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Bioorganic & Medicinal Chemistry

Viharika Bobba, Vishal Nanavaty, Nethrie D Idippily, Anran Zhao, Bibo Li, Bin Su
African trypanosomiasis is still a threat to human health due to the severe side-effects of current drugs. We identified selective tubulin inhibitors that showed the promise to the treatment of this disease, which was based on the tubulin protein structural difference between mammalian and trypanosome cells. Further lead optimization was performed in the current study to improve the efficiency of the drug candidates. We used Trypanosoma brucei brucei cells as the parasite model, and human normal kidney cells and mouse macrophage cells as the host model to evaluate the compounds...
April 8, 2017: Bioorganic & Medicinal Chemistry
Jekaterīna Ivanova, Fabrizio Carta, Daniela Vullo, Janis Leitans, Andris Kazaks, Kaspars Tars, Raivis Žalubovskis, Claudiu T Supuran
A series of N-substituted saccharins incorporating aryl, alkyl and alkynyl moieties, as well as some ring opened derivatives were prepared and investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC The widespread cytosolic isoforms CA I and II were not inhibited by these sulfonamides whereas transmembrane, tumor-associated ones were effectively inhibited, with KIs in the range of 22.1-481nM for CA IX and of 3.9-245nM for hCA XII. Although the inhibition mechanism of these tertiary/secondary sulfonamides is unknown for the moment, the good efficacy and especially selectivity for the inhibition of the tumor-associated over the cytosolic, widespread isoforms, make these derivatives of considerable interest as enzyme inhibitors with various pharmacologic applications...
April 7, 2017: Bioorganic & Medicinal Chemistry
Yuanbiao Tu, Caolin Wang, Shan Xu, Zhou Lan, Wei Li, Jiaqian Han, Yuanzhang Zhou, Pengwu Zheng, Wufu Zhu
Two series of quinazoline derivatives bearing aryl semicarbazone scaffolds (9a-o and 10a-o) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). The selected compound 9o was further evaluated for the inhibitory activity against EGFR kinases. Four of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 values in single-digit μM to nanomole range. Two of them are equal to more active than positive control afatinib against one or more cell lines...
April 6, 2017: Bioorganic & Medicinal Chemistry
Kensaku Nakayama, Jason P Schwans, Eric J Sorin, Trina Tran, Jeannette Gonzalez, Elvis Arteaga, Sean McCoy, Walter Alvarado
A series of dialkyl aryl phosphates and dialkyl arylalkyl phosphates were synthesized. Their inhibitory activities were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The di-n-butyl phosphate series consistently displayed selective inhibition of BChE over AChE. The most potent inhibitors of butyrylcholinesterase were di-n-butyl-3,5-dimethylphenyl phosphate (4b) [KI=1.0±0.4μM] and di-n-butyl 2-naphthyl phosphate (5b) [KI=1.9±0.4μM]. Molecular modeling was used to uncover three subsites within the active site gorge that accommodate the three substituents attached to the phosphate group...
April 5, 2017: Bioorganic & Medicinal Chemistry
Yanmei Zhao, Jiankang Zhang, Rangxiao Zhuang, Ruoyu He, Jianjun Xi, Xuwang Pan, Yidan Shao, Jinming Pan, Jingjing Sun, Zhaobin Cai, Shourong Liu, Weiwei Huang, Xiaoqing Lv
In this study, a series of novel pyridine and pyrimidine-containing derivatives were designed, synthesized and biologically evaluated for their c-Met inhibitory activities. In the biological evaluation, half of the target compounds exhibited moderate to potent c-Met inhibitory activities. Among which, it is noteworthy that compounds 13d not only showed most potent c-Met inhibitory potency but also displayed excellent anti-proliferative activity (IC50=127nM against EBC-1 cell line) as well as an acceptable kinase selectivity profile...
April 5, 2017: Bioorganic & Medicinal Chemistry
Bumki Kim, Ranjala Ratnayake, Hyunji Lee, Guqin Shi, Sabrina L Zeller, Chenglong Li, Hendrik Luesch, Jiyong Hong
Histone acetylation is an extensively investigated post-translational modification that plays an important role as an epigenetic regulator. It is controlled by histone acetyl transferases (HATs) and histone deacetylases (HDACs). The overexpression of HDACs and consequent hypoacetylation of histones have been observed in a variety of different diseases, leading to a recent focus of HDACs as attractive drug targets. The natural product largazole is one of the most potent natural HDAC inhibitors discovered so far and a number of largazole analogs have been prepared to define structural requirements for its HDAC inhibitory activity...
April 4, 2017: Bioorganic & Medicinal Chemistry
Xiaoping Tang, Melodi Demiray, Thomas Wirth, Rudolf K Allemann
Artemisinin is one of the most potent anti-malaria drugs and many often-lengthy routes have been developed for its synthesis. Amorphadiene synthase, a key enzyme in the biosynthetic pathway of artemisinin, is able to convert an oxygenated farnesyl diphosphate analogue directly to dihydroartemisinic aldehyde, which can be converted to artemisinin in only four chemical steps, resulting in an efficient synthetic route to the anti-malaria drug.
April 4, 2017: Bioorganic & Medicinal Chemistry
Verónica Egas, Estrella Millán, Juan A Collado, Teresa Ramírez-Apan, Carlos A Méndez-Cuesta, Eduardo Muñoz, Guillermo Delgado
The effects of ten natural cadinane sesquiterpenoids isolated from Heterotheca inuloides on the pathways of the NF-κB, Nrf2 and STAT3 transcription factors were studied for the first time. The main constituent in this species, 7-hydroxy-3,4-dihydrocadalene (1), showed anti-NF-κB activity and activated the antioxidant Nrf2 pathway, which may explain the properties reported for the traditional use of the plant. In addition to the main metabolite, a structurally similar compound, 7-hydroxy-cadalene (2), also displayed anti-NF-κB activity...
April 2, 2017: Bioorganic & Medicinal Chemistry
Yanqing Pang, Jun Yan, Baijiao An, Ling Huang, Xingshu Li
A series of new butadiene derivatives was synthesized and evaluated as tubulin polymerization inhibitors for the treatment of cancer. The optimal butadiene derivative, 9a, exhibited IC50 values of 0.056-0.089μM for five human cancer cell lines. This paper included a mechanistic study of the antiproliferative activity, including a tubulin polymerization assay, an examination of morphological alterations of cancer cells, an analysis of cell cycle arrest and an apoptosis assay.
April 1, 2017: Bioorganic & Medicinal Chemistry
Suleyman Akocak, Nabih Lolak, Alessio Nocentini, Gulcin Karakoc, Anzel Tufan, Claudiu T Supuran
A series of sixteen novel aromatic and heterocyclic bis-sulfonamide Schiff bases were prepared by conjugation of well known aromatic and heterocyclic aminosulfonamide carbonic anhydrase (CA, EC inhibitor pharmacophores with aromatic and heterocyclic bis-aldehydes. The obtained bis-sulfonamide Schiff bases were investigated as inhibitors of four selected human (h) CA isoforms, hCA I, hCA II, hCA VII and hCA IX. Most of the newly synthesized compounds showed a good inhibitory profile against isoforms hCA II and hCA IX, also showing moderate selectivity against hCA I and VII...
March 31, 2017: Bioorganic & Medicinal Chemistry
Anna M Varizhuk, Timofei S Zatsepin, Andrey V Golovin, Evgeny S Belyaev, Yury I Kostyukevich, Vladimir G Dedkov, German A Shipulin, George V Shpakovski, Andrey V Aralov
Nowadays modified oligonucleotides are widely used in diagnostics and as novel therapeutics. Introduction of modified or unnatural residues into oligonucleotides allows fine tuning of their binding properties to complementary nucleic acids and leads to improved stability both in vitro and in vivo. Previously it was demonstrated that insertion of phenoxazine nucleotides with various groups in C9-position into oligonucleotides leads to a significant increase of duplex stability with complementary DNA and RNA...
March 31, 2017: Bioorganic & Medicinal Chemistry
Ahmed Mohammed, Jennifer Sneathen, Sara Glazier Frojen, Louis Kuo, Cynthia M Dupureur
The inhibition kinetics and stereospecificity of the chiral nerve agent derivative O,S-diethylphenylphosphonothioate (DEPP) were examined for two forms of acetylcholinesterase (human and eel) and equine butyrylcholinesterase. Both S- and R-DEPP are poor inhibitors of eel AChE (IC50 150μM), consistent with a large, nondiscriminatory binding interaction in the active site of this enzyme. However, S-DEPP is active against human and equine AChE with low μM IC50s. DEPP stereospecificities (S/R) toward these enzymes are moderate (20) relative to other cholinesterase-organophosphate (OP) systems...
March 30, 2017: Bioorganic & Medicinal Chemistry
Jun Fujimoto, Takaharu Hirayama, Yasuhiro Hirata, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R Cary
In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50: 2...
March 30, 2017: Bioorganic & Medicinal Chemistry
Bin Zhao, John Sensintaffar, Zhiguo Bian, Johannes Belmar, Taekyu Lee, Edward T Olejniczak, Stephen W Fesik
Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum...
March 29, 2017: Bioorganic & Medicinal Chemistry
Hiroaki Ohno, Maho Honda, Naoka Hamada, Jun Miyagaki, Akira Iwata, Kazuhiro Otsuki, Toru Maruyama, Shinya Nakamura, Isao Nakanishi, Shinsuke Inuki, Nobutaka Fujii, Shinya Oishi
We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity...
March 29, 2017: Bioorganic & Medicinal Chemistry
Susanna Nencetti, Concettina La Motta, Armando Rossello, Stefania Sartini, Elisa Nuti, Lidia Ciccone, Elisabetta Orlandini
Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest...
March 28, 2017: Bioorganic & Medicinal Chemistry
Sheng-Biao Wang, Mu-Tian Cui, Xiao-Feng Wang, Emika Ohkoshi, Masuo Goto, De-Xuan Yang, Linna Li, Shoujun Yuan, Susan L Morris-Natschke, Kuo-Hsiung Lee, Lan Xie
No abstract text is available yet for this article.
March 28, 2017: Bioorganic & Medicinal Chemistry
Haroon Mohammad, Kwaku Kyei-Baffour, Waleed Younis, Dexter C Davis, Hassan Eldesouky, Mohamed N Seleem, Mingji Dai
Invasive fungal infections present a formidable global public health challenge due to the limited number of approved antifungal agents and the emergence of resistance to the frontline treatment options, such as fluconazole. Three fungal pathogens of significant concern are Candida, Cryptococcus, and Aspergillus given their propensity to cause opportunistic infections in immunocompromised individuals. New antifungal agents composed of unique chemical scaffolds are needed to address this public health challenge...
March 27, 2017: Bioorganic & Medicinal Chemistry
Alice Tamburrini, Silvia Achilli, Francesca Vasile, Sara Sattin, Corinne Vivès, Cinzia Colombo, Franck Fieschi, Anna Bernardi
The synthesis and conformational analysis of pseudo-thio-1,2-dimannoside are described. This molecule mimics mannobioside (Manα(1,2)Man) and is an analog of pseudo-1,2-dimannoside, with expected increased stability to enzymatic hydrolysis. A short and efficient synthesis was developed based on an epoxide ring-opening reaction by a mannosyl thiolate, generated in situ from the corresponding thioacetate. NMR-NOESY studies supported by MM3(∗) calculations showed that the pseudo-thio-1,2-dimannoside shares the conformational behavior of the pseudo-1,2-dimannoside and is a structural mimic of the natural disaccharide...
March 22, 2017: Bioorganic & Medicinal Chemistry
Kamel Metwally, Omar Aly, Enayat Aly, Abhijit Banerjee, Rudravajhala Ravindra, Susan Bane
No abstract text is available yet for this article.
March 21, 2017: Bioorganic & Medicinal Chemistry
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