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Kartikey Singh, Prince Joshi, Rohit Mahar, Pragati Baranwal, Sanjeev K Shukla, Renu Tripathi, Rama Pati Tripathi
A series of homologous C -nucleoside mimics have been synthesized via an efficient and facile synthetic protocol involving the conjugate addition of purine to sugar derived olefinic ester in good yields. The synthesized compounds were evaluated for their antiplasmodial activity in vitro against both the CQ-sensitive and resistant strains of P. falciparum . Interestingly, all the synthesized nucleoside analogs exhibited an IC50 of <5 μM, while compounds 22a , 23a , and 23b showed promising antiplasmodial activity with an IC50 of 1...
July 1, 2018: MedChemComm
Ye Guo, Pan-Pan Zhou, Sen-Yan Zhang, Xiao-Wen Fan, Yu-Wei Dou, Xuan-Ling Shi
AIDS has evolved from a fatal infectious disease to a manageable chronic disease under the treatment of anti-AIDS medications. HIV fusion inhibitors with high activity, low side effects and strong selectivity are promising drugs against HIV. Only one fusion inhibitor is currently approved, thereby highly active long-acting fusion inhibitors need to be developed for long-term AIDS treatment. Here, we synthesised MT-SC22EK (a small HIV fusion inhibitor) derivatives containing 1-2 staples to improve its stability...
July 1, 2018: MedChemComm
Anirudha Karvande, Shahnawaz Khan, Irfan Khan, Deepti Singh, Vikram Khedgikar, Priyanka Kushwaha, Naseer Ahmad, Priyanka Kothari, Anupam Dhasmana, Ruchir Kant, Ritu Trivedi, Prem M S Chauhan
β-Carbolines have been assessed for osteoclastogenesis. However, their effect on osteoblasts during estrogen deficiency is still unclear. Here, a series of novel piperazine and tetrazole tag β-carbolines have been synthesized and examined for osteoblast differentiation in vitro . In vitro data suggest that compound 8g is the most promising osteoblast differentiating agent that was evaluated for in vivo studies. Compound 8g promoted osteoblast mineralization, stimulated Runx2, BMP-2 and OCN expression levels, increased BrdU incorporation and inhibited generation of free radicals as well as nitric oxide...
July 1, 2018: MedChemComm
M Trisha C Ang, Roger Gumbau-Brisa, David S Allan, Robert McDonald, Michael J Ferguson, Bruce E Holbein, Matthias Bierenstiel
Depriving microorganisms of bioavailable iron is a promising strategy for new anti-infective agents. The new, highly water-soluble, low molecular weight co-polymer DIBI was developed to selectively bind iron(iii) ions as a tris chelate and acts as a standalone anti-infective. Minimum inhibitory concentration (MIC) studies show DIBI is effective against representative reference strains for Gram-positive and Gram-negative bacteria S. aureus and A. baumannii , and the fungus C. albicans . Compared to the small molecule iron chelators, deferiprone and deferoxamine, DIBI outclassed these by factors of 100 to 1000 for inhibition of initial growth...
July 1, 2018: MedChemComm
Penghui Li, Wenjin Zhang, Hong Jiang, Yongliang Li, Changzhi Dong, Huixiong Chen, Kun Zhang, Zhiyun Du
In this study, a series of benzimidazole-rhodanine conjugates were designed, synthesized and investigated for their topoisomerase II (Topo II) inhibitory and cytotoxic activities. The results from Topo II-mediated pBR322 DNA relaxation and cleavage assays showed that the synthesized compounds might act as Topo II catalytic inhibitors. Certain compounds displayed potent Topo II inhibition at 10 μM. The cytotoxic activities of these compounds against HeLa, A549, Raji, PC-3, MDA-MB-201, and HL-60 cancer cell lines were evaluated...
July 1, 2018: MedChemComm
Yves Ruff, Frédéric Berst
Herein, we describe the development of copper-catalyzed cross-coupling of DNA-conjugated aryl iodides with aliphatic amines. This protocol leverages a novel ligand, 2-((2,6-dimethoxyphenyl)amino)-2-oxoacetic acid, to effect the transformation in aqueous DMSO, under mild conditions and in air, making it an ideal candidate for the synthesis of DNA-encoded libraries.
July 1, 2018: MedChemComm
Bin Sun, Hong Zhang, Min Liu, Zhuang Hou, Xinyong Liu
With the increasing incidence of pathogenic fungi and drug-resistant fungi in clinic, it has become very important to develop the novel rate-limiting enzyme 14α-demethylase (CYP51) as an antifungal inhibitor. In this study, a method involving structure-based virtual screening was employed. First, a publicly available database was obtained from the Dow Chemical Company, and the database was screened by the designed pharmacophore model of CYP51 inhibitors. Then, the pharmacophore search hits were docked into the CYP51 crystal structure...
July 1, 2018: MedChemComm
Cheng Chen, Yang Xiang, Ya Liu, Xiangdong Hu, Ke-Wu Yang
The 'superbug' infection caused by metallo-β-lactamases (MβLs) including L1 has grown into an emerging threat. To probe whether mercaptoacetate thioesters inhibiting L1 is a contribution of the thioester itself or its hydrolysate, ten mercaptoacetate thioesters 1-10 were synthesized, which specifically inhibited L1, exhibiting IC50 values ranging from 0.17 to 1.2 μM, and 8 was found to be the best inhibitor (IC50 = 0.17 μM). These thioesters restored the antimicrobial activity of cefazolin against E. coli expressing L1 by 2-4-fold...
July 1, 2018: MedChemComm
Chandrani Nath, Vishnu Nayak Badavath, Abhishek Thakur, Gulberk Ucar, Orlando Acevedo, Mohd Usman Mohd Siddique, Venkatesan Jayaprakash
A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1 H -pyrazol-3-yl)phenol (pyrazoline) derivatives ( 2-6 ) have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative ( 2 ) behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity ( K i (hMAO-B)/ K i (hMAO-A) > 1751). In addition, 2 exhibited little to no cytotoxic effects up to a 25 μM concentration and provided the best blood-brain barrier permeability among the derivatives synthesized...
July 1, 2018: MedChemComm
Artem R Khabibullin, Aleksandra Karolak, Mikalai M Budzevich, Mark L McLaughlin, David L Morse, Lilia M Woods
The successful delivery of toxic cargo directly to tumor cells is of primary importance in targeted (α) particle therapy. Complexes of radioactive atoms with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelating agent are considered as effective materials for such delivery processes. The DOTA chelator displays high affinity to radioactive metal isotopes and retains this capability after conjugation to tumor targeting moieties. Although the α-decay chains are well defined for many isotopes, the stability of chelations during the decay process and the impact of released energy on their structures remain unknown...
July 1, 2018: MedChemComm
Arpita Ghosh, Natalya Degyatoreva, Casey Kukielski, Sandra Story, Sayantan Bhaduri, Krishnagopal Maiti, Smita Nahar, Arjun Ray, Dev P Arya, Souvik Maiti
Epithelial to mesenchymal transition (EMT) is a process in which epithelial cells lose cell polarity and cell-cell adhesion and gain migratory and invasive properties to become mesenchymal cells that are very vital for development, wound healing and stem cell behavior and contribute pathologically to fibrosis and cancer progression. miR21, a potent regulator of the tumor suppressor gene PTEN, can be silenced to reverse EMT, thereby providing an attractive target for abrogating the malignant behavior of breast cancer...
July 1, 2018: MedChemComm
Guoqiang Dong, Ying Wu, Ying Sun, Na Liu, Shanchao Wu, Wannian Zhang, Chunquan Sheng
Human DNA topoisomerase II (Top2) is a promising target for cancer treatment. To overcome the limitations of known Top2 inhibitors, novel Top2 catalytic inhibitors with new scaffolds were identified by structure-based virtual screening. In particular, compound 8 showed good in vitro antiproliferative activity with a broad spectrum. Top2-mediated cleavage assay and molecular modeling rationalized the mode of action. The new Top2 inhibitors are considered as good starting points for further hit-to-lead optimization in anticancer drug discovery...
July 1, 2018: MedChemComm
Junrong Song, Junjie Lan, Chao Chen, Shengcao Hu, Jialei Song, Wulin Liu, Xueyi Zeng, Huayong Lou, Yaacov Ben-David, Weidong Pan
Twenty-four 14-sulfonamide-tetrandrine derivatives as potential anti-cancer agents were synthesized. The synthetic derivatives were investigated for their cytotoxic activity against human cancer cell lines MDA-MB-231, PC3, WM9, HEL and K562. Initially, the IC50 values (50% inhibitory concentrations) of all of the compounds were determined. These derivatives exhibited potent, but distinct, inhibitory effects on the above-mentioned cell lines. Among them, compound 23 , which was modified with a 2-naphthalenesulfonyl group at the 14-amino position, showed impressive inhibition of all five cancer cell lines, and especially of MDA-MB-231 cells with an IC50 value of 1...
July 1, 2018: MedChemComm
Ashruba B Danne, Amit S Choudhari, Shakti Chakraborty, Dhiman Sarkar, Vijay M Khedkar, Bapurao B Shingate
We describe the synthesis of novel triazole-incorporated diindolylmethanes (DIMs) using a molecular hybridization approach. The in vitro antitubercular activity of the DIMs against Mycobacterium tuberculosis H37Ra (ATCC 25177) was tested in the active and dormant state. Among all the synthesized conjugates, the compounds 6b , 6f , 6l , 6n , 6q , 6r , and 6s displayed good antitubercular activity against both the active and dormant Mtb H37Ra strain. The compound 6l exhibited good antitubercular activity against dormant Mtb H37Ra with an IC50 value of 1 μg mL-1 and IC90 (MIC) value of 3 μg mL-1 ...
July 1, 2018: MedChemComm
Lea Lough, Dan Sherman, Eric Ni, Lauren M Young, Bing Hao, Timothy Cardozo
Skp2 is a member of the F-box family of proteins that serve as substrate-specific adaptors in Skp1-CUL1-ROC1-F-box (SCF) E3 ubiquitin ligases. Skp2 (Fbxl1) directly binds to the tumor suppressor p27 in the context of the SCFSkp2 E3 ubiquitin ligase to ubiquitylate and target-phosphorylated p27 for proteasomal degradation. As p27 is a powerful suppressor of growth in a variety of cells, and as Skp2 is also overexpressed in many human cancers, Skp2 is considered an oncogene and an intriguing drug target. However, despite 20 years of investigation, a valid chemical inhibitor of Skp2-mediated degradation of p27 has not been identified...
July 1, 2018: MedChemComm
Andrew M Riley, Judith Unterlass, Vera Konieczny, Colin W Taylor, Thomas Helleday, Barry V L Potter
Diphosphoinositol phosphates (PP-InsPs) are inositol phosphates (InsPs) that contain PP (diphosphate) groups. Converting a phosphate group in an InsP into a diphosphate has been reported to enhance affinity for some binding proteins. We synthesised 1-PP-Ins(4,5)P2 , the first diphosphate analogue of the intracellular signalling molecule InsP3 , and examined its effects on InsP3 receptors, which are intracellular Ca2+ channels. 1-PP-Ins(4,5)P2 was indistinguishable from InsP3 in its ability to bind to and activate type 1 InsP3 receptors, indicating that the diphosphate modification of InsP3 affected neither affinity nor efficacy...
July 1, 2018: MedChemComm
Mohammad Abdel-Halim, Ashraf H Abadi, Matthias Engel
Much light has been shed on the vital role of protein kinase Czeta (PKCζ) in NF-κB activation and the potential use of PKCζ inhibitors as anti-inflammatory agents. We previously reported a series of 1,3,5-trisubstituted pyrazolines as potent and selective allosteric inhibitors of PKCζ; in that series of compounds, the phenolic OH at the 5-phenyl was essential for binding to the PKCζ PIF pocket. In the present study, we surprisingly found that replacing it by a halogen and at the same time moving the OH to the 3-phenyl still resulted in active compounds...
June 1, 2018: MedChemComm
Moustafa T Gabr, Mohammed S Abdel-Raziq
We designed and synthesized a new biphenyl amide-tryptamine hybrid molecule 7 utilizing a pharmacophore-based approach as a 5-HT2B antagonist. The hybrid compound 7 was evaluated for its affinity to a panel of seven 5-HT receptors, demonstrating high selectivity for the 5-HT2B receptor. Functional assays revealed potent antagonism of 5-HT2B by 7 with an IC50 value of 14.1 nM. Moreover, compound 7 possessed a desirable in vitro pharmacokinetic profile and maintained its antagonistic potency in the presence of physiological concentrations of serum proteins...
June 1, 2018: MedChemComm
Fang Shi, Jinglei Li, Ziyang Ye, Liuqing Yang, Tingting Chen, Xue Chen, Ming Ye
In the present study, we investigated the anti-tumor activities of the intracellular homogeneous melanin (LM) of Lachnum YM226 and its derivative (ALM) on liver cancer using murine H22 hepatocarcinoma model. The results showed that LM and ALM (50 and 200 mg kg-1 ) could effectively inhibit tumor growth of H22 tumour-bearing mice. The body weight, liver, spleen and thymus indices also improved in the LM and ALM treated groups. Moreover, the levels of alanine aminotransferase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), creatinine (CRE), blood urea nitrogen (BUN) and uric acid (UA) were lowered...
June 1, 2018: MedChemComm
Wuji Sun, Shubiao Fang, Hong Yan
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive target for cancer therapy. In our effort, a novel series of picolinamide-based derivatives were designed and synthesized as potent and effective VEGFR-2 inhibitors. All the newly prepared compounds were evaluated in vitro for their antiproliferative activity against A549 and HepG2 cell lines. Among the new compounds, 8j and 8l exhibited better activity against both A549 and HepG2 cell lines...
June 1, 2018: MedChemComm
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