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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 下载免费PDF全文
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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Arylazolyl(azinyl)thioacetanilides: Part 19: Discovery of Novel Substituted Imidazo[4,5‐b]pyridin‐2‐ylthioacetanilides as Potent HIV NNRTIs Via a Structure‐based Bioisosterism Approach 下载免费PDF全文
Xiao Li Boshi Huang Zhongxia Zhou Ping Gao Christophe Pannecouque Dirk Daelemans Erik De Clercq Peng Zhan Xinyong Liu 《Chemical biology & drug design》2016,88(2):241-253
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Antimycobacterial evaluation of novel [4,5‐dihydro‐1H‐pyrazole‐1‐carbonyl]pyridine derivatives synthesized by microwave‐mediated Michael addition 下载免费PDF全文
The focus of this study is the synthesis and biological activity evaluation of a series of dibenzalaceton derivatives (3a‐3n) and novel [4,5‐dihydro‐1H‐pyrazole‐1‐carbonyl]pyridine derivatives (5a‐5g) against Mycobacterium bovis, Bacillus Calmette–Guerin (BCG). Dibenzalacetone derivatives were synthesized by benzaldehyde derivatives. The [4,5‐dihydro‐1H‐pyrazole‐1‐carbonyl]pyridine derivatives were synthesized by Michael addition reaction and using green chemistry microwave‐mediated method. All compounds were evaluated against BCG and the activity expressed as minimum inhibitory concentration (MIC) in μM. The result showed good activity for all the compounds especially compounds (3a), (3n), and (5a) illustrated high activity (7.03, 8.10 and 5.37 μM, respectively). Copyright © 2014 John Wiley & Sons, Ltd. 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
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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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Yuan Tian Yang Hong Samuel J. Bonacorsi Aaron Balog Sharon Gong 《Journal of labelled compounds & radiopharmaceuticals》2014,57(1):1-11
For the first time, [3α‐3H] 17α‐hydroxy pregnenolone (1) was synthesized through a multiple step sequence. The presence of [3β‐3H] isomer in RP‐HPLC purified product was identified by tritium NMR. The [3β‐3H] isomer was then separated from [3α‐3H] 17α‐hydroxy pregnenolone with chiralPAK AD‐H column. [3α‐3H] pregnenolone (2) was synthesized from commercial available 5‐pregnen‐3,20‐dione in one step with an improved procedure. 相似文献
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Esra Tatar İlkay Küçükgüzel Dirk Daelemans Tanaji T. Talele Neerja Kaushik‐Basu Erik De Clercq Christophe Pannecouque 《Archiv der Pharmazie》2013,346(2):140-153
In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 S , 11 S , and 12 S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC50) = 123.8 µM (selectivity index, SI > 3), IC50 = 12.1 µM (SI > 29), IC50 = 17.4 µM (SI > 19), respectively. Enantiomers 8 R , 11 R , and 12 R were inactive against the HIV‐1 strain IIIB. Hydrazones 8 S , 11 S , and 12 S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2003,46(5):395-400
14C‐Labelled myosmine ([2′‐14C]‐3‐(1‐pyrrolin‐2‐yl)pyridine) was synthesized for autoradiography studies starting from [carboxyl‐14C]‐nicotinic acid by initial esterification of the latter in the presence of 1,1,1‐triethoxyethane. Without any purification the ethyl nicotinate formed was directly reacted with N‐vinyl‐2‐pyrrolidinone in the presence of sodium hydride, yielding 14C‐labelled myosmine. The product was purified by silica gel column chromatography. The radiochemical yield was 15% and the specific activity 55.2 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2006,49(9):789-799
[14C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [14C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐14C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐13C4]‐ethyl acetoacetate and [D4]‐methanol in six steps in an overall yield of 2%. [13C4]‐2‐methylnicotic acid, was prepared by condensation of [13C4]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
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Synthesis and Evaluation of 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides as Novel GSK‐3β Inhibitors and Anti‐Ischemic Agents 下载免费PDF全文
Qing Ye Qiu Li Yubo Zhou Lei Xu Weili Mao Yuanxue Gao Chenhui Li Yuan Xu Yazhou Xu Hong Liao Luyong Zhang Jianrong Gao Jia Li Tao Pang 《Chemical biology & drug design》2015,86(4):746-752
A series of novel 3‐(furo[2,3‐b]pyridin‐3‐yl)‐4‐(1H‐indol‐3‐yl)‐maleimides were designed, synthesized, and biologically evaluated for their GSK‐3β inhibitory activities. Most compounds showed favorable inhibitory activities against GSK‐3β protein. Among them, compounds 5n , 5o , and 5p significantly reduced GSK‐3β substrate tau phosphorylation at Ser396 in primary neurons, indicating inhibition of cellular GSK‐3β activity. In the in vitro neuronal injury models, compounds 5n , 5o , and 5p prevented neuronal death against glutamate, oxygen–glucose deprivation, and nutrient serum deprivation which are closely associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 5o reduced infarct size by 10% and improved the neurological deficit. The results may provide new insights into the development of novel GSK‐3β inhibitors with potential neuroprotective activity against brain ischemic stroke. 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 下载免费PDF全文
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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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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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 下载免费PDF全文
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
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Pradip Ghosh Juri G. Gelovani Mian M. Alauddin 《Journal of labelled compounds & radiopharmaceuticals》2007,50(13):1185-1191
Radiosyntheses of two N3‐substituted thymidine analogues, N3‐[(4[18F]fluoromethyl‐phenyl)butyl]thymidine ([18F]‐FMPBT) and N3‐[(4[18F]fluoromethyl‐phenyl)pentyl]thymidine ([18F]‐FMPPT), are reported. The precursor compounds 9 and 10 were synthesized in six steps and the standard compounds 13 and 14 were synthesized from these precursors. For radiosynthesis, compounds 9 and 10 were fluorinated with n‐Bu4N[18F] to produce [18F]‐ 11 and [18F]‐ 12 , which by acid hydrolysis yielded [18F]‐ 13 and [18F]‐ 14 , respectively. The crude products were purified by high‐performance liquid chromatography to obtain [18F]‐FMPBT and [18F]‐FMPPT. The average decay‐corrected radiochemical yield for [18F]‐ 13 was 15% in five runs, and that for [18F]‐ 14 was 10% in four runs. The radiochemical purity was >99% and the specific activity was >74 GBq/µmol at the end of synthesis. The synthesis time was 80–90 min from the end of bombardment. Copyright © 2007 John Wiley & Sons, Ltd. 相似文献