共查询到20条相似文献,搜索用时 24 毫秒
1.
Zhang Q Chen Y Xia P Xia Y Yang ZY Yu D Morris-Natschke SL Lee KH 《Bioorganic & medicinal chemistry letters》2004,14(23):5855-5857
Four 4-methyl-3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (4-methyl DCK) analogs (7a-d) with different alkyl substituents at the 2'-position were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 2'-Methyl-2'-ethyl-4-methyl DCK (7b) was more potent (EC(50)=0.22 microM, TI>175) than the other three compounds (7a, 7c, and 7d), but significantly less potent than 4-methyl DCK (2, EC(50)=0.0059 microM, TI>6600). The bioassay results indicated that the 2'-substituents had a strong effect on the anti-HIV activity, and gem-dimethyl substitution at the 2'-position was greatly preferable to larger alkyl substituents or hydrogen atoms. 相似文献
2.
Hu B Ellingboe J Han S Largis E Lim K Malamas M Mulvey R Niu C Oliphant A Pelletier J Singanallore T Sum FW Tillett J Wong V 《Bioorganic & medicinal chemistry》2001,9(8):2045-2059
A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the beta(3) receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human beta(3) agonists with low affinities for beta(1)- and beta(2)-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the beta(3) potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full beta(3) agonist (EC(50)=0.004 microM, IA=1.0) with > 500-fold selectivity over beta(1)- and beta(2)-ARs. 相似文献
3.
Fifteen novel (E)-alpha-(methoxyimino)-benzeneacetate derivatives, the analogues of strobilurins, which contain two pharmacophoric substructures of (E)-methyl methoxyiminoacetate moiety and 1,3,4-oxadiazole ring were stereoselectively synthesized. It was first found that the coupling reaction could give stereoselectively the key intermediate (E) and (Z)-methyl 2-(hydroxyimino)-2-o-tolylacetate 2 with a ratio of 14:1. The preliminary bioassays indicated that all the compounds 1 showed potent fungicidal activity against Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Physalospora piricola and Bipolaris mayclis, and all of the tested compounds 1a-1o had more potent fungicidal activities against R. solani than Kresoxim-methyl. 相似文献
4.
《Bioorganic & medicinal chemistry letters》2014,24(4):1214-1217
Treatment of 4-hydroxyquinolines with (2-methyl)allyl bromide in the presence of K2CO3 resulted in the formation of novel N-[(2-methyl)allyl]-4-quinolones through selective N-alkylation. Further reaction of N-(2-methylallyl)-4-quinolones with bromine or N-bromosuccinimide yielded the corresponding 3-bromo-1-(2,3-dibromo-2-methylpropyl)-4-quinolones and 3-bromo-1-(2-methylallyl)-4-quinolones, respectively. Furthermore, a copper-catalyzed C–N coupling of the latter 3-bromo-4-quinolones with (5-chloro)indole afforded novel 3-[(5-chloro)indol-1-yl]-4-quinolone hybrids. Antifungal and antiplasmodial assays of all new 4-quinolones were performed and revealed no antifungal properties but moderate antiplasmodial activities. All 15 compounds displayed micromolar activities against a chloroquine-sensitive strain of Plasmodium falciparum, and the five most potent compounds also showed micromolar activities against a chloroquine-resistant strain of P. falciparum with IC50-values ranging between 4 and 70 μM. 相似文献
5.
Das U Molnár J Baráth Z Bata Z Dimmock JR 《Bioorganic & medicinal chemistry letters》2008,18(12):3484-3487
The 1-[4-(2-aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-oxopiperidines 5-8 are a novel cluster of highly potent P-glycoprotein dependent multidrug resistance (MDR) revertants. Using a concentration of 4mug/mL, these compounds possess 11-43 times the potency of verapamil in reversing MDR in murine L-5178 lymphoma cells transfected with the human MDR1 gene. Structure-activity relationships reveal that the attachment of the N-aroyl group to various 3,5-bis(benzylidene)-4-piperidones is essential for MDR reversal to occur. In terms of potencies, the 1-piperidinyl group is the preferred terminal amine while the 4-methyl and 4-chloro substituents are the optimal groups for placement in the benzylidene aryl rings. 相似文献
6.
Compound trans-4-(p-bromophenyl)-4-(dimethylamino)-1-(2-thiophen-2-yl-ethyl)-cyclohexanol (C8813), structurally unrelated to morphine, is a novel analgesic. The present study examined the antinociception, opioid receptor selectivity and in vitro activity of C8813. The antinociceptive activity was evaluated using mouse hot plate and acetic acid writhing tests. In mouse hot plate test, the antinociceptive ED(50) of C8813 was 11.5 microg/kg, being 591 times and 3.4 times more potent than morphine and fentanyl respectively. In mouse writhing test, the antinociceptive ED(50) of C8813 was 16.9 microg/kg, being 55 times and 2.3 times more active than morphine and fentanyl respectively. In the opioid receptor binding assay, C8813 showed high affinity for mu-opioid receptor (K(i) = 1.37 nM) and delta-opioid receptor (K(i) = 3.24 nM) but almost no affinity for kappa-opioid receptor (at 1 microM). In the bioassay, the inhibitory effect of C8813 in the guinea-pig ileum (GPI) was 16.5 times more potent than in the mouse vas deferens (MVD). The inhibitory effects of C8813 in the GPI and MVD could be antagonized by mu-opioid receptor antagonist naloxone and delta-opioid receptor antagonist ICI174,864 respectively. However, the inhibitory effect of C8813 in the rabbit vas deferens was very weak. These results indicated that C8813 was a potent analgesic and a high affinity agonist for the mu- and delta-opioid receptors. 相似文献
7.
Y Murakami S Hagishita T Okada M Kii H Hashizume T Yagami M Fujimoto 《Bioorganic & medicinal chemistry》1999,7(8):1703-1714
A novel class of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Through a blind screening we found the compound 1-N-(3-(N'-(tert-butoxycarbonyl)amino)benzyl)-7-methoxy-(3-(3)-methyl ureido)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (9: IC50 = 1.6 microM). Chemical modifications of 9 gave a potent NPY Y1 antagonist 3-(N-(4-hydroxyphenyl)-N'-methylguanidino)-1-N-(3-(N'-(tert-butoxy carbonyl)amino)benzyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (14c: IC5(0=43 nM), which had no affinity for NPY Y2 and Y5 receptors. 相似文献
8.
Shi-Qing Xu Xin Yan Ying Chen Peng Xia Keduo Qian Donglei Yu Yi Xia Zheng-Yu Yang Susan L. Morris-Natschke Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry》2010,18(20):7203-7211
In a continuing investigation into the pharmacophores and structure–activity relationship (SAR) of (3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) as a potent anti-HIV agent, 2′-monomethyl substituted 1′-oxa, 1′-thia, 1′-sulfoxide, and 1′-sulfone analogs were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Among them, 2′S-monomethyl-4-methyl DCK (5a)3 and 2′S-monomethyl-1′-thia-4-methyl DCK (7a) exhibited potent anti-HIV activity with EC50 values of 40.2 and 39.1 nM and remarkable therapeutic indexes of 705 and 1000, respectively, which were better than those of the lead compound DCK in the same assay. In contrast, the corresponding isomeric 2′R-monomethyl-4-methyl DCK (6) and 2′R-monomethyl-1′-thia-4-methyl DCK (8) showed much weaker inhibitory activity against HIV-1 replication. Therefore, the bioassay results suggest that the spatial orientation of the 2′-methyl group in DCK analogs can have important effects on anti-HIV activity of this compound class. 相似文献
9.
Girón R Abalo R Goicoechea C Martín MI Callado LF Cano C Goya P Jagerovic N 《Life sciences》2002,71(9):1023-1034
Three new fentanyl analogs (compounds 3-4-5) have been synthesized and evaluated for antinociceptive properties using the writhing test. The analgesic property of the active compound, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (compound 4), was tested using the hot plate test in mice. Its opioid agonistic activity was characterized using three isolated tissues: guinea pig ileum, mouse vas deferens, and rabbit vas deferens. Compound 4 was as effective as fentanyl or morphine and it showed less antinociceptive potency than fentanyl but it was more potent than morphine. The duration of the antinociception was similar to that of fentanyl. This compound inhibited the electrically evoked contractions of myenteric plexus-longitudinal muscle strips of guinea pig ileum and of mouse vas deferens but not those of rabbit vas deferens. These effects could be reversed by micro selective antagonists (naloxone and/or CTOP) but not by the delta selective antagonist naltrindole, thus indicating that the compound acted as a micro opioid agonist. Finally, the binding data confirmed that compound 4 had high affinity and selectivity for the micro-receptor. 相似文献
10.
Robert A. Matthiesen Michelle L. Varney Pauline C. Xu Alex S. Rier David F. Wiemer Sarah A. Holstein 《Bioorganic & medicinal chemistry》2018,26(2):376-385
Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates. 相似文献
11.
Narendra Sharath Chandra JN Sadashiva CT Kavitha CV Rangappa KS 《Bioorganic & medicinal chemistry》2006,14(19):6621-6627
A series of novel substituted 1-[bis(4-fluorophenyl)-methyl]piperazine derivatives (4a-g) and (5h-m) have been synthesized. The synthesized compounds were characterized by IR and 1H NMR. All the synthesized compounds were evaluated in vitro for their efficacy as antimicrobial agents against representative strains of Gram-positive (Staphylococcus aureus ATCC 25953, Streptococcus pneumoniae ATCC 49619, Bacillus cereus 11778, and Bacillus subtilis 6051) and Gram-negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 2853, Proteus vulgaris ATCC 2853, and Salmonella typhi ATCC 9484) by paper disc diffusion and microdilution methods. Among the newly synthesized compounds 4e, 5l, and 5m showed potent antimicrobial activities, when compared to the standard drug. 相似文献
12.
Tuba Z Bardin CW Dancsi A Francsics-Czinege E Molnár C Csörgei J Falkay G Koide SS Kumar N Sundaram K Dukát-Abrók V Balogh G 《Steroids》2000,65(5):266-274
The progestational activity of second- and third-generation progestins in oral contraceptives were markedly increased by addition of an 18-methyl group. A new progestin, the 18-methyl analog of Nestorone, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3,2 0-dione acetate (10), was synthesized. The relative binding affinity and biologic activity of 10 was compared with Nestorone, levonorgestrel, and progesterone using a binding assay for rat progesterone receptors, the Clauberg assay in the rabbit, and by assessing pregnancy maintenance in the rat. These studies, as summarized in Table 4, show that 10 is three to ten times more potent than Nestorone. The addition of the 18-methyl group to Nestorone markedly increased its potency as noted above, but is unlikely to change its rate of delivery from sustained release systems. 10 should be ideally suited for administration by implants or small skin patches. 相似文献
13.
Micheli F Cavanni P Di Fabio R Donati D Hamdan M Provera S Tranquillini ME Vitulli G 《Bioorganic & medicinal chemistry letters》2007,17(4):969-973
Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester as a potent and selective mGluR1 non-competitive antagonist, the use of a doubly (13)C-labeled analogue to identify, and consequently prevent, metabolically labile positions is reported. 相似文献
14.
Hauck SI Cederberg C Doucette A Grosser L Hales NJ Poon G Gravestock MB 《Bioorganic & medicinal chemistry letters》2007,17(2):337-340
Substitution of phenyl oxazolidinones with carbon-linked azoles resulted in the discovery of a new class of potent oxazolidinones that have excellent Gram-positive activity. In addition, replacement of the C-5 acetamide side chains with a 4-methyl triazole diminished monoamine oxidase activity. The synthesis and biological evaluation of these compounds are reported. 相似文献
15.
Xu YJ Miao HQ Pan W Navarro EC Tonra JR Mitelman S Camara MM Deevi DS Kiselyov AS Kussie P Wong WC Liu H 《Bioorganic & medicinal chemistry letters》2006,16(2):404-408
A novel class of N-(4-{[4-(1H-benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamides are described as inhibitors of the endo-beta-glucuronidase heparanase. Among them are N-(4-{[4-(1H-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4-methoxy-benzamide (15h), and N-(4-{[5-(1H-benzoimidazol-2-yl)-pyridin-2-ylamino]-methyl}- phenyl)-3-bromo-4-methoxy-benzamide (23) which displayed good heparanase inhibitory activity (IC(50) 0.23-0.29 microM), with the latter showing oral exposure in mice. 相似文献
16.
X Wang Y Ling H Wang J Yu J Tang H Zheng X Zhao D Wang G Chen W Qiu J Tao 《Bioorganic & medicinal chemistry letters》2012,22(19):6166-6172
Owing to the increasingly serious problems caused by multidrug resistance in community-acquired infection pathogens, it has become an urgent need to develop new classes of antibiotics for overcoming the resistance. In this paper, we describe the design and synthesis of novel pleuromutilin derivatives containing the (2-aminothiazol-4-yl)-4-methyl group, as well as their in vitro antibacterial activities against Gram-positive clinical bacteria. Most of the tested compounds displayed strong antibacterial activities against these methicillin-susceptible and methicillin-resistant bacteria. Particularly noteworthy compound 15 and its derivative 16e, both showed potent antibacterial properties (0.0625-0.5μg/mL) that are superior to amoxicillin and tiamulin. Molecular docking studies suggested that the amino thiazole ring on the side chains of the pleuromutilin derivatives can in general be accommodated near the mutilin core in the binding pocket, and thus play an important role in the activity of the whole molecule. The findings reported herein may provide a new insight into the design of novel pleuromutilin derivatives for human clinical use. 相似文献
17.
Hui-jiao Sun Yu-hua Wang Cong-min Yuan Ling-hui Kong Xue-jun Xu Yu-jun Wang Hai-hao Wu Cheng Lin Yuan-yuan Qian Huo-ming Huang Li Xiao Xiao Liu Qian He Sheng-yang Fang Deng-qi Xue Xi-cheng Yang Hao Chen Yi-lin Zheng Li-ming Shao 《Bioorganic & medicinal chemistry》2018,26(14):4254-4263
With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues. Surprisingly, SLL-603, a 7β-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7β-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations. 相似文献
18.
Srgio M.F. Vilela Dario J.S.L. Santos Luis Flix Jos M. Almeida Luis Antunes Francisco Peixoto 《Mitochondrion》2009,9(4):247-253
Fentanyl and remifentanil are potent opioid widely used in routine anesthesia procedures. This study evaluates and compares the effects of fentanyl/remifentanil in isolated brain mitochondria bioenergetic status. Fentanyl and remifentanil in clinical concentrations does not interfere with rat brain isolated mitochondria. Do not withstand, fentanyl concentrations >4 μg/mL, induces an impairment of the respiratory chain characterized by a decrease in respiratory control ratio, state 3 and uncoupled respiration. Additionally, membrane potential collapses and ADP/O were reduced. Remifentanil follows the same profile but with effects at higher concentrations (>10 μg/mL). High concentrations of fentanyl and remifentanil interfere with mitochondrial electron chain (complexes III, IV) and on mitochondrial phosphorylation unit (complex V). Mitochondrial permeability transition pore was not induced by both fentanyl and remifentanil in tested concentrations. These data provide the first indication that fentanyl and remifentanil (μg/mL range) alters mitochondrial metabolism. Fentanyl showed a stronger inhibitory effect on mitochondrial bioenergetics. 相似文献
19.
《Bioorganic & medicinal chemistry》2014,22(1):178-185
(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR. 相似文献
20.
Ravil R. Petrov Yeon Sun Lee Ruben S. Vardanyan Lu Liu Shou-wu Ma Peg Davis Josephine Lai Frank Porreca Todd W. Vanderah Victor J. Hruby 《Bioorganic & medicinal chemistry letters》2013,23(11):3434-3437
We report here the design, synthesis, and in vitro characterization of new opioid peptides featuring a 4-anilidopiperidine moiety. Despite the fact that the chemical structures of fentanyl surrogates have been found suboptimal per se for the opioid activity, the corresponding conjugates with opioid peptides displayed potent opioid activity. These studies shed an instructive light on the strategies and potential therapeutic values of anchoring the 4-anilidopiperidine scaffold to different classes of opioid peptides. 相似文献