全文获取类型
收费全文 | 2319篇 |
免费 | 71篇 |
国内免费 | 25篇 |
出版年
2023年 | 27篇 |
2022年 | 12篇 |
2021年 | 33篇 |
2020年 | 78篇 |
2019年 | 133篇 |
2018年 | 131篇 |
2017年 | 107篇 |
2016年 | 94篇 |
2015年 | 45篇 |
2014年 | 136篇 |
2013年 | 244篇 |
2012年 | 32篇 |
2011年 | 103篇 |
2010年 | 51篇 |
2009年 | 80篇 |
2008年 | 83篇 |
2007年 | 79篇 |
2006年 | 84篇 |
2005年 | 51篇 |
2004年 | 50篇 |
2003年 | 56篇 |
2002年 | 49篇 |
2001年 | 19篇 |
2000年 | 15篇 |
1999年 | 15篇 |
1998年 | 19篇 |
1997年 | 12篇 |
1996年 | 12篇 |
1995年 | 18篇 |
1994年 | 22篇 |
1993年 | 18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 | 55篇 |
1984年 | 54篇 |
1983年 | 21篇 |
1982年 | 48篇 |
1981年 | 43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 | 6篇 |
1973年 | 16篇 |
排序方式: 共有2415条查询结果,搜索用时 70 毫秒
81.
Jean Guillon Anita Cohen Clotilde Boudot Alessandra Valle Vittoria Milano Rabindra Nath Das 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):432-459
Abstract A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in?vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in?vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays. 相似文献
82.
《Nucleosides, nucleotides & nucleic acids》2013,32(4-5):385-392
ABSTRACT Lead tetraacetate (LTA) oxidation of α-Phenyl-N-(4-biphenyl)nitrone (8) to give a new ultimate carcinogen, N-acetoxy-N-benzoyl-4-aminobiphenyl (9) which was reacted with deoxyguanosine (dG) at pH 6.9 to give nucleoside derivative, N-(benzoyl)-N-(deoxyguanosin-8-yl)-4-aminobiphenyl (10). Following debenzoylation with sodium carbonate-methanol leads to N-(2′-deoxyguanosin-8-yl)-4-aminobiphenyl (11). 相似文献
83.
《Nucleosides, nucleotides & nucleic acids》2013,32(4-5):401-409
ABSTRACT Reaction of glycosyl isothiocyanate 1a-c with 3-indolylaminomethyl-ketone hydrochloride(2) yielded glycosylthiourea derivatives 3a-c. Cyclodehydration of 3a-c with acetic anhydride afforded 5-(indol-3-yl)-2-[N-per-O-acetyl-D-glycopyranosyl)amino]thiazoles 4a-c. Deacetylation of 4a-c gave 5-(indol-3-yl)-2-[N-(D-glycopyranosyl) amino]thiazoles 5a-c. 相似文献
84.
Synthesis and biological evaluation of BMS-986120 and its deuterated derivatives as PAR4 antagonists
Panpan Chen Shenhong Ren Hangyu Song Cai Chen Fangjun Chen Qinglong Xu Yi Kong Hongbin Sun 《Bioorganic & medicinal chemistry》2019,27(1):116-124
BMS-986120 is a PAR4 antagonist that is being investigated as an antiplatelet agent in phase I clinical trial. An improved synthesis of BMS-986120 has been developed. Based on the novel synthetic approach to BMS-986120, a series of deuterated derivatives of BMS-986120 have been synthesized and biologically evaluated to search for more potent antiplatelet agents. The in vitro antiplatelet assay by turbidimetry demonstrated that PC-2 and PC-6 had IC50 values of 6.30?nM and 6.97?nM, respectively, versus BMS-986120 with an IC50 of 7.80?nM. The result of in vitro metabolic stability study showed that all of the deuterated compounds had similar half-life (T1/2) and intrinsic clearance (Clint) in comparison with BMS-986120. Further probing the metabolic profile of BMS-986120 is worth being conducted. 相似文献
85.
Muhammad Taha Sadia Sultan Syahrul Imran Fazal Rahim Khalid Zaman Abdul Wadood Ashfaq Ur Rehman Nizam Uddin Khalid Mohammed Khan 《Bioorganic & medicinal chemistry》2019,27(18):4081-4088
In searchof the potenttherapeutic agent as an α-glucosidase inhibitor, we have synthesized twenty-five analogs (1–25) of quinoline-based Schiff bases as an inhibitoragainst α-glucosidase enzyme under positive control acarbose (IC50 = 38.45 ± 0.80 µM). From the activity profile it was foundthat analogs 1, 2, 3, 4, 11, 12 and 20with IC50values 12.40 ± 0.40, 9.40 ± 0.30, 14.10 ± 0.40, 6.20 ± 0.30, 14.40 ± 0.40, 7.40 ± 0.20 and 13.20 ± 0.40 µMrespectively showed most potent inhibition among the series even than standard drug acarbose (IC50 = 38.45 ± 0.80 µM). Here in the present study analog 4 (IC50 = 6.20 ± 0.30 µM) was found with many folds better α-glucosidase inhibitory activity than the reference drug. Eight analogs like 5, 7, 8, 16, 17, 22, 24 and 25 among the whole series displayed less than 50% inhibition. The substituents effects on phenyl ring thereby superficially established through SAR study. Binding interactions of analogs and the active site of ligands proteins were confirmed through molecular docking study. Spectroscopic techniques like 1H NMR, 13C NMR and ESIMS were used for characterization. 相似文献
86.
《Bioorganic & medicinal chemistry》2019,27(18):4143-4150
Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H37Rv) strain and two isoniazid-resistant strains (INHR1 and INHR2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H37Rv and INHR1 (katG S315T) or INHR2 (inhA C(−5)T) strains. Compounds 1a, 2a, and 8a were effective against the INHR1 strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INHR2 strain, with MICs in the range of 3.12–6.25 µg/mL. Compounds 1b and 5b were the most active against H37Rv, with MIC of 0.78 µg/mL. Based on the selectivity index, 1b and 5b can be considered safe as a drug candidate compounds. These results demonstrate that quinoidal compounds can be used as promising scaffolds for the development of new anti-TB drugs and hybrids with activity against M. tuberculosis-susceptible and INH-resistant strains. 相似文献
87.
《Bioorganic & medicinal chemistry》2019,27(12):2657-2665
Two series of moscatilin derivatives were designed, synthesized and evaluated as anti-tumor and anti-angiogenesis agents. Most of these compounds showed moderate-to-obvious cytotoxicity against five cancer cell lines (A549, HepG2, MDA-MB-231, MKN-45, HCT116). Among these cell lines, compounds had obvious effects on HCT116. Especially for 8Ae, the IC50 was low to 0.25 μM. 8Ae can inhibit the viability and induce the apoptosis of HCT116 cells but exhibit no cytotoxic activity in noncancerous NCM460 colon cells. 8Ae can also arrest the G2/M cell cycle in HCT116 cells by inhibiting the α-tubulin expression. Zebrafish bioassay-guided screen showed the 22 moscatilin derivatives had potent anti-angiogenic activities and compound 8Ae had better activities than positive compound. Molecular docking indicated 8Ae interacted with tubulin at the affinity of −7.2 Kcal/mol. In conclusion, compound 8Ae was a potential antitumor and anti-angiogenesis candidate for further development. 相似文献
88.
Weiwei Li Jianjie Chu Tingting Fan Wei Zhang Minna Yao Zeqiong Ning Mingming Wang Jin Sun Xian Zhao Aidong Wen 《Bioorganic & medicinal chemistry letters》2019,29(14):1831-1835
In this investigation, a series of 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea receptor tyrosine kinase inhibitors were synthesized by a simple and efficient structure-based design. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against human chronic myeloid leukemia (CML) cell line K562, but very weak or no cellular toxicity through monitoring the growth kinetics of K562 cell during a period of 72 h using the real-time live-cell imaging. Among these compounds, 1-(5-((6-((3-morpholinopropyl) amino)pyrimidin-4-yl)thio)-1,3,4-thiadiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (7) exhibited the least cellular toxicity and better biological activity in cellular assays (K562, IC50: 0.038 μM). Compound 7 also displayed very good induced-apoptosis effect for human CML cell line K562 and exerted its effect via a significantly reduced protein phosphorylation of PI3K/Akt signal pathway by Human phospho-kinase array analysis. In vitro results indicate that 1-phenyl-3-(5-(pyrimidin-4-ylthio)-1,3,4- thiadiazol-2-yl)urea derivatives are lead molecules for further development as treatment of chronic myeloid leukemia and cancer. 相似文献
89.
Ping Yu Wenjing Liu Jinghui Ren Yingying Wang Yao Ning Mingqi Huang Xinyi Hu Lili Wei Min Ji Jin Cai 《Bioorganic & medicinal chemistry letters》2019,29(16):2168-2172
Bromodomain-containing protein 4 (BRD4) is a new therapeutic target for the treatment of diseases including cardiovascular diseases, cancer, inflammation and central nervous system (CNS) disorders. In this study, we introduced the pharmacophore of fibrates to a BRD4 inhibitor, RVX-208, to design dual-active hypolipidemic compounds, and found that some of new analogues showed favorable hypolipidemic activities. Synthetic accessibility towards this class of compounds optimized RVX-208 as well as would supply more thoughts on hypolipidemic drugs. 相似文献
90.
Dorota Żelaszczyk Magdalena Jakubczyk Karolina Pytka Anna Rapacz Maria Walczak Paulina Janiszewska Katarzyna Pańczyk Paweł Żmudzki Karolina Słoczyńska Henryk Marona Anna M. Waszkielewicz 《Bioorganic & medicinal chemistry letters》2019,29(21):126679
Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT2 receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT2A, 5-HT2B receptors and sodium channels. 相似文献