Che Seung Won Chung Carol A. Menard Mark Mitton-Fry Lisa M. Mullins Mark C. Noe John P. O’Donnell Robert M. Oliver Joseph B. Penzien Mark Plummer Loren M. Price Veerabahu Shanmugasundaram Andrew P. Tomaras Daniel P. Uccello 《Bioorganic & medicinal chemistry letters》2012,22(22):6832-6838
The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae. 相似文献
8.
《Bioorganic & medicinal chemistry》2016,24(5):1032-1044
Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol (S,S)-4 on the inhibitory activity against LpxC, glyceric acid ethers (R)-7a, (S)-7a, (R)-7b, and (S)-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids (R)-7b (Ki = 230 nM) and (S)-7b (Ki = 390 nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives 7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes 6. 相似文献
9.
Rama Jain Michelle Mathur Jiong Lan Abran Costales Gordana Atallah Savithri Ramurthy Sharadha Subramanian Lina Setti Paul Feucht Bob Warne Laura Doyle Stephen Basham Anne B. Jefferson Brent A. Appleton Mika Lindvall Cynthia M. Shafer 《Bioorganic & medicinal chemistry letters》2018,28(19):3197-3201
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation. 相似文献
10.
Sund C Belda O Wiktelius D Sahlberg C Vrang L Sedig S Hamelink E Henderson I Agback T Jansson K Borkakoti N Derbyshire D Eneroth A Samuelsson B 《Bioorganic & medicinal chemistry letters》2011,21(1):358-362
Two types of P1-P3-linked macrocyclic renin inhibitors containing the hydroxyethylene isostere (HE) scaffold just outside the macrocyclic ring have been synthesized. An aromatic or aliphatic substituent (P3sp) was introduced in the macrocyclic ring aiming at the S3 subpocket (S3sp) in order to optimize the potency. A 5-6-fold improvement in both the Ki and the human plasma renin activity (HPRA)IC50 was observed when moving from the starting linear peptidomimetic compound 1 to the most potent macrocycle 42 (Ki = 3.3 nM and HPRA IC50 = 7 nM). Truncation of the prime side of 42 led to 8-10-fold loss of inhibitory activity in macrocycle 43 (Ki = 34 nM and HPRA IC50 = 56 nM). All macrocycles were epimeric mixtures in regard to the P3sp substituent and X-ray crystallographic data of the representative renin macrocycle 43 complex showed that only the S-isomer buried the substituent into the S3sp. Inhibitory selectivity over cathepsin D (Cat-D) and BACE-1 was also investigated for all the macrocycles and showed that truncation of the prime side increased selectivity of inhibition in favor of renin. 相似文献
11.
Fournier PA Arbour M Cauchon E Chen A Chefson A Ducharme Y Falgueyret JP Gagné S Grimm E Han Y Houle R Lacombe P Lévesque JF MacDonald D Mackay B McKay D Percival MD Ramtohul Y St-Jacques R Toulmond S 《Bioorganic & medicinal chemistry letters》2012,22(8):2670-2674
The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential. 相似文献
12.
Nantermet PG Barrow JC Newton CL Pellicore JM Young M Lewis SD Lucas BJ Krueger JA McMasters DR Yan Y Kuo LC Vacca JP Selnick HG 《Bioorganic & medicinal chemistry letters》2003,13(16):2781-2784
A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity. 相似文献
13.
Amarasinghe KK Evdokimov AG Evidokimov AG Xu K Clark CM Maier MB Srivastava A Colson AO Gerwe GS Stake GE Howard BW Pokross ME Gray JL Peters KG 《Bioorganic & medicinal chemistry letters》2006,16(16):4252-4256
The sulfamic acid phosphotyrosine mimetic was coupled with a previously known malonate template to obtain highly selective and potent inhibitors of HPTPbeta. Potentially hydrolyzable malonate ester functionalities were replaced with 1,2,4-oxadiazoles without a significant effect on HPTPbeta potency. 相似文献
14.
The combination in one molecule of functional groups that can interact specifically with different substrate binding areas at the active site of carboxypeptidases A and B has led to the development of potent and specific inhibitors of these enzymes. 2-Benzyl-3-mercaptopropanoic acid (SQ 14,603) has a Ki of 1.1 x 10(-8) M vs. carboxypeptidase A and a Ki of 1.6 x 10(-4) M vs. the B enzyme. 2-Mercaptomethyl-5-guanidinopentanoic acid (SQ 24,798) has a Ki of 4 x 10(-10) M vs. carboxypeptidase B and a Ki of 1.2 x 10(-5) M vs. carboxypeptidase A. It is proposed that the sulfhydryl groups of these inhibitors bind to the catalytically important zinc ions of these enzymes, and that, in conjunction with the benzyl and guanidinopropyl side chains, they are responsible for their specificity. 相似文献
15.
Esra Onen F Boum Y Jacquement C Spanedda MV Jaber N Scherman D Myllykallio H Herscovici J 《Bioorganic & medicinal chemistry letters》2008,18(12):3628-3631
Three synthesized series of compounds based on a thiazolidine core allowed identification of potent inhibitors of thymidylate synthase X. The evaluation of the catalytic activity of the enzyme in the presence of these molecules revealed two distinct classes of compounds that inhibit ThyX with submicromolar concentrations, which could lead, after optimization, to effective inhibitors with potential biomedical interest. 相似文献
16.
Hing L. Sham Herman Stein Cheryl A. Rempel Jerome Cohen Jacob J. Plattner 《FEBS letters》1987,220(2):299-301
We have designed and synthesized a series of small peptides containing a perfluoroalkyl ketone group at the C-terminal position of the angiotensin I sequence as inhibitors of human renin. From this series of compounds, 8 and 10 showed strong inhibition of human renin (IC50 = 3 × 10−9, 7 × 10−9 M, respectively). Compound 10 did not inhibit pepsin and cathepsin D at 10−4 M. Comparison of the IC50 of compound 8 and compound 11 (8.7 × 10−7 M) demonstrated the marked effect of the perfluoropropyl group on the potency of inhibition on renin, presumably due to the strong electron-withdrawing effect causing the ketone in 8 to exist predominantly as the hydrate — thus mimicking the tetrahedral transition state during hydrolysis of the scissile Leu10—Val11 amide bond. 相似文献
17.
Dominguez C Duffy DE Han Q Alexander RS Galemmo RA Park JM Wong PC Amparo EC Knabb RM Luettgen J Wexler RR 《Bioorganic & medicinal chemistry letters》1999,9(7):925-930
Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity. 相似文献
18.
T Kokubu K Hiwada Y Sato T Iwata Y Imamura R Matsueda Y Yabe H Kogen M Yamazaki Y Iijima 《Biochemical and biophysical research communications》1984,118(3):929-933
We designed aldehyde derivatives of small peptides representing the C-terminal portion of angiotensin I sequence as an inhibitor of human renin. Among compounds that we synthesized, benzyloxycarbonyl (Z)-Phe-His-Leucinal (compound V), Z-Pro-Phe-His-Leucinal (Compound IV) and Z-[3-(1'-naphthyl)Ala]-His-Leucinal (compound VII) markedly inhibited human renin (IC50, 7.5 X 10(-7), 3.2 X 10(-7) and 8.0 X 10(-8) mol/l, respectively). Compound VII was shown to be noncompetitive (Ki = 2.4 X 10(-7) mol/l). It did not inhibit either cathepsin D or pepsin. Compound V had slight or no inhibitory effect at the concentration of 10(-5) mol/l on six animal renins except for monkey and rabbit renins. Results obtained show that these aldehyde compounds are highly selective and species specific inhibitors for human and monkey renins. 相似文献
19.
Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1 总被引:2,自引:0,他引:2
Fink CA Moskal M Firooznia F Hoyer D Symonsbergen D Wei D Qiao Y Savage P Beil ME Trapani AJ Jeng AY 《Bioorganic & medicinal chemistry letters》2000,10(17):2037-2039
Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50 = 77 nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration. 相似文献
20.
Tamayo N Liao L Goldberg M Powers D Tudor YY Yu V Wong LM Henkle B Middleton S Syed R Harvey T Jang G Hungate R Dominguez C 《Bioorganic & medicinal chemistry letters》2005,15(9):2409-2413
Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-alpha production in mice and exhibited good efficacy in the rat collagen induced arthritis model. 相似文献