- Synthesis, antimicrobial evaluation, and in silico studies of quinoline—1H-1,2,3-triazole molecular hybrids
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Abstract: Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline—1H-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound 16 as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC80 value of 75.39?μM against methicillin-resistant S. aureus, E. coli, A. baumannii, and multidrug-resistant K. pneumoniae. The compound also showed interesting antifungal profile against C. albicans and C. neoformans at an MIC80 value of 37.69 and 2.36?μM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound 16 as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency. Graphic abstract: [Figure not available: see fulltext.].
- Awolade, Paul,Cele, Nosipho,Kerru, Nagaraju,Singh, Parvesh
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p. 2201 - 2218
(2020/06/17)
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- An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors
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Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.
- Vettorazzi, Marcela,Angelina, Emilio,Lima, Santiago,Gonec, Tomas,Otevrel, Jan,Marvanova, Pavlina,Padrtova, Tereza,Mokry, Petr,Bobal, Pavel,Acosta, Lina M.,Palma, Alirio,Cobo, Justo,Bobalova, Janette,Csollei, Jozef,Malik, Ivan,Alvarez, Sergio,Spiegel, Sarah,Jampilek, Josef,Enriz, Ricardo D.
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p. 461 - 481
(2017/08/21)
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- Method for synthesizing asymmetric C-O coupled compound and application of asymmetric C-O coupled compound
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The invention discloses a method for synthesizing an asymmetric C-O coupled compound and application of the asymmetric C-O coupled compound and belongs to the technical field of chemical synthesis. According to the method, a compound represented by a form
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Paragraph 0221; 0225
(2016/10/07)
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- Synthesis and pharmacological activity of a new series of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol analogs
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β-Adrenergic receptor antagonists are important therapeutics for the treatment of cardiovascular disorders. In the group of β-blockers, much attention is being paid to the third-generation drugs that possess important ancillary properties besides inhibiting β-adrenoceptors. Vasodilating activity of these drugs is produced through different mechanisms, such as nitric oxide (NO) release, β2-agonistic action, α1-blockade, antioxidant action, and Ca2t entry blockade. Here, a study on evaluation of the cardiovascular activity of five new compounds is presented. Compound 3a is a methyl and four of the tested compounds (3b–e) are dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)-ethylamino)propan-2-ol. The obtained results confirmed that the methyl and dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and their enantiomers possess α1- and β1-adrenolytic activities and that the antiarrhythmic and hypotensive effects of the tested compounds are related to their adrenolytic properties.
- Bednarski, Marek,Otto, Monika,Dudek, Magdalena,Ko?aczkowski, Marcin,Bucki, Adam,Siwek, Agata,Groszek, Gra?yna,Maziarz, El?bieta,Wilk, Piotr,Sapa, Jacek
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p. 211 - 223
(2018/05/08)
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