全文获取类型
收费全文 | 2292篇 |
免费 | 67篇 |
国内免费 | 25篇 |
出版年
2023年 | 26篇 |
2022年 | 21篇 |
2021年 | 35篇 |
2020年 | 76篇 |
2019年 | 125篇 |
2018年 | 122篇 |
2017年 | 101篇 |
2016年 | 90篇 |
2015年 | 43篇 |
2014年 | 128篇 |
2013年 | 237篇 |
2012年 | 32篇 |
2011年 | 98篇 |
2010年 | 51篇 |
2009年 | 79篇 |
2008年 | 78篇 |
2007年 | 78篇 |
2006年 | 83篇 |
2005年 | 49篇 |
2004年 | 50篇 |
2003年 | 55篇 |
2002年 | 48篇 |
2001年 | 19篇 |
2000年 | 15篇 |
1999年 | 20篇 |
1998年 | 23篇 |
1997年 | 21篇 |
1996年 | 16篇 |
1995年 | 18篇 |
1994年 | 22篇 |
1993年 | 17篇 |
1992年 | 25篇 |
1991年 | 13篇 |
1990年 | 7篇 |
1989年 | 9篇 |
1987年 | 8篇 |
1986年 | 6篇 |
1985年 | 56篇 |
1984年 | 54篇 |
1983年 | 20篇 |
1982年 | 48篇 |
1981年 | 44篇 |
1980年 | 52篇 |
1979年 | 50篇 |
1978年 | 36篇 |
1977年 | 25篇 |
1976年 | 17篇 |
1975年 | 10篇 |
1974年 | 5篇 |
1973年 | 16篇 |
排序方式: 共有2384条查询结果,搜索用时 953 毫秒
111.
A.M. Waszkielewicz A. Gunia N. Szkaradek K. Pytka A. Siwek G. Satała A.J. Bojarski E. Szneler H. Marona 《Bioorganic & medicinal chemistry letters》2013,23(15):4419-4423
A series of new xanthone derivatives with piperazine moiety [1–7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α1 and β1 adrenergic as well as 5-HT1A, 5-HT6 and 5-HT7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT1A receptors (Ki = 24 nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED50 determined in maximal electroshock (MES) seizure assay was 105 mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration. 相似文献
112.
Hai-Chuan Zhao Yan-Ping Shi Yu-Ming Liu Cai-Wen Li Li-Na Xuan Peng Wang Kai Zhang Bao-Quan Chen 《Bioorganic & medicinal chemistry letters》2013,23(24):6577-6579
A series of novel 1,3-selenazole-containing 1,3,4-thiadiazole derivatives bearing Schiff base moieties were synthesized and evaluated for their in vitro antiproliferative activities against human breast cancer cell MCF-7 and mouse lymphocyte leukemia cell L1210 by CCK-8 assay. The majority of the compounds showed better activity against MCF-7 cell, compared with lead compound PCS. In particular, compound 6c was the most potent compound with IC50 value of 4.02 μM. 相似文献
113.
Keimei Oh Kazuhiro Yamada Yuko Yoshizawa 《Bioorganic & medicinal chemistry letters》2013,23(24):6915-6919
The four stereoisomers of 2RS,4RS-1-[[2-(2,4-dichlorophenyl)-4-(2-(2-propenyloxy)phenoxymethyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole (YCZ-2013), a novel brassinosteroid biosynthesis inhibitor, were prepared. The diastereomers of 2RS,4R-5 and 2RS,4S-5 were prepared by using the corresponding optically pure R and S toluene-4-sulfonic acid 2,3-dihydroxypropyl ester (R-4,S-4). The enatiomerically and diastereomerically pure acetonide (5) was obtained by a method involving diastereoselective crystallisation of the tosylate salt, followed by re-equilibration with the mother liquor and chromatography. The optical purity of four target compounds (YCZ-2013) was confirmed by chiral high-performance liquid chromatography (HPLC) and NMR. The effects of these stereoisomers on Arabidopsis stem elongation indicated that the cis isomers of 2S,4R-YCZ-2013 and 2R,4S-YCZ-2013 exhibited potent inhibitory activity with IC50 values of approximately 24 ± 3 and 24 ± 2 nM, respectively. The IC50 values of the trans isomers of 2S,4S-YCZ-2013 and 2R,4R-YCZ-2013 are approximately 1510 ± 50 and 3900 ± 332 nM, respectively. Co-application of brassinolide (10 nM), the most potent BR, and GA3 (1 μM) to Arabidopsis seedlings grown in the dark with 2R,4S-YCZ-2013 and 2S,4R-YCZ-2013 revealed that brassinolide recovered the induced dwarfism of Arabidopsis seedlings, whereas GA3 showed no effect. 相似文献
114.
Youguang Zheng Ming Zheng Xin Ling Yi Liu Yunsheng Xue Lin An Ning Gu Min Jin 《Bioorganic & medicinal chemistry letters》2013,23(12):3523-3530
Novel pyrazole–benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence. 相似文献
115.
Xifu Liang Gunnar Grue-Sørensen Kristoffer Månsson Per Vedsø Anke Soor Martin Stahlhut Malene Bertelsen Karen Margrethe Engell Thomas Högberg 《Bioorganic & medicinal chemistry letters》2013,23(20):5624-5629
Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified. 相似文献
116.
Claudia Mara Maciel-Rezende Letícia de Almeida Éderson D’Martin Costa Francieli Ribeiro Pires Karina Ferreira Alves Cláudio Viegas Junior Danielle Ferreira Dias Antônio Carlos Doriguetto Marcos José Marques Marcelo Henrique dos Santos 《Bioorganic & medicinal chemistry》2013,21(11):3114-3119
Nine O-alkyl and O-prenyl derivatives were synthesized from commercial 2,4-dihydroxybenzophenone, 4,e4,4′-dihydroxybenzophenone and were evaluated for their leishmanicidal activity against promastigote forms of Leishmania amazonensis, as well their toxicity in murine macrophages. All derivatives exhibited better biological activity than their hydroxylated benzophenones precursors, and new compound LFQM-123 (3c) was 250-fold more active than its precursor 4,4′-dihydroxybenzophenone (3). Moreover, some of the results were comparable to the standard drug Amphotericin B, suggesting that the increase in lipophilicity could facilitate protozoa membrane permeation. In this study we confirmed that benzophenone derivatives exhibit leishmanicidal properties, with relatively low toxicity, and thus could be exploited as promise prototypes for the design and development of new drug for the treatment of leishmaniasis. 相似文献
117.
Max Keller Melanie Kaske Tobias Holzammer Günther Bernhardt Armin Buschauer 《Bioorganic & medicinal chemistry》2013,21(21):6303-6322
The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y1R, Y2R, Y4R and Y5R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y1R, Y2R and Y5R, but such compounds are still lacking for the Y4R. In this work, the structures of the high affinity selective (R)-argininamide-type Y1R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y1R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y1R versus Y4R subtype, resulting in comparable affinities of bivalent ligands for Y1R and Y4R (e.g. UR-MK177 ((R,R)-49): Ki = 230 nM (Y1R) and 290 nM (Y4R)). With a Ki value of 130 nM and a Kb value of 20 nM, UR-MK188 ((R,R)-51) was superior to all Y4R antagonists known to date. The S,S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S,S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R,R-configured argininamides was characteristic of the Y1R, stereochemical discrimination by the Y4R was not observed. This may pave the way to selective Y4R antagonists. 相似文献
118.
Daniella Takács Orsolya Egyed László Drahos Pál Szabó Katalin Jemnitz Mónika Szabó Zsuzsa Veres Júlia Visy József Molnár Zsuzsanna Riedl György Hajós 《Bioorganic & medicinal chemistry》2013,21(13):3760-3779
Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration–oxidation of dienes followed by Buchwald–Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity. 相似文献
119.
Xiaoke Guo Qian Yang Jing Xu Li Zhang Hongxi Chu Peng Yu Yingying Zhu Jinglian Wei Weilin Chen Yaozhong Zhang Xiaojin Zhang Haopeng Sun Yiqun Tang Qidong You 《Bioorganic & medicinal chemistry》2013,21(21):6466-6476
Atrial fibrillation (AF) is one of the common arrhythmias that threaten human health. Kv1.5 potassium channel is reported as an efficacious and safe target for the treatment of AF. In this paper, we designed and synthesized three series of compounds through modifying the lead compound RH01617 that was screened out by the pharmacophore model we reported earlier. All of the compounds were evaluated by the whole-patch lamp technology and most of them possessed potent inhibitory activities against Kv1.5. Compounds IIIi and IIIl were evaluated for the target selectivity as well as the pharmacodynamic effects in an isolated rat model. Due to the promising pharmacological behavior, compound IIIl deserves further pharmacodynamic and pharmacokinetic evaluations. 相似文献
120.
Mikhail S. Novikov Denis A. Babkov Maria P. Paramonova Anastasia L. Khandazhinskaya Alexander A. Ozerov Alexander O. Chizhov Graciela Andrei Robert Snoeck Jan Balzarini Katherine L. Seley-Radtke 《Bioorganic & medicinal chemistry》2013,21(14):4151-4157
HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[ω-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC50 values within 5.5–12 μM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure–activity relationship for the linker region. 相似文献