共查询到20条相似文献,搜索用时 31 毫秒
1.
《Bioorganic & medicinal chemistry》2016,24(16):3771-3780
Various 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines have been synthesized based on the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SNH) reactions starting from commercially available 5-bromopyrimidine and their antitubercular activity against Mycobacterium tuberculosis H37Rv has been explored. The outcome of the study disclose that, some of the compounds have showed promising activity in micromolar concentration against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant strains isolated from tuberculosis patients in Ural region (Russia). The data concerning the ‘structure–activity’ relationship for fluorinated compounds have been discussed. 相似文献
2.
Romagnoli R Baraldi PG Cruz-Lopez O Tolomeo M Di Cristina A Pipitone RM Grimaudo S Balzarini J Brancale A Hamel E 《Bioorganic & medicinal chemistry letters》2011,21(9):2746-2751
Microtubules are dynamic structures that play a crucial role in cellular division and are recognized as an important target for cancer therapy. In search of new compounds with strong antiproliferative activity and simple molecular structure, a new series of 2-amino-3-(3′,4′,5′-trimethoxybenzoyl)-5-(hetero)aryl ethynyl thiophene derivatives was prepared by the Sonogashira coupling reaction of the corresponding 5-bromothiophenes with several (hetero)aryl acetylenes. When these compounds were analyzed in vitro for their inhibition of cell proliferation, the 2- and 3-thiophenyl acetylene derivatives were the most powerful compounds, both of which exerted cytostatic effects at submicromolar concentrations. In contrast, the presence of a more flexible ethyl chain between the (hetero)aryl and the 5-position of the thiophene ring resulted in significant reduction in activity relative to the 5-(hetero)aryl acetylene substituted derivatives. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. We found that the antiproliferative effects of the most active compounds were associated with increase of the proportion of cells in the G2/M and sub-G1 phases of the cell cycle. 相似文献
3.
Aditya S. Gundugola Kusum Lata Chandra Elisabeth M. Perchellet Andrew M. Waters Jean-Pierre H. Perchellet Sundeep Rayat 《Bioorganic & medicinal chemistry letters》2010,20(13):3920-3924
A series of 1,4-diaryl tetrazol-5-ones were synthesized by copper mediated N-arylation of 1-phenyl-1H-tetrazol-5(4H)-one with aryl boronic acids, o-R1C6H4B(OH)2 where R1 = H, OMe, Cl, CF3, Br, CCH. The 1,4-diaryl tetrazol-5-ones substituted with OMe, Cl, CF3, Br underwent thionation with Lawesson’s reagent to yield the corresponding 5-thio derivatives. The 1-(2-bromophenyl)-4-phenyl-1H-tetrazole-5(4H)-thione so obtained was subjected to lithiation/protonation and Sonogashira coupling to produce 1,4-diphenyl-1H-tetrazole-5(4H)-thione and 1-(2-ethynylphenyl)-4-phenyl tetrazole-5-thione, respectively. The title compounds were found to be stable to strong Lewis acid conditions. Three of these novel compounds were found to inhibit L1210 leukemia cell proliferation and SK-BR-3 breast cancer cell growth over several days in culture in vitro. Shorter tetrazole derivative treatments also reduced the expression of the Ki-67 marker of cell proliferation in SK-BR-3 cells and the rate of DNA synthesis in L1210 cells. 相似文献
4.
Chamseddine Derabli Imen Boualia Ahmed B. Abdelwahab Raouf Boulcina Chawki Bensouici Gilbert Kirsch Abdelmadjid Debache 《Bioorganic & medicinal chemistry letters》2018,28(14):2481-2484
In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80?µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044?µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. 相似文献
5.
Chromone-Fused Cytosine Analogues: Synthesis,Biological Activity,and Structure–Activity Relationship
Dhaval D. Haveliwala Nimesh R. Kamdar Prashant T. Mistry 《Nucleosides, nucleotides & nucleic acids》2013,32(2):80-91
The preparation of a series of novel chromone-fused cytosine analogues, i.e., chromeno[2,3-d]pyrimidines has been carried out from substituted 2-amino-4-oxo-4H-chromene-3-carbonitriles with urea, thiourea, and guanidine under different reaction conditions. These chromone-fused cytosine analogues were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv strain and different microbial pathogenic strains in cell culture for their structure–activity relationships, respectively. Among the synthesized compounds, 2d, 3a, and 4e showed better results against Mycobacterium tuberculosis H37Rv. The compounds 2a, 2b, and 3a showed potential antibacterial activity against E. coli and P. aeruginosa, while the majority of compounds were found to be active against S. aureus as compared to ampicillin. The synthesized cytosine analogues having an imine (–C&dbnd;NH) have been less sensitive to the bacterial and fungal strains but have a more beneficial effect on Mycobacterium tuberculosis H37Rv. 相似文献
6.
《Bioorganic & medicinal chemistry letters》2014,24(8):1974-1979
A series of novel 1,2,3-triazole-adamantylacetamide hybrids 5a–u, designed by combining bioactive fragments from antitubercular I-A09 and substituted adamantyl urea, were synthesized using copper catalyzed click chemistry. N-(1-Adamantyl)-2-azido acetamide 3 prepared from 1-adamantylamine was reacted with a series of alkyl/aryl acetylenes in the presence of copper sulfate and sodium ascorbate to give new analogues 5a–u in very good yields. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted N-(1-adamantan-1-yl)-2-(4-(phenanthren-2-yl)-1H-1,2,3-triazol-1-yl)acetamide (5t) as most promising lead MIC: 3.12 μg/mL) with selectivity index >15. 相似文献
7.
Benzylidenehydrazinyl imidazoles ( 3 ) are prepared from 2‐hydrazinyl imidazoles ( 2 ) on treatment with hydrazine. The imine functionality in 3 is utilized to develop 5′‐aryl‐N‐(4‐aryl‐1H‐imidazol‐2‐yl)‐1H‐1,2,3‐triazol‐1‐amines ( 5 ) by 1,3‐dipolar cycloaddition of diazomethane followed by aromatization with I2 in DMSO. Compounds 3 are also explored to prepare 4′‐aryl‐1‐(4‐aryl‐1H‐imidazol‐2‐ylamino)‐3‐chloroazetidin‐2‐ones ( 6 ) on treatment with chloroacetyl chloride. The Molinspiration calculations predicted that 3 , 5 and 6 have molecular hydrophobicity, conformational flexibility, good intestinal absorption and bioactivity scores. The chloro, bromo and nitro substituted imidazolyl azetidinones ( 6c , 6d , 6f ) and nitro substituted imidazolyl triazole ( 5f ) exhibited excellent antibacterial activity on B. subtilis, whereas chloro and nitro substituted imidazolyl triazoles ( 5c , 5f ) showed prominent antifungal activity on A. niger. 相似文献
8.
Rositsa Zamfirova Nikola Pavlov Petar Todorov Polina Mateeva Jean Martinez Monique Calmès Emilia Naydenova 《Bioorganic & medicinal chemistry letters》2013,23(14):4052-4055
We report the synthesis and the biological activity of new analogues of Ac-RFMWMK-NH2 and Ac-RYYRWK-NH2, modified in position 4 and 5, respectively, with incorporation of newly synthesized β2-tryptophan analogues. Trp was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or by (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The biological activity (pEC50 and Emax) of these compounds was tested on electrically stimulated preparations of rat vas deferens. The 5-methoxy β-tryptophan group reverses the affinity of the compounds. 相似文献
9.
The action of six synthetic Biginelli pyrimidines on the production of reactive oxygen species (ROS) by polymorphonuclear
leukocytes has been studied. It has been shown using the method of luminoldependent chemiluminescence that, at concentrations
of 10–100 μM, these compounds stimulate the production of ROS by neutrophils stimulated by phorbol-12-myristate-13-acetate
(PMA). The ROS production by PMA-stimulated neutrophils in the presence of 10 μM 1-(3,4-dimethoxyphenylethyl)-4-(alkyl/aryl)
substituted Biginelli pyrimidines increased by 50–90%. The priming action of Biginelli pyrimidines on the ROS production by
neutrophils has been shown to increase when the furyl radical was replaced by phenyl and isopropyl radicals by the C(4) pyrimidine cycle and replacement of the benzyl substitute at N(1) by 3,4-phenylethyl. At a concentration
of 0.01–0.1 μM, 1-(3,4-dimethoxyphenylethyl)-4-(alkyl/aryl) substituted Biginelli pyrimidines had a high inhibitory activity.
It has been found that 1-(2-[3,4-dimethoxyphenyl]-ethyl)-4-phenyl-5-carbethoxy-6-methyl-3,4-dihydro-2(1H)-pyrimidinethion
at high concentrations (1 mM and more) is able to induce a respiratory burst of neutrophils without additional stimulation. 相似文献
10.
Christopher McGuigan Olivier Bidet Marco Derudas Graciela Andrei Robert Snoeck Jan Balzarini 《Bioorganic & medicinal chemistry》2009,17(8):3025-3027
Novel alkenyl substituted aryl bicyclic furano pyrimidines have been prepared and evaluated in vitro against Varicella Zoster Virus (VZV). The para-substituted analogues retain the nanomolar potency we have reported for p-alkyl analogues, while the ortho- and meta-alkenyl systems lose 3–4 orders of potency. 相似文献
11.
Yu Sun 《Inorganica chimica acta》2006,359(15):4807-4810
3(5)-Pyrazolyl substituted triphenylphosphines have been investigated as ligands for the palladium catalyzed Heck reaction of aryl halides with styrene. Catalysts formed in situ from those phosphines and PdII(OAc)2 are comparable in activity and selectivity with the corresponding pre-synthesized Pd(II) complexes, while Pd2(dba)3 has turned out to be a less suitable palladium source. Among the ligands investigated, the bidentate P,N-ligand 2-[3(5)-pyrazolylphenyl]diphenylphosphine has shown the highest activities for the coupling of bromobenzene with styrene in the presence of PdII(OAc)2. In the presence of 1 equiv. of nBu4NI as the additive, unreactive 4-chloroacetophenone also undergoes Heck coupling with styrene. 相似文献
12.
An expedient and eco-friendly synthesis of 1-aryl/heteroaryl-[1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones (4) has been accomplished via iodobenzene diacetate mediated oxidative intramolecular cyclization of 3-(2-(aryl/heteroarylidene)hydrazinyl)-quinoxalin-2(1H)-ones (3). Ten synthesized compounds 3 and 4 (10–40 μg) on irradiation with UV light at λmax 312 nm could lead to cleavage of supercoiled pMaxGFP DNA (Form I) into the relaxed DNA (Form II) without any additive. Further, DNA cleaving ability of triazoles was quantitatively evaluated and was found to be dependent on its structure, concentration, and strictly on photoirradiation time. Mechanistic investigations using several additives as potential inhibitors/activator revealed that the DNA photocleavage reaction involves Type-I pathway leading to formation of superoxide anion radicals (O2−) as the major reactive oxygen species responsible for photocleavage process. 相似文献
13.
Adriana Bocheva Hristina Nocheva Nikola Pavlov Petar Todorov Monique Calmès Jean Martinez Emilia Naydenova 《Amino acids》2013,45(4):983-988
Aiming to develop more potent analgesic substances a new series of hexapeptides containing β2-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists—naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β2-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH2) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects. 相似文献
14.
E. Amadio A. Scrivanti G. Chessa U. Matteoli A. Dolmella 《Inorganica chimica acta》2011,370(1):388-12124
The synthesis and characterization of the cationic complex [Pd(η3-C3H5)(2-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)pyridine)](BF4) (2) are reported. The solid-state structure of 2 has been unambiguously confirmed by single-crystal X-ray diffraction analysis. 1H NMR spectroscopy reveals that in solution complex 2 is dynamic and that syn-syn, anti-anti exchange of the allyl protons occurs. Complex 2 exhibits good activity in the Suzuki-Miyaura coupling of aryl bromides with phenyl boronic acid. 相似文献
15.
Christoph Eibl Lenka Munoz Isabelle Tomassoli Clare Stokes Roger L. Papke Daniela Gündisch 《Bioorganic & medicinal chemistry》2013,21(23):7309-7329
3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β21 nAChR. Compounds 15, 25, and 47 with Ki values of about 1 nM displayed the highest affinities for α4β21 nAChR. All evaluated compounds are partial agonists or antagonists at α4β21, with reduced or no effects on α3β41 with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes. 相似文献
16.
Angelino Doppiu 《Inorganica chimica acta》2004,357(6):1773-1780
The dimer [Ir(μ-Cl)(C8H14)2]2 reacts with the ligands (S)-(C5H4CH2CH(Ph)PPh2)Li and (R)-(C5H4CH(Cy)CH2PPh2)Li to give (S)-[Ir(η5-C5H4CH2CH(Ph)PPh2-κP)(C8H14)] and (R)-[Ir(η5-C5H4CH(Cy)CH2PPh2-κP)(C8H14)], which upon treatment with CH3I at room temperature afford the cationic iridium(III) compounds (S,SIr)-[Ir(η5-C5H4CH2CH(Ph)PPh2-κP)(CH3)(C8H14)][I] as a single diastereomer, and (R)-[Ir(η5-C5H4CH(Cy)CH2PPh2-κP)(CH3)(C8H14)][I] as a 9:1 mixture of two diastereomers. If the oxidative addition reaction is performed at reflux in methylene chloride, the starting complexes convert to the neutral compounds (S)-[Ir(η5-C5H4CH2CH(Ph)PPh2-κP)(CH3)(I)] and (R)-[Ir(η5-C5H4CH(Cy)CH2PPh2-κP)(CH3)(I)] as 1.6:1 and 3.3:1 mixtures of diastereoisomers, respectively. Carbonyl iridium complexes are synthesized by reacting [IrCl(CO)(PPh3)2] with the ligands to afford (S)-[Ir(η5-C5H4CH2CH(Ph)PPh2-κP)(CO)] and (R)-[Ir(η5-C5H4CH(Cy)CH2PPh2-κP)(CO)]. They give upon treatment with CH3I the cationic species (S)-[Ir(η5-C5H4CH2CH(Ph)PPh2-κP)(CH3)(CO)][I] and (R)-[Ir(η5-C5H4CH(Cy)CH2PPh2-κP)(CH3)(CO)][I] as 1.6:1 and 3:1 mixture of diastereomers, respectively. No migratory-insertion of the methyl group into the carbonyl-metal bond has been observed even after prolonged heating. 相似文献
17.
《Bioorganic & medicinal chemistry letters》2014,24(23):5520-5524
Here a series of 2-butyl-4-chloroimidazole based substituted piperazine-thiosemicarbazone hybrids were designed by combining three different pharmacophoric fragments in single molecular architecture. 2-Butyl-4-chloro-1-(3-(4-substituted)piperazin-1-yl)propyl)-1H-imidazole-5-carbaldehydes (4a–p) prepared by reacting carboxaldehyde 2 with N-alkyl piperazines 3a–p which were condensed with thiosemicarbazine to give desired compounds 5a–p in very good yields. Among all sixteen compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB), two compounds (E)-2-((2-butyl-4-chloro-1-(3-(4-(o-tolyl) piperazin-1-yl)propyl)-1H-imidazol-5-yl)methylene)hydrazinecarbothioamide 5e and (E)-2-((2-butyl-4-chloro-1-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-1H-imidazol-5-yl)methylene) hydrazine carbothioamide 5f were found to be the most potent antitubercular agents (MIC: 3.13 μg/mL) with low toxicity profile. 相似文献
18.
Nisheeth C. Desai Kiran M. Rajpara Vivek V. Joshi 《Bioorganic & medicinal chemistry letters》2012,22(22):6871-6875
The synthesis of a novel series of 2-(5-(2-chloro-6-fluoroquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-ones (4a–l) and N-(4-(2-chloro-6-fluoroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-morpholinoacetamides (7a–l) are described in the present paper. The chemical structures of compounds have been elucidated by IR, 1H NMR, 13C NMR and mass spectral data. Antimicrobial activity was measured against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282) and Aspergillus clavatus (MTCC 1323) by serial broth dilution. Evaluation of antimicrobial activity showed that several compounds exhibited greater activity than reference drugs and thus could be promising new lead molecules. 相似文献
19.
Annika Frank Francisco Meza-Arriagada Cristian O. Salas Christian Espinosa-Bustos Holger Stark 《Bioorganic & medicinal chemistry》2019,27(14):3194-3200
Inspired by marine compounds the derivatization of the natural pyrrolo[2,3-d]pyrimidine lead scaffold led to a series of novel compounds targeting the histamine H3 receptor. The focus was set on improved binding towards the receptor and to establish an initial structure-activity relationship for this compound class based on the lead structure (compound V, Ki value of 126 nM). As highest binding affinities were found with 1,4-bipiperidines as basic part of the ligands, further optimization was focused on 4-([1,4′-bipiperidin]-1′-yl)-pyrrolo[2,3-d]pyrimidines. Related pyrrolo[2,3-d]pyrimidines that were isolated from marine sponges like 4-amino-5-bromopyrrolo[2,3-d]pyrimidine (compound III), showed variations in halogenation pattern, though in a next step the impact of halogenation at 2-position was evaluated. The chloro variations did not improve the affinity compared to the dehalogenated compounds. However, the simultaneous introduction of lipophilic cores with electron-withdrawing substitution patterns in 7-position and dehalogenation at 2-position (11b, 12b) resulted in compounds with significantly higher binding affinities (Ki values of 7 nM and 6 nM, respectively) than the initial lead structure compound V. The presented structures allow for a reasonable structure-activity relationship of pyrrolo[2,3-d]pyrimidines as histamine H3 receptor ligands and yielded novel lead structures within the natural compound library against this target. 相似文献
20.
The pyrazole analogues of podophyllotoxin were synthesized by the chalcone route. This route attracts the attention because of its simple operating conditions and easy availability of the chemicals. Initially, benzylideneacetophenones (chalcones) were prepared in high yields by Claisen-Schmidt reaction of acetophenones with 4-(methylthio)benzaldehyde. The cyclopropyl ketones were prepared in good yields by the reaction of chalcones with trimethylsulfoxonium iodide. Tetralones were prepared in good yields by the Friedel-Craft’s intramolecular cyclization reaction of cyclopropyle ketones in the presence of anhyd. stannic chloride and acetic anhydride. The tetralones on formylation to give substituted hydroxylmethylene tetralones. Condensation of substituted hydroxylmethylene tetralones with hydrazine hydrate afforded target compounds. The structures of the synthesized compounds were confirmed by IR, 1H NMR and Mass spectral technique. The title compounds were screened for their antimitotic and antimicrobial activities. Among the synthesized compounds cyclopropyl ketones and pyrazole analogues of podophyllotoxin, compound 7-(methylthio)-5-(4-(methylthio)phenyl)-4,5-dihydro-2 H-benzo[g]indazole is more active than 5-(4-(methylthio)phenyl)-4,5-dihydro-2 H-benzo[g]indazole, 7-methyl-5-(4-(methylthio)phenyl)-4,5-dihydro-2 H-benzo[g]indazole, 7-methoxy-5-(4-(methylthio)phenyl)-4,5-dihydro-2 H-benzo[g]indazole and the key intermediate tetralones in 100, 200 and 400 ppm at 12, 18 and 24 h and also showed very good activity against screened bacteria and fungi compared to their standard. 相似文献