共查询到20条相似文献,搜索用时 15 毫秒
1.
Chao Gao Ting-Hong Ye Ning-Yu Wang Xiu-Xiu Zeng Li-Dan Zhang Ying Xiong Xin-Yu You Yong Xia Ying Xu Cui-Ting Peng Wei-Qiong Zuo Yuquan Wei Luo-Ting Yu 《Bioorganic & medicinal chemistry letters》2013,23(17):4919-4922
N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study. 相似文献
2.
Hiroshi Morita Yuichiro Tomizawa Jun Deguchi Tokio Ishikawa Hiroko Arai Kazumasa Zaima Takahiro Hosoya Yusuke Hirasawa Takayuki Matsumoto Katsuo Kamata Wiwied Ekasari Aty Widyawaruyanti Tutik Sri Wahyuni Noor Cholies Zaini Toshio Honda 《Bioorganic & medicinal chemistry》2009,17(24):8234-8240
Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria. Nitric oxide (NO) reduces endothelial expression of receptors/adhesion molecules used by pRBC to adhere to vascular endothelium, and reduces cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 showed vasorelaxation activity against rat aortic ring, which may be related with NO production. A series of a hydroxyl and a nitrogen-substituted derivatives and a dehydroxy derivative of 1 have been synthesized as having potent antimalarials against P. falciparum with vasodilator activity, which may reduce cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 exhibited a potent antimalarial activity and a high selectivity index in vitro, suggesting that the presence of a hydroxyl and a nitrogen atom without any substituents may be important to show antimalarial activity. Relative to cassiarin A, a methoxy derivative showed more potent vasorelaxant activity, although it did not show improvement for inhibition of P. falciparum in vitro. These cassiarin derivatives may be promising candidates as antimalarials with different mode of actions. 相似文献
3.
Kohsuke Asoh Masami Kohchi Ikumi Hyoudoh Tatsuo Ohtsuka Miyako Masubuchi Kenichi Kawasaki Hirosato Ebiike Yasuhiko Shiratori Takaaki A. Fukami Osamu Kondoh Toshiyuki Tsukaguchi Nobuya Ishii Yuko Aoki Nobuo Shimma Masahiro Sakaitani 《Bioorganic & medicinal chemistry letters》2009,19(6):1753-1757
A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC50 = 1.1 nM) and antitumor activity in human cancer xenografts in mice. 相似文献
4.
Seung Kyu Lee Kwang Hyun Choi Sang Jae Lee Se Won Suh B. Moon Kim Bong Jin Lee 《Bioorganic & medicinal chemistry letters》2010,20(15):4317-4319
Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins. Thus inhibition of PDF activity is considered to be one of the most effective antibiotic strategies. Reported herein are the synthesis and structure–activity relationship studies of retro-amide inhibitors based on actinonin, a naturally occurring PDF inhibitor. Analysis of the structure–activity relationships led to the discovery of 7a, which exhibits potent enzyme inhibition and antibacterial activity against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. 相似文献
5.
Saliha Alyar 《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):986-992
A series of aromatic disulfonamide (1-8) derivatives and 4-methylbenzenesulfonyl hydrazide (9) were synthesized and characterized. All compounds were evaluated in vitro for their antimicrobial activity against Staphylococcus aureus ATCC 25953, Bacillus cereus ATCC 6633, Bacillus magaterium RSKK 5117, Escherichia coli ATCC 11230, Salmonella enterititis ATCC 13076 by microdilution and disc diffusion methods. Antimicrobial activity of the aromatic disulfonamides decreased as the length of the carbon chain increased. An analysis of the structure- activity relationship (SAR) along with computational studies showed that the most active compound (9) possessed low lipophilicity (AlogP=0.59) and high solubility (logS = -1.33). 相似文献
6.
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
7.
John L. Gilmore James E. Sheppeck Jim Wang T.G. Murali Dhar Cullen Cavallaro Arthur M. Doweyko Lorraine Mckay Mark D. Cunningham Sium F. Habte Steven G. Nadler John H. Dodd John E. Somerville Joel C. Barrish 《Bioorganic & medicinal chemistry letters》2013,23(19):5448-5451
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. 相似文献
8.
Claudio Luis Donnici Maria Helena Araújo Henrique S. Oliveira Diogo Rodrigo Magalhães Moreira Valéria R. Alves Pereira Marina de Assis Souza Maria Carolina Accioly Brelaz de Castro Ana Cristina Lima Leite 《Bioorganic & medicinal chemistry》2009,17(14):5038-5043
Although effective against epimastigotes (proliferative form) and of low cytotoxicity in mammals, the aryl-4-oxothiazolylhydrazones (ATZ) display only limited activity against trypomastigotes (bloodstream form) of Trypanosoma cruzi. Considering the metal complexation approach with bioactive ligands as one possible strategy for improving the biological efficacy of ATZ, a set of eight new ruthenium–ATZ complexes (RuCl2ATZCOD, COD is 1,5-cyclooctadiene) were prepared, chemically and biologically characterized, including in vitro assays against epimastigotes and trypomastigote forms of the parasite and also assessment of cytotoxicity in mammals. Two of these complexes presented antitrypanosomal activity at non-cytotoxic concentrations on mammalian cells and of higher potency than its metal–free ligands, while the metallic precursor [RuCl2COD(MeCN)2] showed only moderate antitrypanosomal activity. Comparative analysis between the ruthenium complexes and metal–free ligands demonstrated the usefulness of this approach, with the establishment of new SAR data. Additional pharmacological tests, including a DNA bond assay, gave rise to the proposal of a single preliminary explanation for the molecular origin of the bioactivity. 相似文献
9.
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
10.
Fluorotelomer alcohols (FTOHs) have been shown to degrade via abiotic and biotic mechanisms to perfluorocarboxylates (PFCAs)
which are environmentally persistent and bioaccumulate in humans and wildlife depending on their chain length. Fluorotelomer
unsaturated aldehydes (FTUALs) and acids (FTUCAs) are intermediate metabolites that form from the degradation of FTOHs. Their
potential for toxicity is not yet defined and may be more significant compared to PFCAs. Past studies have shown that these
intermediates form adducts with glutathione (GSH). The purpose of this study was to further assess the reactivity of these
intermediate compounds. In vitro experiments were carried out in an aqueous buffer system (pH 7.4) where FTUCAs and FTUALs
of varying chain lengths were reacted with GSH. To quantify the reactivity of FTUCAs and FTUALs, unreacted free GSH was derivatized
with 5,5′-dithiobis(2-nitrobenzoic acid), its absorbance measured at 412 nm, and the percentage of unconjugated free GSH evaluated
over time. EC50 values were obtained for the reactions of GSH with acrolein and methyl methacrylate to assess the accuracy of the method,
as well as for acrylic acid, FTUCAs, and FTUALs. The results of this study indicated that α,β-unsaturated aldehydes are comparatively
the most reactive and reaction with GSH may be influenced by the length of the fluorinated tail. This is the first study to
examine the relationship of FTUCAs and FTUALs with biological nucleophiles by quantifying their intrinsic reactivity. 相似文献
11.
Meng Huang Xin Zhao Meng Zhang Jun Gu Xiaoguang Chen Dali Yin 《Bioorganic & medicinal chemistry letters》2010,20(18):5418-5421
Two types of sinenxan A derivatives with different side chains at C-5 were synthesized and evaluated for their in vitro multidrug resistant reversal activities. Several derivatives exhibited better activities than the positive control verapamil. The structure–activity relationships of these derivatives suggested that a carbonyl group at C-13 and the length of side chain at C-5 are important for the activity. 相似文献
12.
Josep Bonjoch Faïza Diaba Lluís Pagès Daniel Pérez Lidia Soca Montserrat Miralpeix Dolors Vilella Paquita Anton Carles Puig 《Bioorganic & medicinal chemistry letters》2009,19(15):4299-4302
A γ-carboline series of cysLT1 receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2014,24(14):3158-3163
A series of barbigerone analogues (7a–7w, 13a–13x) were designed, synthesized and biologically evaluated for their anti-proliferative and anti-angiogenic activities. Among these compounds, compound 13a exhibited the most potent inhibitory effect on the proliferation of HUVECs, HepG2, A375, U251, B16, and HCT116 cells (IC50 = 3.80, 0.28, 1.58, 3.50, 1.09 and 0.68 μM, respectively). Compound 13a inhibited the angiogenesis in zebrafish embryo assay in a concentration-dependent manner. Furthermore, 13a also effectively inhibited the migration and capillary like tube formation of human umbilical vein endothelial cell in vitro. These results support the further investigation of this class of compounds as potential anti-proliferative and anti-angiogenesis agents. 相似文献
14.
Wen-Shan Li Shivaji V. More Chie-Hong Wang Ya Ching Jen Ching-Fa Yao Tein-Fu Wang Chin-Chun Hung Shu-Chuan Jao 《Bioorganic & medicinal chemistry letters》2010,20(3):1148-1152
This study describes the synthesis and structure–activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect. 相似文献
15.
Dawn A. Delfín Rachel E. Morgan Xiaohua Zhu Karl A. Werbovetz 《Bioorganic & medicinal chemistry》2009,17(2):820-829
BTB 06237 (2-[(2,4-dichloro-5-methylphenyl)sulfanyl]-1,3-dinitro-5-(trifluoromethyl) benzene), a compound previously identified through QSAR pharmacophore development and a virtual screen of the Maybridge database, possesses potent and selective activity against Leishmania parasites. In the present study, several analogs of BTB 06237 were synthesized and analyzed for activity against Leishmania axenic amastigotes, their ability to reduce the level of parasitemia in peritoneal macrophages, and their ability to generate reactive oxygen species (ROS) in L. donovani promastigotes. It was found that an aromatic ring must be present in the position occupied by the 2,4-dichloro-5-methylphenyl group in the lead compound, but changing the functional groups generally has little effect on the antileishmanial potency. Alterations to the 1,3-dinitro-5-(trifluoromethyl)benzene ring have more influence on antiparasitic activity with two aromatic nitro groups and a third electron-withdrawing group being required. This structural requirement corresponds with redox potential, the ability to generate ROS in the parasites, and dissipation of the mitochondrial membrane potential. Finally, we used this collection of data to design a new antileishmanial compound with strong activity in vitro and improved properties as an antileishmanial candidate. 相似文献
16.
John P. Caldwell Julius J. Matasi Xiomara Fernandez Robbie L. McLeod Hongtao Zhang Ahmad Fawzi Deen B. Tulshian 《Bioorganic & medicinal chemistry letters》2009,19(4):1164-1167
A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R = H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure–activity relationship (SAR) of these and related compounds are discussed. 相似文献
17.
Kwan-Young Jung Joong-Heui Cho Jung Sun Lee Hyo Jun Kim Yong-Chul Kim 《Bioorganic & medicinal chemistry》2013,21(9):2643-2650
Carboxylic acid derivatives of pyridoxal were developed as potent P2X1 and P2X3 receptor antagonists with modifications of a lead compound, pyridoxal-5′-phosphate-6-azophenyl-2′,5′-disulfonate (5b, iso-PPADS). The designing strategies included the modifications of aldehyde, phosphate or sulfonate groups of 5b, which may be interacted with lysine residues of the receptor binding pocket, to weak anionic carboxylic acid groups. The corresponding carboxylic acid analogs of pyridoxal-5′-phosphate (1), 13 and 14, showed parallel antagonistic potencies. Also, most of 6-azophenyl derivatives (24–28) of compound 13 or 14 showed potent antagonistic activities similar to that of 5b at human P2X3 receptors with 100 nM range of IC50 values in two-electrode voltage clamp (TEVC) assay system on the Xenopus oocyte. The results indicated that aldehyde and phosphoric or sulfonic acids in 5b could be changed to a carboxylic acid without affecting antagonistic potency at mouse P2X1 and human P2X3 receptors. 相似文献
18.
Toshitake Kobayashi Satoshi Sasaki Naoki Tomita Seiji Fukui Noritaka Kuroda Masaharu Nakayama Atsushi Kiba Yoshihiro Takatsu Tetsuya Ohtaki Fumio Itoh Atsuo Baba 《Bioorganic & medicinal chemistry》2010,18(11):3841-3859
GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor has an essential role to modulate sex-hormones including GnRH. Though antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis, small molecule GPR54 antagonists have not been reported. We have synthesized a series of 2-acylamino-4,6-diphenylpyridines to identify potent GPR54 antagonists. Detailed structure–activity relationship studies led to compound 9l with an IC50 value of 3.7 nM in a GPR54 binding assay, and apparent antagonistic activity in a cellular functional assay. 相似文献
19.
Melatonin (MLT) is a hormone produced in the brain by the pineal gland, from the amino acid tryptophan. It is also an antioxidant hormone with a particular role in the protection of nuclear and mitochondrial DNA. In recent years, many physiological properties of MLT have been described resulting in much attention in the development of synthetic compounds possessing the indole ring. Sixteen MLT analogue indole hydrazide/hydrazone derivatives were synthesized and in vitro antioxidant activity was investigated. Most of the compounds showed significantly higher activity than MLT at 10? 3 M and 10? 4 M concentrations. 相似文献
20.
A series of 2-hydrazinyladenosine derivatives was synthesized and investigated in radioligand binding studies for their affinity at the adenosine receptor subtypes with the goal to obtain potent and A2AAR selective agonists and to explore the structure–activity relationships of this class of compounds at A2AAR. Modifications included introduction of a second sugar moiety at position 2 of adenosine to form new bis-sugar nucleosides and/or modifications of the 2-position linker in different ways. The performed modifications were found to produce compounds with relatively high A2AAR affinity and very high selectivity toward A2AAR. The most potent bis-sugar nucleoside was obtained with the d-galactose derivative 16 which exhibited a Ki value of 329 nM at A2AAR with marked selectivity against the other AR subtypes. In another set of compounds, compound 3 was modified via replacement of its cyclic structure with mono- and disubstituted phenyl moieties and the resulting hydrazones 10–14 were found to have low nanomolar affinity for A2AAR. In addition to 3, compounds 10, 11 and 13 have been identified as the most potent compounds in the present series with Ki values of 16.1, 24.4, and 12.0 nM, respectively, at rat A2AAR. Species differences were tested and found to exist in different rates. Functional properties of the most potent compounds 10, 11, 13 and 16 were assessed showing that the compounds acted as agonists at A2AAR. 相似文献