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Ramilya R Starodubtseva, Elmira M Gibadullina, Nurbala B Pazilova, Anastasiia S Sapunova, Alexandra D Voloshina, Igor A Sudakov, Alexandra B Vyshtakalyuk, Michael A Pudovik, Alexander R Burilov, Sergey V Bukharov
Here, we present an approach to novel "hybrid" biologically active compounds based on a combination of sterically hindered phenol and ammonium pharmacophores in a single molecule. The novel target ammonium salts were obtained by the reaction of 3-(3,5-di- tert -butyl-4-hydroxyphenyl)- N -(2-(dimethylamino)alkyl)propanamide with aliphatic bromides or by the reaction of phosphorylated methylenequinones with diamines followed by alkylation with organic bromides. A series of twenty-three novel multifunctional ammonium salts that contain a sterically hindered phenolic fragment were assessed for antimicrobial, cytotoxic and antioxidant activity...
December 1, 2018: MedChemComm
Li Liu, Wanqi Wang, Jin Huang, Zhenjiang Zhao, Honglin Li, Yufang Xu
CA IX has attracted much attention as a promising target for the development of new anticancer agents. In this study, a series of sulfonamide derivatives were designed and synthesized as potential CA IX inhibitors from a lead compound (benzoyl thioureido benzene sulfonamide) discovered by virtual screening. The bioassay demonstrated that some of the synthesized compounds exhibited potent inhibitory activity against CA IX in the subnanomolar range and high selectivity over isozymes CA I and CA II. Among them, compound 6a displayed inhibitory activity against CA IX with an IC50 value of 0...
December 1, 2018: MedChemComm
Fengyi Zhao, Wen Lu, Fan Su, Li Xu, Dong Jiang, Xu Sun, Jiuzhou Shi, Mengyi Zhou, Feng Lin, Fuliang Cao
To seek more efficient and lower toxicity anticancer compounds, several imidazole combining dehydroabietylamine derivatives including organic salts ( L 1 - L 2 ) and amides ( L 3 - L 5 ) were synthesized. Their antineoplastic activity against HeLa (cervix), MCF-7 (breast), A549 (lung) and HepG2 (liver) cells and HUVECs (umbilical vein, normal cells) in vitro were evaluated by MTT assay. The results unequivocally showed that nearly all compounds had better antineoplastic activity and lower toxicity than dehydroabietylamine ( L 0 )...
December 1, 2018: MedChemComm
Iman Daryaei, Karin Sandoval, Ken Witt, Maria Kontoyianni, A Michael Crider
A series of compounds containing a 1,2,4-triazole moiety were synthesized, targeting the somatostatin receptor subtype-4 (sst4 ). Compounds were developed in which the Phe6 /Phe7 /Phe11 , Trp8 , and Lys9 mimetic groups were interchanged at positions 3, 4, and 5 of the 1,2,4-triazole ring. The 1,2,4-triazoles containing an 2-(imidazol-4-yl)ethyl substituent at position-3 demonstrated moderate binding affinity at sst4 . 1,2,4-Triazoles containing an (indol-3-yl)methyl substituent at position-5 lacked affinity at sst4 ...
December 1, 2018: MedChemComm
Kseniya S Kovaleva, Fedor I Zubkov, Nikolay I Bormotov, Roman A Novikov, Pavel V Dorovatovskii, Victor N Khrustalev, Yuriy V Gatilov, Vladimir V Zarubaev, Olga I Yarovaya, Larisa N Shishkina, Nariman F Salakhutdinov
The design and synthesis of a series of novel d-(+)-camphor N -acylhydrazones exhibiting inhibitory activity against vaccinia and influenza viruses are presented. An easy pathway to camphor-based N -acylhydrazones containing in their structure aliphatic, aromatic, and heterocyclic pharmacophore scaffolds has been developed. The conformation and configuration of the synthesized hydrazones were thoroughly characterized by a complete set of spectral characterization techniques, including 2D NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis...
December 1, 2018: MedChemComm
Brigitte Renoux, Laure Fangous, Camille Hötten, Elodie Péraudeau, Balkis Eddhif, Pauline Poinot, Jonathan Clarhaut, Sébastien Papot
We report on the synthesis, in vitro and in vivo biological evaluations of a dimeric β-glucuronidase-responsive albumin-binding prodrug designed for the double release of MMAE upon a single enzymatic activation step. This prodrug produced a significant antitumour activity in mice bearing subcutaneous LS174T colorectal adenocarcinoma xenografts without inducing side effects.
December 1, 2018: MedChemComm
Gianluigi Lauro, Vincenza Cantone, Marianna Potenza, Katrin Fischer, Andreas Koeberle, Oliver Werz, Raffaele Riccio, Giuseppe Bifulco
Targeting microsomal prostaglandin E2 synthase-1 (mPGES-1) represents an efficient strategy for the development of novel drugs against inflammation and cancer with potentially reduced side effects. With this aim, a virtual screening was performed on a large library of commercially available molecules using the X-ray structure of mPGES-1 co-complexed with a potent inhibitor. Combining fast ligand-based shape alignment, molecular docking experiments, and qualitative analysis of the binding poses, a small set of molecules was selected for the subsequent steps of validation of the biological activity...
December 1, 2018: MedChemComm
Jovana Francuz, Mirjana Popsavin, Sanja Djokić, Vesna Kojić, Tatjana Srdić-Rajić, Marko V Rodić, Dimitar Jakimov, Velimir Popsavin
Novel goniofufurone ( 1 ) and 7- epi -goniofufurone ( 2 ) derivatives bearing a methoxy group at the C-5 and/or C-7 positions were prepared and their in vitro antitumour activity against some human tumour cell lines was evaluated. Some of the analogues displayed powerful antiproliferative effects against the studied tumour cells, but almost all of them were non-cytotoxic toward the normal cells (MRC-5). A SAR study reveals that the introduction of a methoxy group at the C-7 position may increase the antiproliferative effects of the analogues...
December 1, 2018: MedChemComm
Enrico Speri, Jennifer Fishovitz, Shahriar Mobashery
Methicillin-resistant Staphylococcus aureus (MRSA) is a global public health threat. MRSA has evolved a complex set of biochemical processes that mobilize the organism for inducible resistance on challenge by β-lactam antibiotics. Interfering pharmacologically with this machinery has the potential to reverse the β-lactam-resistance phenotype, whereby susceptibility to obsolete antibiotics would be restored. We describe herein our discovery of one class of such agents, the cinnamamide family of antibiotic potentiators...
December 1, 2018: MedChemComm
Anna G Cooper, Caitlin R M Oyagawa, Jamie J Manning, Sameek Singh, Sarah Hook, Natasha L Grimsey, Michelle Glass, Joel D A Tyndall, Andrea J Vernall
Cannabinoid type 2 (CB2 ) receptor has been implicated in several diseases and conditions, however no CB2 receptor selective drugs have made it to market. The aim of this study was to develop fluorescent ligands as CB2 receptor tools, to enable an increased understanding of CB2 receptor expression and signalling and thereby accelerate drug discovery. Fluorescent ligands have been successfully developed for other receptors, however none with adequate subtype selectivity or imaging properties have been reported for CB2 receptor...
December 1, 2018: MedChemComm
Michele Tonelli, Elena Cichero, Alì Mokhtar Mahmoud, Alessandro Rabbito, Bruno Tasso, Paola Fossa, Alessia Ligresti
Herein we continued our previous work on the development of CB2 ligands, reporting the design and synthesis of a series of benzimidazole-containing derivatives that were explored as selective CB2 ligands with binding affinity towards both CB1 and CB2 receptors. Seven out of eighteen compounds exhibited preferential binding ability to CB2 over CB1 receptors with potencies in the sub-micromolar or low micromolar range. In particular, we identified two promising hit compounds, the agonist 1-[2-( N , N -diethylamino)ethyl]-2-(4-ethoxybenzyl)-5-trifluoromethylbenzimidazole ( 3 ) (CB2: K i = 0...
December 1, 2018: MedChemComm
Clinton G L Veale, Heinrich C Hoppe
This study aimed to uncover new starting points for anti-trypansomal drug discovery through the screening of the Pathogen Box against Trypanosoma brucei brucei . Our study identified compounds 35 , 39 , 46 , 53 and 56 whose activity and selectivity highlighted them as promising candidates with potential for further study and optimisation.
December 1, 2018: MedChemComm
Sara N Journey, Stephanie L Alden, Will M Hewitt, Megan L Peach, Marc C Nicklaus, John S Schneekloth
Non-B DNA structures represent intriguing and challenging targets for small molecules. For example, the promoter of the HRAS oncogene contains multiple G-quadruplex and i-motif structures, atypical globular folds that serve as molecular switches for gene expression. Of the two, i-motif structures are far less studied. Here, we report the first example of small organic compounds that directly interact with the hras -1Y i-motif. We use a small molecule microarray screen to identify drug-like small molecules that bind to the hras -1Y i-motif but not to several other DNA or RNA secondary structures...
December 1, 2018: MedChemComm
Rama Alhasan, Ammar Kharma, Muhammad Jawad Nasim, Ahmad Yaman Abdin, Justine Bonetti, Philippe Giummelly, Chukwunonso E C C Ejike, Pierre Leroy, Caroline Gaucher, Claus Jacob
S -Nitrosothiols are ˙NO releasing agents renowned for vasodilatory and antioxidant properties. O2 ˙- promotes their decomposition, forming highly aggressive peroxynitrite ions (ONOO- ). Since the production of O2 ˙- can be controlled by enzymes or by visible light, such otherwise harmless components can be turned into effective antimicrobial and nematicidal combinations with numerous potential applications in medicine.
December 1, 2018: MedChemComm
Gary B Evans, Vern L Schramm, Peter C Tyler
In the absence of industry partnerships, most academic groups lack the infrastructure to rationally design and build drugs via methods used in industry. Instead, academia needs to work smarter using mechanism-based design. Working smarter can mean the development of new drug discovery paradigms and then demonstrating their utility and reproducibility to industry. The collaboration between Vern Schramm's group at the Albert Einstein College of Medicine, USA and Peter Tyler at the Ferrier Research Institute at The Victoria University of Wellington, NZ has refined a drug discovery process called transition state analogue design...
December 1, 2018: MedChemComm
Shuheng Huang, Hu Mei, Duo Zhang, Yubin Ren, MuliadiYeremia Kevin, Xianchao Pan
Toll-like receptors (TLRs) are important pattern recognition receptors to human innate immunity, which can recognize pathogen-associated molecular patterns and initiate innate immune responses. As the receptor of single stranded RNA (ssRNA), toll-like receptor 8 (TLR8) has potential in the treatment of tumors, microbial infection, and inflammatory diseases. Herein, an emerging chemical pattern (ECP) method was utilized to predict the key chemical patterns of TLR8 agonists. Based on the ECPs discovered, a robust and predictive ECP model was derived with prediction accuracies of 83...
November 1, 2018: MedChemComm
Xueyan Hou, Hao Luo, Mengqi Zhang, Guoyi Yan, Chunlan Pu, Suke Lan, Rui Li
A series of novel 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1 H )-one derivatives were synthesized and their anti-cancer as well as cisplatin sensitization activities were evaluated. Among them, compounds 6e and 6h exhibited significant cisplatin sensitization activity against HCT116. Hoechst staining and annexin V-FITC/PI dual-labeling studies demonstrated that the combination of 6e / 6h and cisplatin can induce tumour cell apoptosis. Western blot showed that the expression of ATR downstream protein, CHK1, decreased in 6e + cisplatin and 6h + cisplatin groups compared with that in the test compound and cisplatin group...
November 1, 2018: MedChemComm
Katarzyna Pańczyk, Dorota Żelaszczyk, Paulina Koczurkiewicz, Karolina Słoczyńska, Elżbieta Pękala, Ewa Żesławska, Wojciech Nitek, Paweł Żmudzki, Henryk Marona, Anna Waszkielewicz
A series of 17 new phenoxyacetamides has been prepared via multistep chemical synthesis as a continuation of the research carried out by our group on di- and tri-substituted phenoxyalkyl and phenoxyacetyl derivatives of amines. The obtained compounds vary in an amide component, for example aminoalkanol or (un)modified amino acid moieties were introduced. The structures of selected products were confirmed by means of crystallographic methods. All 17 compounds were the subject of preliminary screening for potential anticonvulsant activity (MES, 6 Hz and/or scMET tests) and neurotoxicity (rotarod) in mice after intraperitoneal administration, while several active compounds were subsequently examined in additional models ( e...
November 1, 2018: MedChemComm
Jinha Yu, Philip Mannes, Young-Hwan Jung, Antonella Ciancetta, Amelia Bitant, David I Lieberman, Sami Khaznadar, John A Auchampach, Zhan-Guo Gao, Kenneth A Jacobson
Recognition of nucleosides at adenosine receptors (ARs) is supported by multiple X-ray structures, but the structure of an adenine complex is unknown. We examined the selectivity of predicted A1 AR and A3 AR adenine antagonists that incorporated known agonist affinity-enhancing N 6 and C2 substituents. Adenines with A1 AR-favoring N 6 -alkyl, cycloalkyl and arylalkyl substitutions combined with an A3 AR-favoring 2-((5-chlorothiophen-2-yl)ethynyl) group were human (h) A3 AR-selective, e.g. MRS7497 17 (∼1000-fold over A1 AR)...
November 1, 2018: MedChemComm
Yumeng Zhang, Weihui Yuan, Xude Wang, Hongyu Zhang, Yuanyuan Sun, Xiaoshu Zhang, Yuqing Zhao
Panaxadiol (PD), a diol-type ginseng saponin, with a dammarane skeleton plays a potential role in the apoptosis of tumor cells. In this study, 28 oxidation and nitrogen hybrid derivatives of PD were synthesized, of which 20 were novel compounds. All the obtained compounds were screened for their cytotoxic activity in six cell lines. As compared with the positive control, some compounds showed better anti-proliferative activities while having much weaker effect on the growth of normal cells. Among them, ring-A fused pyrazoline of PD ( 1j ) displayed impressive cytotoxic activity with IC50 9...
November 1, 2018: MedChemComm
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