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Venugopala K. Narayanaswamy Susanta K. Nayak Melendhran Pillay Renuka Prasanna Yacoob M. Coovadia Bharti Odhav 《Chemical biology & drug design》2013,81(2):219-227
A series of 2‐(substituted phenyl/benzyl‐amino)‐6‐(4‐chlorophenyl)‐5‐(methoxycarbonyl)‐4‐methyl‐3,6‐dihydropyrimidin‐1‐ium chlorides 7–13 and 15 was synthesized in their hydrochloride salt form. The title compounds were characterized by FT‐IR, NMR (1H and 13C) and elemental analysis. They were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, multidrug resistance tuberculosis and extensively drug resistance tuberculosis by agar diffusion method and tested for the cytotoxic action on peripheral blood mononuclear cells by MTT assay. Among all the tested compounds in the series, compounds 7 and 11 emerged as promising antitubercular agents at 16 μg/mL against multidrug resistance tuberculosis and over 64 μg/mL against extensively drug resistance tuberculosis. The conformational features and supramolecular assembly of the promising compounds 7 and 11 were determined by single crystal X‐ray study. 相似文献
3.
Synthesis and Biological Evaluation of a Series of 2‐((1‐substituted‐1H‐1,2,3‐triazol‐4‐yl)methylthio)‐6‐(naphthalen‐1‐ylmethyl)pyrimidin‐4(3H)‐one As Potential HIV‐1 Inhibitors
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Lingzi Zhang Boshi Huang Huiqing Liu Christophe Pannecouque Erik De Clercq Peng Zhan Xinyong Liu 《Chemical biology & drug design》2015,86(4):614-618
A series of novel S‐DABO derivatives with the substituted 1,2,3‐triazole moiety on the C‐2 side chain were synthesized using the simple and efficient CuAAC reaction, and biologically evaluated as inhibitors of HIV‐1. Among them, the most active HIV‐1 inhibitor was compound 4‐((4‐((4‐(2,6‐dichlorobenzyl)‐5‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzenesulfonamide ( B5b7) , which exhibited similar HIV‐1 inhibitory potency (EC50 = 3.22 μm ) compared with 3TC (EC50 = 2.24 μm ). None of these compounds demonstrated inhibition against HIV‐2 replication. The preliminary structure–activity relationship (SAR) of these new derivatives was discussed briefly. 相似文献
4.
Design,Synthesis, and Biological Evaluation of 1‐(thiophen‐2‐yl)‐9H‐pyrido[3,4‐b]indole Derivatives as Anti‐HIV‐1 Agents
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Penta Ashok Cui‐Lin Lu Subhash Chander Yong‐Tang Zheng Sankarnarayanan Murugesan 《Chemical biology & drug design》2015,85(6):722-728
A novel series of 1‐(thiophen‐2‐yl)‐9H‐pyrido [3,4‐b]indole derivatives were synthesized using DL‐tryptophan as starting material. All the compounds were characterized by spectral analysis such as 1H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV‐1 replication. Among the reported analogues, compound 7g exhibited significant anti‐HIV activity with EC50 0.53 μm and selectivity index 483; compounds 7e , 7i , and 7o displayed moderate activity with EC50 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV‐1IIIB infected cell line C8166 with EC50 1.1 μm . In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug‐likeness, and drug score of the synthesized analogues. 相似文献
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Palaniappan Senthilkumar Murugesan Dinakaran Yogesh Chandraseakaran Perumal Yogeeswari Dharmarajan Sriram 《Archiv der Pharmazie》2009,342(2):100-112
Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC2). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM. 相似文献
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《Chemical biology & drug design》2018,91(2):526-533
A series of 5‐(4‐(pyridin‐4‐yl)‐1H‐1,2,3‐triazol‐1‐yl)benzonitrile derivatives ( 1a–p ) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC50 values of 8.1 and 6.7 μm , respectively. The Lineweaver–Burk plot revealed that compound 1k acted as a mixed‐type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso‐pentyloxy or a cyclopentyloxy at the 2‐position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2004,47(9):557-569
Derivatives of nido‐carborate have potential use in tumour targeting as hydrophilic boron‐rich compounds for boron neutron capture therapy (BNCT) and as pendant groups for attachment of radiohalogens to tumour‐seeking molecules. For this purpose, functionalized derivatives of nido‐carborates that can be conjugated to biomolecules should be synthesized and evaluated. In this study, racemic 1 , 7‐(3′‐ammoniopropyl)‐7,8‐dicarba‐nido‐undecaborate(‐1) (acronym ANC ) was obtained by degradation of the corresponding aminopropyl‐o‐carborane, which was synthesized in three steps from 1‐tert‐butyldimethylsilyl‐2‐(3‐bromopropyl)‐o‐carborane, with sodium hydroxide in absolute ethanol. The racemate 1 was radioiodinated (125 I ) using the Chloramine‐T method. Radio‐TLC results showed that radiolabelling with 125 I was achieved in a yield greater than 95%. Copyright © 2004 John Wiley & Sons, Ltd. 相似文献
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Design,Synthesis, and Biological Evaluation of Novel 4‐Aminopiperidinyl‐linked 3,5‐Disubstituted‐1,2,6‐thiadiazine‐1,1‐dione Derivatives as HIV‐1 NNRTIs
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Tao Liu Boshi Huang Ye Tian Xin Liang Hong Liu Huiqing Liu Peng Zhan Erik De Clercq Christophe Pannecouque Xinyong Liu 《Chemical biology & drug design》2015,86(1):107-113
Based on the hybridization of the privileged fragments in DABO and DAPY‐typed HIV‐1 NNRTIs, a novel series of 4‐aminopiperidinyl‐linked 3,5‐disubstituted‐1,2,6‐thiadiazine‐1,1‐dione derivatives were designed, synthesized, and evaluated for their in vitro anti‐HIV activities in MT‐4 cells. Most of the target compounds showed weak inhibitory activity against WT HIV‐1. In order to confirm the mode of action of the target compounds, representative compounds Ba8 and Bb8 were selected to perform the HIV‐1 RT inhibitory assay. In this assay, Ba8 and Bb8 displayed good activity with IC50 values of 3.15 and 1.52 μm , respectively. Additionally, preliminary structure–activity relationships (SARs) analysis and molecular docking studies of newly synthesized compounds are also discussed. 相似文献
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A series of (1‐substituted aryl)‐3‐(1H‐imidazol‐1‐yl)‐1‐propanones was synthesized through the N‐alkylation of imidazole with 3‐dimethylamino‐1‐(substituted aryl)‐1‐propanone hydrochlorides (ketonic Mannich bases). A second series of N1‐substituted imidazoles was obtained by the reduction of the carbonyl function of the imidazole–ketones in the previous series by means of NaBH4. All of the compounds were evaluated for antifungal activity against 16 strains of Candida, and 3‐(1H‐imidazol‐1‐yl)‐1‐(4‐biphenylyl)‐1‐propanone emerged as a broad‐spectrum antifungal agent. Several 3‐(1H‐imidazol‐1‐yl)‐1‐(2′‐(substituted benzyl)oxyphenyl)‐1‐propanones were also active towards Candida kefyr. 相似文献
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Ebrahim Naimi Leonard I. Wiebe Jan Balzarini Erik De Clercq Edward E. Knaus 《Drug development research》2001,52(3):492-499
A group of unnatural 1‐(2‐deoxy‐β‐D ‐ribofuranosyl)‐2,4‐difluorobenzenes having a variety of C‐5 substituents, designed as thymidine mimics, were synthesized for evaluation as antiviral and anticancer agents. The regiospecific addition of HOBr (generated from N‐bromosuccinimide in aqueous dioxane) across the 5‐vinyl substituent ( 4 ) afforded the corresponding 5‐[‐CH(OH)CH2Br] product ( 5 ), whereas reaction of 4 with iodine in the presence of iodic acid (HOI) yielded the 5‐[CH(OH)CH2I] product ( 6 ). The related 5‐[‐CH(OH)CHX2 (X = Br, I)] analogs ( 11 , 12 ) were similarly prepared from the (E)‐5‐(2‐halovinyl) precursors ( 9 , 10 ). Treatment of the 5‐[‐CH(OH)CH2X (X = Br, I)] compounds ( 5 , 6 ) with NaOH in aqueous dioxane afforded the 5‐oxiranyl product ( 8 ). The 5‐[‐CH(OMe)CH2I] compound ( 7 ) was prepared by reaction of the 5‐vinyl compound (4) with ICl in MeOH (MeOI). This group of compounds ( 5 – 8 , 11 , 12 ) showed similar (marginal) activity against varicella‐zoster virus thymidine kinase positive (VZV/TK+) and thymidine kinase deficient (VZV/TK–) infected cells. Thus, the viral TK enzyme did not provide a gene therapeutic effect. This group of compounds, which were evaluated using a wide variety of antiviral assay systems [(herpes simplex virus HSV‐1, HSV‐2), varicella‐zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalovirus (CMV), and human immunodeficiency virus (HIV‐1, HIV‐2)], showed that these unnatural C‐aryl nucleoside mimics are inactive antiviral agents. Their failure to exhibit antiviral/anticancer activity could be due to the fact that they are not phosphorylated to the 5′‐monophosphate, or that incorporation of the active 5′‐triphosphate into DNA does not produce a cytotoxic effect, and/or that these C‐aryl nucleoside mimics do not act as inhibitors of thymidylate synthase, which may be required to produce a cytotoxic effect. Drug Dev. Res. 52:492–499, 2001. © 2001 Wiley‐Liss, Inc. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2002,45(8):647-664
Carboxylic acid derivatives of the amyloid‐binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid‐imaging agents. A neutral amyloid probe, (E,E)‐1‐(3′,4′‐dihydroxystyryl)‐4‐(3′‐methoxy‐4′‐hydroxystyryl)benzene ( 3 ), devoid of any carboxylate groups has been designed and synthesized via a 12‐step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C‐11 via [11C]methyl iodide ([11C]CH3I) methylation of a symmetric 4,4′‐dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post‐mortem AD brain, and exhibited good binding affinity (Ki=38±8 nM) for Aβ(1–40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [11C] 3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [11C] 3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR‐beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
13.
Nawar S. Hamad Nahed H. Al‐Haidery Iman A. Al‐Masoudi Mey Sabri Luma Sabri Najim A. Al‐Masoudi 《Archiv der Pharmazie》2010,343(7):397-403
A new series of 2‐(naphthalen‐2‐yloxy)‐N‐[(aryl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐3‐yl)methyl] acetamides 5a–f was synthesized from naphthalene‐derived glycine derivative 2 via the hydrazinoacetamide analogs 4a–f . Alternatively, treatment of 4a with H2SO4 afforded 2‐(naphthalen‐2‐yloxy)‐N‐((5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl)methyl) acetamide 6a . Alkylation or sulphonylation of 5a afforded the S‐alkylated derivatives 7 and 8 , respectively. Interestingly, treatment of 3 with methoxide ion gave the triazine derivative 9 . The synthesized compounds have been screened for their inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells. However, 7 was found to be the potent inhibitor in vitro for the replication of HIV‐1 (EC50 = 0.20 μg/mL), suggesting a new lead in the development of an antiviral agent. 相似文献
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The reaction of benzoyl hydrazine 1a or benzothiazole‐2‐carbohydrazide 1b with 2‐oxo‐N‐arylpropanehydrazonoyl chlorides 2a–d yielded (1Z,2E)‐2‐[(benzoyl/benzothiazol‐2‐oyl)hydrazono]‐N‐(aryl)propanehydrazonoyl chlorides 3a–e . The reaction of 3a–c with sodium benzenesulphinate furnished sulphones 5a–c while the reaction of 5d , e with hydroxyl amine afforded hydroxomoyl derivatives 6a , b . The one‐pot sterioselective reaction of N‐(aryl)propanehydrazonoyl chlorides 3 with certain aromatic aldehydes in the presence of piperidine resulted in the formation of (1E,2Z,3E)‐1‐(piperidin‐1‐yl)‐1‐(arylhydrazono)‐2‐[(benzoyl/benzothiazol‐2‐oyl)hydrazono]‐4‐(aryl1)‐but‐3‐enes 7a–g . X‐ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperidinyl amidrazones 7a–g possessed a significant antiviral activity against herpes simplex viruses (HSV‐1). Compound 7d reduced the number of viral plaques of herpes simplex type‐1 (HSV‐1) by 67%, with respect to the effect of reference drug Aphidicolin. 相似文献
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Suresh Kumar Neeraj Upmanyu Obaid Afzal Sandhya Bawa 《Chemical biology & drug design》2014,84(5):522-530
A series of 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]thiocarbamide and 1‐(substituted‐phenyl)‐1‐[(2‐chloroquinolin‐3‐yl)methyl]methylthiocarbamide derivatives was synthesized as antitubercular agent. The structure of quinolinyl amines and their thiocarbamide derivatives were established on the basis of IR, 1H and 13C‐NMR and mass spectral data. All the compounds were tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis (ATCC‐25177) in Lowenstein‐Jensen medium by well diffusion method and MIC by twofold serial dilution method. Results of the antitubercular screening revealed that compounds showed moderate to good antitubercular activity. Compound having two halogens in the phenyl rings viz. 3g , 3h , 4g, and 4h exhibited MIC of 50 μg/mL. The computational parameters relevant to absorption and permeation of target compounds were also calculated and found to be well correlated with antitubercular activity. 相似文献
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Design,synthesis, and biological evaluation of novel 5‐Alkyl‐6‐Adamantylmethylpyrimidin‐4(3H)‐ones as HIV‐1 non‐nucleoside reverse‐transcriptase inhibitors
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Wenxin Li Boshi Huang Dongwei Kang Erik De Clercq Dirk Daelemans Christophe Pannecouque Peng Zhan Xinyong Liu 《Chemical biology & drug design》2016,88(3):380-385
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《Journal of labelled compounds & radiopharmaceuticals》2002,45(9):763-774
Tolbutamide ( 1 ) is a sulfonurea agent used to stimulate insulin secretion in type 2 diabetic patients. Its analogue 1‐(4‐(2‐[18F]fluoroethoxy)benzenesulfonyl)‐3‐butyl urea ( 3 ) was synthesized in overall radiochemical yields of 45% as a potential β‐cell imaging agent. Compound 3 was synthesized by 18F‐fluoroalkylation of the corresponding hydroxy precursor ( 2 ) with 2‐[18F]fluoroethyltosylate in DMF at 120°C for 10 min followed by purification with HPLC in a synthesis time of 50 min. Insulin secretion experiments of the authentic 19F‐standard compound on rat islets showed that the compound has a similar stimulating effect on insulin secretion as that of tolbutamide ( 1 ). The partition coefficient of compound 3 between octanol/water was determined to be 1.3±0.3 (n=5). Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
18.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(12):1069-1077
2‐(4‐Methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methylpiperidin‐4‐yl)acetamide (AC90179, 4 ), a highly potent and selective competitive 5‐HT2A antagonist, was labeled by [11C]‐methylation of the corresponding desmethyl analogue 5 with [11C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p‐tolylmethylamine in three steps with 46% overall yield. [11C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [11C] 4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [11C] 4 cannot be used as PET ligand for imaging 5‐HT2A receptors. Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
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Solid‐Supported Synthesis and 5‐HT7/5‐HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one
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Katarzyna Grychowska Nicolas Masurier Pascal Verdié Grzegorz Satała Andrzej J. Bojarski Jean Martinez Maciej Pawłowski Gilles Subra Paweł Zajdel 《Chemical biology & drug design》2015,86(4):697-703
A series of arylpiperazinylbutyl derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6(1H)‐ones was designed and synthesized according to the new solid‐supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc‐protected glycine. The library representatives showed different levels of affinity for 5‐HT7 and 5‐HT1A receptors; compounds 13 , 14 and 18 – 20 were classified as dual 5‐HT7/5‐HT1A receptors ligands. The structure–affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety. 相似文献
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Simone Carradori Daniela Secci Adriana Bolasco Celeste De Monte Matilde Yáñez 《Archiv der Pharmazie》2012,345(12):973-979
Novel 1‐(4‐ethyl carboxylate‐thiazol‐2‐yl)‐3,5‐di(hetero)aryl‐2‐pyrazoline derivatives were obtained by reacting 3,5‐di(hetero)aryl‐1‐thiocarbamoyl‐2‐pyrazolines with the ethyl ester of α‐bromo‐pyruvic acid. The synthesized compounds were confirmed by spectroscopic data and assayed to evaluate their in vitro ability to inhibit both isoforms of human cyclooxygenase (hCOX). Some derivatives (compounds 5 , 6 , 13 , 16 , and 17 ) displayed promising selectivity against hCOX‐1 in the micromolar range and were shown to have a selectivity index similar or better than the reference drugs (indometacin, diclofenac). The introduction of a phenyl or a 4‐F‐phenyl ring on the C5 associated with a 4‐substituted phenyl or a heteroaryl group on the C3 of (4‐substituted‐thiazol‐2‐yl)pyrazoline derivatives improved the activity against hCOX‐1. Thanks to these preliminary results it could be possible to extend our knowledge of the pharmacophoric requirements for the discovery of new pyrazoline‐based hCOX‐1 inhibitors. 相似文献