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1.
Potential inhibitors of Leptosphaeria maculans mediated detoxification of the phytoalexin brassilexin were designed and synthesized based on the planar heteroaromatic structure of isothiazolo[5,4-b]indole. Screening of these compounds for inhibition of brassilexin detoxification in cultures of L. maculans indicated that 4-(2-chlorophenyl)isothiazole had the largest effect on the rate of brassilexin detoxification. However, the most antifungal compound among the potential inhibitors, isothiazolo[5,4-b]quinoline, did not appear to affect the metabolism of brassilexin noticeably, suggesting that growth inhibition is not sufficient to slow down the rate of brassilexin detoxification. Furthermore, it was determined that 4-arylisothiazoles as well as isothiazolo[5,4-b]thianaphthene displayed antifungal activity against L. maculans. 相似文献
2.
Mathes BM Hudziak KJ Schaus JM Xu YC Nelson DL Wainscott DB Nutter SE Gough WH Branchek TA Zgombick JM Filla SA 《Bioorganic & medicinal chemistry letters》2004,14(1):167-170
Synthesis and evaluation of a series of 2,3,5- and 3,5-substituted furo[3,2-b]pyridines were undertaken in order to investigate their utility as bioisosteres of 5-HT(1F) receptor agonist indole analogues, 1-3. The replacement proved to be effective, providing compounds with similar 5-HT(1F) receptor affinity and improved selectivity when compared with the indole analogues. Through these studies we identified 4-fluoro-N-[3-(1-methyl-piperidin-4-yl)-furo[3,2-b]pyridin-5-yl]-benzamide (5), a potent and selective 5-HT(1F) receptor agonist with the potential to treat acute migraine. 相似文献
3.
6-(4H-Selenolo[3,2-b]pyrrolyl)-L-alanine 1, 4-(6H-selenolo[2,3-b]pyrrolyl)-L-alanine 2, and 6-(4H-furo[3,2-b]pyrrolyl)-L-alanine 3 have been synthesized via reactions of selenolo[3,2-b]pyrrole, selenolo[2,3-b]pyrrole, and furo[3,2-b]pyrrole, respectively, with L-serine. The reactions are catalyzed by Salmonella typhimurium tryptophan synthase. 相似文献
4.
Pan W Miao HQ Xu YJ Navarro EC Tonra JR Corcoran E Lahiji A Kussie P Kiselyov AS Wong WC Liu H 《Bioorganic & medicinal chemistry letters》2006,16(2):409-412
A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase inhibitory activity (IC(50) 0.075-0.27 microM). Compound 7a showed good efficacy in a B16 metastasis model. 相似文献
5.
Elokdah H Li D McFarlane G Bernotas RC Robichaud AJ Magolda RL Zhang GM Smith D Schechter LE 《Bioorganic & medicinal chemistry》2007,15(18):6208-6226
1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists. 相似文献
6.
Romeo G Materia L Marucci G Modica M Pittalà V Salerno L Siracusa MA Buccioni M Angeli P Minneman KP 《Bioorganic & medicinal chemistry letters》2006,16(24):6200-6203
A number of new pyrimido[5,4-b]indole and [1]benzothieno[3,2-d]pyrimidine derivatives were synthesized and evaluated for their binding and functional properties at alpha(1)-adrenergic receptor (alpha(1)-AR) subtypes. They behaved as potent alpha(1)-AR antagonists. In binding experiments, some of them (RC24 and RC23) showed very high affinity for the alpha(1D)-AR subtype. 相似文献
7.
N. V. Nagaraja S. K. Singh R. C. Gupta 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1995,664(2)
A sensitive high-performance liquid chromatographic assay has been developed and validated for the determination of methyl N-[5-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1H-benzimidazol-2-yl] carbamate (CDRI compound 81/470) in normal rat blood. The method described herein is simple, with improved selectivity and sensitivity over a previously reported HPLC method. The limit of quantitation is 10 ng/ml (method 1) and 2.5 ng/ml (method 2) in blood, as compared with 40 ng/ml for the previous method. The standard curve in blood is linear over the concentration range 10–1000 ng/ml in method 1 and 2.5–1000 ng/ml in method 2 and the extraction recovery is higher than 80% for both methods. 相似文献
8.
Trabanco AA Pullan S Alonso JM Alvarez RM Andrés JI Boeckx I Fernández J Gómez A Iturrino L Janssens FE Leenaerts JE De Lucas AI Matesanz E Meert T Steckler T 《Bioorganic & medicinal chemistry letters》2006,16(1):146-149
A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for delta-, mu-, and kappa-opioid receptors, as well as the functional activity in the [(35)S]GTPgammaS assay are reported. The most potent and selective delta-opioid agonist 18a exhibited a K(i) of 18 nM, and was >258-fold and 28-fold selective over mu- and kappa-receptors, respectively; the compound is a full agonist with an EC(50) value of 14 nM. 相似文献
9.
Ahsan MJ Samy JG Jain CB Dutt KR Khalilullah H Nomani MS 《Bioorganic & medicinal chemistry letters》2012,22(2):969-972
In search of potential therapeutics for tuberculosis, we describe herewith the synthesis, characterization and antimycobacterial activity of 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues. Among the synthesized compounds, 4-[(5-[(4-fluorophenylamino]-1,3,4-oxadiazol-2-yl)methylamino]-1,2-dihydro-1,5-dimethyl-2-phenylpyrazol-3-one (4a) was found to be the most promising compound active against Mycobacterium tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis with minimum inhibitory concentrations, 0.78 and 3.12μg/mL, respectively, free from any cytotoxicity (>62.5μg/mL). 相似文献
10.
Huang S Lin R Yu Y Lu Y Connolly PJ Chiu G Li S Emanuel SL Middleton SA 《Bioorganic & medicinal chemistry letters》2007,17(5):1243-1245
The novel compound 3-(1H-benzimidazol-2-yl)-5-isoquinolin-4-ylpyrazolo[1,2-b]pyridine was discovered to be a potent CDK1 inhibitor. Described here is the chemistry for its synthesis, including Pd(II) catalyzed Stille coupling reaction and sulfur(0) induced benzimidazole formation. Its effects on VEGFR-2 kinase activity and tumour cell proliferation are also described. 相似文献
11.
Reed AB Lanman BA Neira S Harrington PE Sham KK Frohn M Pickrell AJ Tasker AS Gore A Fiorino M Itano A McElvain M Middleton S Morrison H Xu H Xu Y Wong M Cee VJ 《Bioorganic & medicinal chemistry letters》2012,22(4):1779-1783
Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats. 相似文献
12.
Han SY Choi JW Yang J Chae CH Lee J Jung H Lee K Ha JD Kim HR Cho SY 《Bioorganic & medicinal chemistry letters》2012,22(8):2837-2842
A series of 3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-quinolin-2-ones have been identified as a new class of VEGFR-2 kinase inhibitors. A variety of (4,5,6,7-tetrahydro-imidazo[5,4-c]pyridin-2-yl)-acetic acid ethyl esters were synthesized, and their VEGFR-2 inhibitory activity was evaluated. Described herein are the preparation of the series and the effects of the compounds on VEGFR-2 kinase activity. 相似文献
13.
J K Srivastava S Gupta J C Katiyar V M Srivastava 《Indian journal of experimental biology》1989,27(8):735-738
Effects of methyl [5[[4-(2-pyridinyl)-1-piperazinyl] carbonyl] 1H-benzimidazol-2-yl] carbamate (CDRI Comp. 81-470) and mebendazole on the energy metabolism of A. ceylanicum and N. brasiliensis were compared. At 10 and 50 microM concentration both compounds inhibited glucose uptake and its conversion into metabolic endproducts. The shift towards the increased production of lactic acid appeared to be the result of inhibition of PEP carboxykinase and increase in LDH activity. The compounds also caused significant inhibition of ATP production in mitochondria. 相似文献
14.
Certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCIs 60 cancer cell lines. The preliminary results indicated these tricyclic 4-(phenylamino)furo[2,3-b]quinolines were more cytotoxic than their corresponding 2-(furan-2-yl)-4-(phenylamino)quinoline isomers. For the 4-(phenylamino)furo[2,3-b]quinolines, compounds 2a and 3d are two of the most potent with a mean GI50 value of 0.025 microM in each case. Inactivity of 2b and 2c (positional isomers of 2a) indicated that both electronic environment, and the distance between intercalating pharmacophore and H-bond-donating MeO group are important. For the 2-(furan-2-yl)-4-(phenylamino)quinoline isomers, compound 12 (a mean GI50 of 4.36 microM), which bears a para-COMe substituent, is more active than its meta-substituted counterpart 13 (10.5 microM). However, the electron-donating MeO substituent is preferred at the meta-position, and the cytotoxicity for the meta-substituted derivatives decreased in the order: MeO derivative 14b (3.05 microM) > oxime 16 (6.85 microM) > ketone 13 (10.5 microM) > methyl oxime 18 (20.6 microM). 相似文献
15.
dos Santos L Lima LA Cechinel-Filho V Corrêa R de Campos Buzzi F Nunes RJ 《Bioorganic & medicinal chemistry》2008,16(18):8526-8534
Chalcones or 1,3-diaryl-2-propen-1-ones are known to be useful for treating pain, inflammation, and certain diseases although their uses have not been scientifically verified. Due to the limitations of opioid and NSAID therapy, there is a continuing search for new analgesics. A series of novel new 1-phenyl-3-{4-[(2E)-3-phenylprop-2-enoyl]phenyl}-thiourea and urea derivatives were synthesized and evaluated against writhing test in mice, following the aromatic substitution pattern proposed by Topliss. The results of the preliminary bioassays indicate that compound 3 presents promising anti-nociceptive activity in acetic acid-, formalin-, and glutamate-induced pain in mice, compared with some well-known non-steroidal anti-inflammatory and analgesic drugs. 相似文献
16.
Hundsdörfer C Hemmerling HJ Götz C Totzke F Bednarski P Le Borgne M Jose J 《Bioorganic & medicinal chemistry》2012,20(7):2282-2289
Herein we describe the synthesis and properties of indeno[1,2-b]indole derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 19 compounds was obtained using a convenient and straightforward synthesis protocol. The compounds were tested for inhibition of human protein kinase CK2, which was recombinantly expressed in Escherichia coli. New inhibitors with IC(50) in the micro- and sub-micromolar range were identified. Compound 4b (5-isopropyl-7,8-dihydroindeno[1,2-b]indole-9,10(5H,6H)-dione) inhibited human CK2 with an IC(50) of 0.11 μM and did not significantly inhibit 22 other human protein kinases, suggesting selectivity towards CK2. ATP-competitive inhibition by compound 4b was shown and a K(i) of 0.06 μM was determined. Our findings indicate that indeno[1,2-b]indoles are a promising starting point for further development and optimization of human protein kinase CK2 inhibitors. 相似文献
17.
Upadhayaya RS Sinha N Jain S Kishore N Chandra R Arora SK 《Bioorganic & medicinal chemistry》2004,12(9):2225-2238
A series of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (11a-n) and (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazole-1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (12a-n) has been synthesized. The antifungal activity of compounds was evaluated by in vitro agar diffusion and broth dilution assay. Compounds 11d and its positional isomer 12d having 3-trifluoromethyl substitution on the phenyl ring of piperazine demonstrated significant antifungal activity against variety of fungal cultures (Candida spp. C. neoformans and Aspergillus spp.). The compound 12d showed MIC value of 0.12 microg/mL for C. albicans, C. albicans V-01-191A-261 (resistant strain); 0.25 microg/mL for C. tropicalis, C. parapsilosis ATCC 22019 and C. krusei and MIC value of 0.5 microg/mL for C. glabrata, C. krusei ATCC 6258, which is comparable to itraconazole and better than fluconazole. Further, compound 11d showed significant activity (MIC; 0.25-0.5 microg/mL) against Candida spp. and strong anticryptococcal activity (MIC; 0.25 microg/mL) against C. neoformans. 相似文献
18.
Lin NH Wang L Cohen J Gu WZ Frost D Zhang H Rosenberg S Sham H 《Bioorganic & medicinal chemistry letters》2003,13(21):3821-3825
Farnesyltransferase inhibitors (FTIs) have emerged as a novel class of anticancer agents. Analogues of the potent FTI, 4-[3-biphenyl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl]-1-yl-benzonitrile, were synthesized and tested in vitro for their inhibitory activities. The most promising compound identified from this series is analogue 11 that possesses potent enzymatic and cellular activities. 相似文献
19.
Summary
S-[2-Carboxy-1-(1H-imidazol-4-yl)ethyl]-3-mercaptopyruvic acid (I) was chemically synthesized in 15% yield by incubating a reaction mixture oftrans-urocanic acid and 3-fold excess of 3-mercaptopyruvic acid at 45°C for 6 days. The synthesized compound was characterized by fast-atom-bombardment mass spectrometry and high-voltage paper electrophoresis. CompoundI was identified with a product of an enzymatic reaction ofS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-l-cysteine (II) with rat liver homogenate in a phosphate buffer, pH 7.4. CompoundI was degraded toS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-3-mercaptolactic acid (III), a compound previously found in human urine [Kinuta et al. (1994) Biochem J 297: 475–478], by incubation with rat liver homogenate. From these results, we suggest that compoundI is a metabolic intermediate for the formation of compoundIII from compoundII. The present pathway follows a formation of compoundII fromS-[2-carboxy-1-(1H-imidazol-4-yl)ethyl] gluthathione [Kinuta et al. (1993) Biochim Biophys Acta 1157: 192–198], a proposed metabolite ofl-histidine. 相似文献
20.
Twenty-two new 1-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]pyrrolidine-2,5-diones were synthesized and tested for anticonvulsant activity. Initial anticonvulsant screening was performed using standard maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens in mice. Several compounds were tested additionally in the 6-Hz psychomotor seizure model. The neurotoxicity was determined applying the rotarod test. Excluding one compound, all other molecules were found to be effective in at least one seizure model. The most active were 1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (14), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3-methylpyrrolidine-2,5-dione (17), 1-{2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-dimethylpyrrolidine-2,5-dione (23) and 3,3-dimethyl-1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidine-2,5-dione (26). These compounds showed high activity in the 6-Hz psychomotor seizure test as well as were active in the maximal electroshock and subcutaneous pentylenetetrazole (14 and 23) screens. Initial SAR studies for anticonvulsant activity have been discussed. 相似文献