共查询到20条相似文献,搜索用时 31 毫秒
1.
Kin‐Fai Chan Dr. Yunzhe Zhao Dr. Toby W. S. Chow Clare S. W. Yan Dik Lung Ma Dr. Brendan A. Burkett Dr. Iris L. K. Wong Dr. Larry M. C. Chow Prof. Tak Hang Chan Prof. 《ChemMedChem》2009,4(4):594-614
Bivalent modulators of P‐glycoprotein : A small library of flavonoid homodimers and heterodimers was synthesized, and their in vitro activity in reversing paclitaxel resistance was evaluated along with structure–activity relationships. SAR trends indicate that flavonoid dimers with nonpolar, hydrophobic, less bulky substituents generally show more potent reversing activity. This will help guide future efforts in the search for more potent compounds.
2.
Yu Zhou Xun Ji Guannan Liu Dengyou Zhang Linxiang Zhao Hualiang Jiang Hong Liu 《Advanced Synthesis \u0026amp; Catalysis》2010,352(10):1711-1717
An efficient and convenient method was developed for the one‐pot construction of the complex polycyclic heterocycles pyrrolo[1,2‐a:2′,1′‐c]‐/pyrido[2,1‐c]pyrrolo[1,2‐a]quinoxalinones from two simple starting materials via a gold(I)‐catalyzed domino reaction. This strategy presents an atom economical and environmentally friendly transformation, in which two new C N bonds and one new C C bond are formed in a one‐pot reaction process. 相似文献
3.
1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors 下载免费PDF全文
Dr. Arnaud Hequet Dr. Olga N. Burchak Dr. Matthieu Jeanty Dr. Xavier Guinchard Dr. Emmanuelle Le Pihive Dr. Laure Maigre Pascale Bouhours Prof. Dominique Schneider Prof. Max Maurin Dr. Jean‐Marc Paris Dr. Jean‐Noël Denis Prof. Dr. Claude Jolivalt 《ChemMedChem》2014,9(7):1534-1545
The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5 mg L ?1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found. 相似文献
4.
Francisco Snchez‐Sancho Enrique Mann Bernardo Herradn 《Advanced Synthesis \u0026amp; Catalysis》2001,343(4):360-368
The palladium(0)‐catalyzed reaction of derivatives of γ‐amino‐α,β‐unsaturated esters bearing an N‐(2‐iodobenzoyl) substituent results in an intramolecular Heck reaction, the outcome of which depends on the structure of the substrate as well as on the experimental conditions. The methodology developed has been applied to the efficient syntheses of chiral isoquinoline and pyrido[1,2‐b]–isoquinoline derivatives. 相似文献
5.
Prashant S. Kharkar Dr. Angela M. Batman Juan Zhen Dr. Patrick M. Beardsley Prof. Maarten E. A. Reith Prof. Aloke K. Dutta Prof. 《ChemMedChem》2009,4(7):1075-1085
A novel series of optically active molecules based on a 4‐(2‐(benzhydryloxy)ethyl)‐1‐((R)‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.
6.
The Na+/I? symporter (NIS) mediates iodide uptake in the thyroid gland as well as in other NIS‐expressing cells. This transport is the basis for an emerging approach to selective cancer cell destruction by using radioiodide after targeted NIS gene transfer. Therapeutic efficacy requires that radioiodide retention be maximized in tumor cells. A first generation of forty imidazo[2,1‐b]thiazole derivatives as iodide efflux inhibitors is described along with the evaluation of their biological properties. Structure–activity relationship studies by using radioiodide uptake in rat thyroid‐derived cells (FRTL5) revealed that the 5,6‐dihydroimidazo[2,1‐b]thiazole heterocycle is required for activity. Introduction of electron‐donor substituents on the 3‐biphenyl moiety led to the discovery of novel potent compounds. A compound was identified with enhanced potency compared to reference 1 . These molecules give the possibility to increase the cellular retention of radioiodide in NIS‐expressing tumors, leading to higher absorbed doses and killing efficacy. 相似文献
7.
Jun Young Kim Ji Won Lee Young Soo Kim Yuno Lee Dr. Young Bae Ryu Songmi Kim Hyung Won Ryu Marcus J. Curtis‐Long Prof. Dr. Keun Woo Lee Dr. Woo Song Lee Prof. Dr. Ki Hun Park 《Chembiochem : a European journal of chemical biology》2010,11(15):2125-2131
Competitive glycosidase inhibitors are generally sugar mimics that are costly and tedious to obtain because they require challenging and elongated chemical synthesis, which must be stereo‐ and regiocontrolled. Here, we show that readily accessible achiral (E)‐1‐phenyl‐3‐(4‐strylphenyl)ureas are potent competitive α‐glucosidase inhibitors. A systematic synthesis study shows that the 1‐phenyl moiety on the urea is critical for ensuring competitive inhibition, and substituents on both terminal phenyl groups contribute to inhibition potency. The most potent inhibitor, compound 12 (IC50=8.4 μM , Ki=3.2 μM ), manifested a simple slow‐binding inhibition profile for α‐glucosidase with the kinetic parameters k3=0.005256 μM ?1 min?1, k4=0.003024 min?1, and ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$ =0.5753 μM . 相似文献
8.
6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance 下载免费PDF全文
Dr. Baomin Liu Qianqian Qiu Tianxiao Zhao Lei Jiao Prof. Yunman Li Prof. Wenlong Huang Prof. Hai Qian 《ChemMedChem》2015,10(2):336-344
P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC50=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development. 相似文献
9.
Gheorghe Roman Dr. Jason Z. Vlahakis Dr. Dragic Vukomanovic Dr. Kanji Nakatsu Prof. Walter A. Szarek Prof. 《ChemMedChem》2010,5(9):1541-1555
Previous studies by our research group have been concerned with the design of selective inhibitors of heme oxygenases (HO‐1 and HO‐2). The majority of these were based on a four‐carbon linkage of an azole, usually an imidazole, and an aromatic moiety. In the present study, we designed and synthesized a series of inhibition candidates containing a shorter linkage between these groups, specifically, a series of 1‐aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and their derivatives. As regards HO‐1 inhibition, the aromatic moieties yielding best results were found to be halogen‐substituted residues such as 3‐bromophenyl, 4‐bromophenyl, and 3,4‐dichlorophenyl, or hydrocarbon residues such as 2‐naphthyl, 4‐biphenyl, 4‐benzylphenyl, and 4‐(2‐phenethyl)phenyl. Among the imidazole‐ketones, five ( 36 – 39 , and 44 ) were found to be very potent (IC50<5 μM ) toward both isozymes. Relative to the imidazole‐ketones, the series of corresponding triazole‐ketones showed four compounds ( 54 , 55 , 61 , and 62 ) having a selectivity index >50 in favor of HO‐1. In the case of the azole‐dioxolanes, two of them ( 80 and 85 ), each possessing a 2‐naphthyl moiety, were found to be particularly potent and selective HO‐1 inhibitors. Three non‐carbonyl analogues ( 87 , 89 , and 91 ) of 1‐(4‐chlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone were found to be good inhibitors of HO‐1. For the first time in our studies, two azole‐based inhibitors ( 37 and 39 ) were found to exhibit a modest selectivity index in favor of HO‐2. The present study has revealed additional candidates based on inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications. 相似文献
10.
Romeo Romagnoli Dr. Pier Giovanni Baraldi Prof. Olga Cruz‐Lopez Dr. Delia Preti Jaime Bermejo Prof. Francisco Estévez Prof. 《ChemMedChem》2009,4(10):1668-1676
A novel series of α‐bromoacryloyl N‐substituted isatin analogues were found to inhibit the growth and viability of human myeloid leukemia HL‐60 and U‐937 cells as well as human lymphoid leukemia MOLT‐3 cells. Cell death induced by these molecules was preceded by a rapid release of cytochrome c from mitochondria into the cytosol and subsequent caspase activation involving caspase‐3, to cleave poly(ADP‐ribose) polymerase (PARP). These findings suggest that these compounds present antiproliferative activity which may be mediated by apoptosis caused by cytochrome c release and caspase activation in human leukemia cells. 相似文献
11.
Jidan Liu Zixi Xue Zhizhao Zeng Yi‐xin Chen Guoshu Chen 《Advanced Synthesis \u0026amp; Catalysis》2016,358(23):3694-3699
An efficient copper‐mediated tandem C(sp2)–H sulfenylation and annulation of arenes with 2‐mercaptoimidazoles to provide polycyclic fused imidazo[2,1‐b][1,3]thiazinones has been developed. This tandem reaction is likely initiated by C(sp2)–H thiolation of benzamide with 2‐mercaptoimidazole followed by intramolecular nucleophilic substitution of the amide carbonyl group. A notable feature of this reaction is that it can afford rather complex products in a single synthesis step from easily accessible starting materials using amide‐oxazoline as a removable bidentate directing group. A variety of benzamides and 2‐mercaptoimidazoles bearing different substituents are compatible with this transformation.
12.
He Huang Qinghua Yang Qianqian Zhang Jie Wu Yizhen Liu Chuanjun Song Junbiao Chang 《Advanced Synthesis \u0026amp; Catalysis》2016,358(7):1130-1135
Treatment of cyclobutanecarboxamide with bis(trifluoroacetoxy)iodobenzene, PhI(OCOCF3)2, resulted in the formation of 1‐pyrroline via Hofmann rearrangement of the former followed by in situ ring expansion reaction of the cyclobutylamine intermediate. Further elaboration of this methodology to the synthesis of 2,3‐dihydro‐1H‐pyrrolo[2,1‐a]isoquinolinium salts has also been described.
13.
GluN2B‐Selective N‐Methyl‐d‐aspartate (NMDA) Receptor Antagonists Derived from 3‐Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7]annulen‐7‐amines 下载免费PDF全文
Dr. Andre Benner Alessandro Bonifazi Chikako Shirataki Louisa Temme Dr. Dirk Schepmann Prof. Wilma Quaglia Prof. Osami Shoji Prof. Yoshihito Watanabe Dr. Constantin Daniliuc Prof. Dr. Bernhard Wünsch 《ChemMedChem》2014,9(4):741-751
Given their high neuroprotective potential, ligands that block GluN2B‐containing N‐methyl‐D ‐aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B‐selective NMDA receptor antagonists with the benzo[7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N‐(2‐methoxy‐5‐oxo‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐yl)acetamide ( 11 ), was obtained by cyclization of 3‐acetamido‐5‐(3‐methoxyphenyl)pentanoic acid ( 10 b ). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis‐ and trans‐configured 7‐(ω‐phenylalkylamino)benzo[7]annulen‐5‐ols. High GluN2B affinity was observed with cis‐configured γ‐amino alcohols substituted with a 3‐phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2‐methoxy‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 20 a , Ki=10 nM ) and 2‐methoxy‐N‐methyl‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 23 a , Ki=7.9 nM ). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ1 and σ2 receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo[7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit‐containing NMDA receptors was not inhibited by the new ligands. 相似文献
14.
Mei‐Jung Lai Ching‐Chuan Kuo Dr. Teng‐Kuang Yeh Dr. Hsing‐Pang Hsieh Dr. Li‐Tzong Chen Dr. Wen‐Yu Pan Kuang‐Yang Hsu Dr. Jang‐Yang Chang Dr. Jing‐Ping Liou Dr. 《ChemMedChem》2009,4(4):588-593
Combretastatin A‐4 derivatives : A series of combretastatin A‐4‐derived 1‐benzyl‐4,5,6‐trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site on the microtubule.
15.
Silvia Franchini Dr. Annalisa Tait Prof. Adolfo Prandi Dr. Claudia Sorbi Dr. Rossella Gallesi Michela Buccioni Dr. Gabriella Marucci Prof. Carla De Stefani Dr. Antonio Cilia Dr. Livio Brasili Prof. 《ChemMedChem》2009,4(2):196-203
A selective 5‐HT 1A receptor agonist : A new series of ligands acting at 5‐HT1A serotonin receptor were identified. Among them (2,2‐diphenyl‐[1,3]oxathiolan‐5‐yl‐methyl)‐(3‐phenyl‐propyl)amine (shown) possesses outstanding activity (pKi=8.72, pD2=7.67, Emax=85) and selectivity (5‐HT1A/α1D>150), and represents a new 5‐HT1A agonist chemotype.
16.
Dr. Laurent Provins Dr. Frédéric Denonne Dr. Sylvain Célanire Dr. Bernard Christophe Sabine Defays Christel Delaunoy Dr. Marie‐Laure Delporte Thierry Demaude Véronique Durieu Dr. Michel Gillard Delphine Hubert Dr. Yves Lamberty Dr. Geneviève Lorent Dr. Anne Valade Alain Vanbellinghen Nathalie Van houtvin 《ChemMedChem》2012,7(12):2087-2092
17.
New Insight into the Structure–Activity Relationships of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitors UCPH‐101 and UCPH‐102 下载免费PDF全文
Dr. Stinne W. Hansen Dr. Mette N. Erichsen Dr. Tri H. V. Huynh Dr. Josep A. Ruiz Dr. Isabell Haym Dr. Walden E. Bjørn‐Yoshimoto Dr. Bjarke Abrahamsen Jeanette Hansen Dr. Morten Storgaard Anette L. Eriksen Prof. Anders A. Jensen Prof. Lennart Bunch 《ChemMedChem》2016,11(4):382-402
In the present study, we made further investigations on the structure–activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2‐amino‐4‐(4‐methoxyphenyl)‐7‐(naphthalen‐1‐yl)‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene‐3‐carbonitrile (UCPH‐101), by exploring 15 different substituents (R1) at the 7‐position in combination with eight different substituents (R2) at the 4‐position. Among the 63 new analogues synthesized, we identified a number of compounds that unexpectedly displayed inhibitory activities at EAAT1 in light of understanding the structure–activity relationship (SAR) of this inhibitor class extracted from previous studies. Moreover, the nature of the R1 and R2 substituents were observed to contribute to the functional properties of the various analogues in additive and non‐additive ways. Finally, separation of the four stereoisomers of analogue 14 g (2‐amino‐4‐([1,1′‐biphenyl]‐4‐yl)‐3‐cyano‐7‐isopropyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromene) was carried out, and in agreement with a study of a related scaffold, the R configuration at C4 was found to be mandatory for inhibitory activity, while both the C7 diastereomers were found to be active as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g ‐ A – D showed that epimerization takes places at C7 via a ring‐opening, C?C bond rotation, ring‐closing mechanism. 相似文献
18.
Synthesis,Structure–Activity Relationship Studies,and ADMET Properties of 3‐Aminocyclohex‐2‐en‐1‐ones as Chemokine Receptor 2 (CXCR2) Antagonists 下载免费PDF全文
Weiyang Dai Dr. Wenmin Chen Dr. Bikash Debnath Prof. Yong Wu Prof. Nouri Neamati 《ChemMedChem》2018,13(9):916-930
Herein we describe the synthesis and structure–activity relationships of 3‐aminocyclohex‐2‐en‐1‐one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 μm . In silico ADMET prediction suggests that all active compounds possess drug‐like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure–activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists. 相似文献
19.
Zhigang Lv Jing Liu Wei Wei Jie Wu Wenquan Yu Junbiao Chang 《Advanced Synthesis \u0026amp; Catalysis》2016,358(17):2759-2766
An intramolecular aryl C−H amination reaction has been achieved using molecular iodine as the sole oxidant for the synthesis of benzimidazole derivatives. The required substrates were readily prepared by addition or coupling of arylamines with the corresponding nitriles or aryl iodides. Iodine‐mediated oxidative cyclization of these substrates in the presence of potassium carbonate (K2CO3) as base afforded the corresponding products in moderate to good yields. The transition metal‐free protocol presented here is insensitive to air and operationally simple. This versatile and eco‐friendly synthetic methodology is broadly applicable to a variety of N‐aryl‐substituted amidines and pyridin‐2‐amines, and provides direct access to both 1H‐benzo[d]imidazole and pyrido[1,2‐a]benzimidazole derivatives from the corresponding precursors.
20.
The sodium iodide symporter (NIS) is responsible for the accumulation of iodide in the thyroid gland. This transport process is involved in numerous thyroid dysfunctions and is the basis for human contamination in the case of exposure to radioactive iodine species. 4‐Aryl‐3,4‐dihydropyrimidin‐2(1H)‐ones were recently discovered by high‐throughput screening as the first NIS inhibitors. Described herein are the synthesis and evaluation of 115 derivatives with structural modifications at five key positions on the pyrimidone core. This study provides extensive structure–activity relationships for this new class of inhibitors that will serve as a basis for further development of compounds with in vivo efficacy and adequate pharmacokinetic properties. In addition, the SAR investigation provided a more potent compound, which exhibits an IC50 value of 3.2 nM in a rat thyroid cell line (FRTL5). 相似文献