journal
https://read.qxmd.com/read/31673311/synthesis-of-bicyclic-1-4-thiazepines-as-novel-anti-trypanosoma-brucei-brucei-agents
#61
JOURNAL ARTICLE
Franco Vairoletti, Andrea Medeiros, Pablo Fontán, Jennifer Meléndrez, Carlos Tabárez, Gustavo Salinas, Jaime Franco, Marcelo A Comini, Jenny Saldaña, Vojtech Jancik, Graciela Mahler, Cecilia Saiz
1,4-Thiazepines derivatives are pharmacologically important heterocycles with different applications in medicinal chemistry. In the present work, we describe the preparation of new bicyclic thiazolidinyl-1,4-thiazepines 3 by reaction between azadithiane compounds and Michael acceptors. The reaction scope was explored and the yields were optimized. The activity of the new compounds was evaluated against Nippostrongylus brasiliensis and Caenorhabditis elegans as anthelmintic models and Trypanosoma brucei brucei...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31673310/exploration-of-2-2-2-cyclotrimerisation-methodology-to-prepare-tetrahydroisoquinoline-based-compounds-with-potential-aldo-keto-reductase-1c3-target-affinity
#62
JOURNAL ARTICLE
Ana R N Santos, Helen M Sheldrake, Ali I M Ibrahim, Chhanda Charan Danta, Davide Bonanni, Martina Daga, Simonetta Oliaro-Bosso, Donatella Boschi, Marco L Lolli, Klaus Pors
Tetrahydroisoquinoline (THIQ) is a key structural component in many biologically active molecules including natural products and synthetic pharmaceuticals. Here, we report on the use of transition-metal mediated [2 + 2 + 2] cyclotrimerisation of alkynes to generate tricyclic THIQs with potential to selectively inhibit AKR1C3.
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31673309/the-winding-road-of-the-uvaretin-class-of-natural-products-from-total-synthesis-to-bioactive-agent-discovery
#63
JOURNAL ARTICLE
Johnathan Dallman, Ashabha Lansakara, Thi Nguyen, Chamitha Weeramange, Wasundara Hulangamuwa, Ryan J Rafferty
Herein, we disclose the development of a synthetic route to gain access to the uvaretin class of chalcone natural products. In this, the construction of a small library was achieved, and the collection was evaluated for cytotoxicity and other biological properties. Uvaretin ( 1 ) was accessed via a seven-step route in an overall yield of 15.1%. Within this route, the unsaturated enone variant of uvaretin ( 2 ), also a natural product, was accessed in a 16.7% yield over six steps. This route provides a nearly three-fold increase in yields of 1 and 2 in comparison to the previous synthetic route accessing them in 5...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31673308/dissecting-the-allosteric-fxr-modulation-a-chemical-biology-approach-using-guggulsterone-as-a-chemical-tool
#64
JOURNAL ARTICLE
Daniela Passeri, Andrea Carotti, Jose M Ramos Pittol, Gianmario Ciaccioli, Roberto Pellicciari, Saskia W C van Mil, Antimo Gioiello
Guggulsterone is a promiscuous ligand for endocrine and metabolic lipid receptors traditionally used to treat a number of diseases including diabesity, hyperlipidemia, atherosclerosis, and osteoarthritis. Although relatively weak, its activity at the farnesoid X receptor (FXR) is particularly intriguing as guggulsterone acts as an antagonist with a peculiar ability of gene selective modulation. We report here a chemical biology study with the aim to further characterize the biological action of guggulsterone at the FXR and to obtain further insights into the functional role played by noncanonical FXR binding pockets S2 and S3...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31673307/synthesis-and-antitumor-activity-of-fluorouracil-oleanolic-acid-ursolic-acid-glycyrrhetinic-acid-conjugates
#65
JOURNAL ARTICLE
Chun-Mei Liu, Jia-Yan Huang, Li-Xin Sheng, Xiao-An Wen, Ke-Guang Cheng
Due to the obvious adverse effects of 5-fluorouracil that limit its clinical usefulness and considering the diverse biological activities of pentacyclic triterpenes, twelve pentacyclic triterpene-5-fluorouracil conjugates were synthesized and their antitumor activities were evaluated. The results indicated that all the single substitution targeted hybrids ( 7a-12a ) possessed much better antiproliferative activities than the double substitution targeted hybrids ( 7b-12b ). Hybrid 12a exhibited good antiproliferative activities against all the tested MDR cell lines...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534661/fgapt2-a-biocatalytic-tool-for-alkyl-diversification-of-indole-natural-products
#66
JOURNAL ARTICLE
Chandrasekhar Bandari, Erin M Scull, Tejaswi Bavineni, Susan L Nimmo, Eric D Gardner, Ryan C Bensen, Anthony W Burgett, Shanteri Singh
Aromatic prenyltransferases from natural product biosynthetic pathways display relaxed specificity for their aromatic substrates. While a growing body of evidence suggests aromatic prenyltransferases to be more tolerant towards their alkyl-donor substrates, most studies aimed at probing their donor-substrate specificity are limited to only a small set of alkyl pyrophosphate donors, restricting their broader utility as biocatalysts for synthetic applications. Here, we assess the donor substrate specificity of an l-tryptophan C4-prenyltransferase, also known as C4-dimethylallyltryptophan synthase, FgaPT2 from Aspergillus fumigatus , using an array of 34 synthetic unnatural alkyl-pyrophosphate analogues, and demonstrate FgaPT2 can catalyze the transfer of 25 of the 34 non-native alkyl groups from their corresponding synthetic alkyl-pyrophosphate analogues at N1, C3, C4 and C5 position of tryptophan in a normal and reverse manner...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534660/kaolin-alleviates-the-toxicity-of-graphene-oxide-for-mammalian-cells
#67
JOURNAL ARTICLE
Elvira Rozhina, Svetlana Batasheva, Anna Danilushkina, Marina Kryuchkova, Marina Gomzikova, Yuliya Cherednichenko, Läysän Nigamatzyanova, Farida Akhatova, Rawil Fakhrullin
The development of novel nanoscale vehicles for drug delivery promotes the growth of interest in investigations of interaction between nanomaterials. In this paper, we report the in vitro studies of eukaryotic cell physiological response to incubation with graphene oxide and planar kaolin nanoclay. Graphene family materials, including graphene oxide (GO), hold promise for numerous applications due to their unique electronic properties. However, graphene oxide reveals toxicity to some cell lines through an unidentified mechanism...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534659/synthesis-and-biological-evaluation-of-structurally-diverse-%C3%AE-conformationally-restricted-chalcones-and-related-analogues
#68
JOURNAL ARTICLE
Casey J Maguire, Graham J Carlson, Jacob W Ford, Tracy E Strecker, Ernest Hamel, Mary Lynn Trawick, Kevin G Pinney
Numerous members of the combretastatin and chalcone families of natural products function as inhibitors of tubulin polymerization through a binding interaction at the colchicine site on β-tubulin. These molecular scaffolds inspired the development of many structurally modified derivatives and analogues as promising anticancer agents. A productive design blueprint that involved molecular hybridization of the pharmacophore moieties of combretastatin A-4 ( CA4 ) and the chalcones led to the discovery of two promising lead molecules referred to as KGP413 and SD400 ...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534658/synthetic-studies-on-the-reverse-antibiotic-natural-products-the-nybomycins
#69
JOURNAL ARTICLE
Oliver A Bardell-Cox, Andrew J P White, Luis Aragón, Matthew J Fuchter
Antimicrobial resistance (AMR) is a serious issue that could have severe consequences if steps are not taken. The nybomycin natural products have the potential to extend the clinical efficacy of the marketed fluoroquinolone class of antibiotics through a 'reverse antibiotic' approach. However, only very limited structure-activity relationships are known for these fascinating compounds, in part due to challenges with their synthesis. Here we report a new scalable and robust synthetic route to the nybomycin natural products to aid in the development of this series...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534657/derivatives-of-a-new-heterocyclic-system-pyrano-3-4-c-1-2-4-triazolo-4-3-a-pyridines-synthesis-docking-analysis-and-neurotropic-activity
#70
JOURNAL ARTICLE
Ervand G Paronikyan, Anthi Petrou, Maria Fesatidou, Athina Geronikaki, Shushanik Sh Dashyan, Suren S Mamyan, Ruzanna G Paronikyan, Ivetta M Nazaryan, Hasmik H Hakopyan
8-Hydrazino derivatives of pyrano[3,4- c ]pyridines and derivatives of the new heterocyclic system 3-thioxopyrano[3,4- c ][1,2,4]triazolo[4,3- a ]pyridines on the basis of methanesulfonates of pyrano[3,4- c ]pyridinium were synthesized by optimization of a previously used method. Derivatives of alkylsulfonyl pyrano[3,4- c ][1,2,4]triazolo[4,3- a ]pyridines were also synthesized. All compounds were evaluated for their neurotropic activity. Among all the compounds tested for anticonvulsant activity by pentylenetetrazole and maximal electric shock seizure (MES) tests, six compounds ( 5a , 5b , 5e , 5g , 5j , and 5p ) appeared to be active...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534656/iridium-piano-stool-complexes-with-activity-against-s-aureus-and-mrsa-it-is-past-time-to-truly-think-outside-of-the-box
#71
JOURNAL ARTICLE
Christine M DuChane, George W Karpin, Marion Ehrich, Joseph O Falkinham, Joseph S Merola
A new class of piano-stool iridium complexes with 1,2-diaminoethane ligands are shown to be effective and safe antimicrobials with activity against Staphylococcus aureus , including various isolates of methicillin-resistant strains (MRSA). Comparison to other piano stool complexes with activity against mycobacteria are made along with a discussion of structure-activity relationships. The structures of one the most active complexes with the ligand cis -1,2-diaminocyclohexane and one of the least active complexes with the ligand trans -1,2-diaminocyclohexane are compared and discussed with respect to their drastically different activities...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534655/discovery-of-2-phenoxyacetamides-as-inhibitors-of-the-wnt-depalmitoleating-enzyme-notum-from-an-x-ray-fragment-screen
#72
JOURNAL ARTICLE
Benjamin N Atkinson, David Steadman, Yuguang Zhao, James Sipthorp, Luca Vecchia, Reinis R Ruza, Fiona Jeganathan, Georgie Lines, Sarah Frew, Amy Monaghan, Svend Kjær, Magda Bictash, E Yvonne Jones, Paul V Fish
NOTUM is a carboxylesterase that has been shown to act by mediating the O -depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 μM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534654/drug-resistance-in-mycobacterium-tuberculosis-where-we-stand
#73
REVIEW
Amanda Mabhula, Vinayak Singh
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis ( Mtb ), has burdened vulnerable populations in modern day societies for decades. Recently, this global health threat has been heightened by the emergence and propagation of multi drug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mtb that are resistant to current treatment regimens. The End-TB strategy, launched by the World Health Organization (WHO), aims to reduce TB-related deaths by 90%. This program encourages universal access to drug susceptibility testing, which is not widely available owing to the lack of laboratory capacity or resources in certain under-resourced areas...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534653/recent-development-of-leucyl-trna-synthetase-inhibitors-as-antimicrobial-agents
#74
REVIEW
Panpan Zhang, Shutao Ma
Aminoacyl-tRNA synthetases (aaRSs) widely exist in organisms and mediate protein synthesis. Inhibiting these synthetases can lead to the termination of protein synthesis and subsequently achieve antibacterial and antiparasitic purposes. Moreover, the structures of aaRSs found in eukaryotes have considerable structural differences compared to those in prokaryotes, based on which it is possible to develop highly selective inhibitors. Leucyl-tRNA synthetase (LeuRS) with unique synthesis and editing sites is one of 20 kinds of aaRSs...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534652/tailored-therapeutics-based-on-1-2-3-1-h-triazoles-a-mini-review
#75
REVIEW
Parteek Prasher, Mousmee Sharma
Contemporary drug discovery approaches rely on library synthesis coupled with combinatorial methods and high-throughput screening to identify leads. However, due to the multitude of components involved, a majority of optimization techniques face persistent challenges related to the efficiency of synthetic processes and the purity of compound libraries. These methods have recently found an upgradation as fragment-based approaches for target-guided synthesis of lead molecules with active involvement of their biological target...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534651/inhibitors-of-inosine-5-monophosphate-dehydrogenase-as-emerging-new-generation-antimicrobial-agents
#76
REVIEW
Kapil Juvale, Althaf Shaik, Sivapriya Kirubakaran
Inosine 5'-monophosphate dehydrogenase (IMPDH) is a vital enzyme involved in the de novo synthesis of guanine nucleotides. IMPDH catalyzes a crucial step of converting IMP into XMP that is further converted into GMP. Microbial infections rely on the rapid proliferation of bacteria, and this requires the rate-limiting enzyme IMPDH to expand the guanine nucleotide pool and hence, IMPDH has recently received lots of attention as a potential target for treating infections. Owing to the structural and kinetic differences in the host IMPDH and bacterial IMPDH, a selective targeting is possible and is a crucial feature in the development of new potent and selective inhibitors of bacterial IMPDH...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534650/on-the-road-to-structure-based-development-of-anti-virulence-therapeutics-targeting-the-type-iii-secretion-system-injectisome
#77
REVIEW
Bronwyn J E Lyons, Natalie C J Strynadka
The type III secretion system injectisome is a syringe-like multimembrane spanning nanomachine that is essential to the pathogenicity but not viability of many clinically relevant Gram-negative bacteria, such as enteropathogenic Escherichia coli , Salmonella enterica and Pseudomonas aeruginosa . Due to the rise in antibiotic resistance, new strategies must be developed to treat the growing spectre of drug resistant infections. Targeting the injectisome via an 'anti-virulence strategy' is a promising avenue to pursue as an alternative to the more commonly used bactericidal therapeutics, which have a high propensity for resulting resistance development and often more broad killing profile, including unwanted side effects in eliminating favourable members of the microbiome...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534649/synthetic-small-molecule-rna-ligands-future-prospects-as-therapeutic-agents
#78
REVIEW
A Di Giorgio, M Duca
RNA is one of the most intriguing and promising biological targets for the discovery of innovative drugs in many pathologies and various biologically relevant RNAs that could serve as drug targets have already been identified. Among the most important ones, one can mention prokaryotic ribosomal RNA which is the target of several marketed antibiotics, viral RNAs or oncogenic microRNAs that are tightly involved in the development and progression of various cancers. Oligonucleotides are efficient and specific RNA targeting agents but suffer from poor pharmacodynamic and pharmacokinetic properties...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31534648/methicillin-resistant-staphylococcus-aureus-mrsa-antibiotic-resistance-and-the-biofilm-phenotype
#79
REVIEW
Kelly M Craft, Johny M Nguyen, Lawrence J Berg, Steven D Townsend
Staphylococcus aureus ( S. aureus ) is an asymptomatic colonizer of 30% of all human beings. While generally benign, antibiotic resistance contributes to the success of S. aureus as a human pathogen. Resistance is rapidly evolved through a wide portfolio of mechanisms including horizontal gene transfer and chromosomal mutation. In addition to traditional resistance mechanisms, a special feature of S. aureus pathogenesis is its ability to survive on both biotic and abiotic surfaces in the biofilm state. Due to this characteristic, S...
August 1, 2019: MedChemComm
https://read.qxmd.com/read/31741730/biochemical-and-microbiological-evaluation-of-n-aryl-urea-derivatives-against-mycobacteria-and-mycobacterial-hydrolases
#80
JOURNAL ARTICLE
Abhishek Vartak, Christopher Goins, Vinicius Calado Nogueira de Moura, Celine M Schreidah, Alexander D Landgraf, Boren Lin, Jianyang Du, Mary Jackson, Donald R Ronning, Steven J Sucheck
A focused library of 24 N -aryl urea derivatives was prepared and evaluated against serine esterases of Mycobacterium tuberculosis ( Mtb ) Rv3802c and Mtb Ag85C. The members of the library were evaluated for both selectivity and mode of inhibition. Furan-based urea derivative 6c was found to be the most potent non-covalent inhibitor of Rv3802c with a K i value of 5.2 ± 0.7 μM. On the other hand, triazole-based ureas 10a and 10b selectively inhibited Ag85C irreversibly with a k inact / K i value of 2.3 ± 0...
July 1, 2019: MedChemComm
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