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1.
Bioorg Med Chem ; 40: 116164, 2021 06 15.
Article in English | MEDLINE | ID: mdl-34020276

ABSTRACT

A diversity-oriented synthesis of hydroxylated aryl-quinones via CH oxygenation reactions and their evaluation against Trypanosoma cruzi, the etiological agent of Chagas disease, was accomplished. With the use of ruthenium(II)- or palladium(II)-based catalysts, complementary regioselectivities were observed in the hydroxylation reactions and we have identified 9 compounds more potent than benznidazole (Bz) among these novel arylated and hydroxylated quinones. For instance, 5-hydroxy-2-[4-(trifluoromethyl)phenyl]-1,4-naphthoquinone (4h) with an IC50/24 h value of 22.8 µM is 4.5-fold more active than the state-of-the-art drug Bz. This article provides the first example of the application of CH activation for the position-selective hydroxylation of arylated quinones and the identification of these compounds as trypanocidal drug candidates.


Subject(s)
Oxygen/chemistry , Palladium/chemistry , Quinones/pharmacology , Ruthenium/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Catalysis , Chagas Disease/drug therapy , Dose-Response Relationship, Drug , Mice , Molecular Structure , Parasitic Sensitivity Tests , Quinones/chemical synthesis , Quinones/chemistry , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry
2.
Bioorg Chem ; 109: 104662, 2021 04.
Article in English | MEDLINE | ID: mdl-33626452

ABSTRACT

Two new series of hitherto unknown dipeptides, containing an electrophilic nitrile or a non-electrophilic 2-amino-1,3,4-oxadiazole moiety were synthesized and evaluated in vitro as Cathepsin K (Cat K) inhibitors. From 14 compounds obtained, the oxadiazole derivatives 10a, 10b, 10e, and 10g acted as enzymatic competitive inhibitors with Ki values between 2.13 and 7.33 µM. Molecular docking calculations were carried out and demonstrated that all inhibitors performed hydrogen bonds with residues from the enzyme active site, such as Asn18. The best inhibitors (10a, 10b, 10g) could also perform these bonds with Cys25, and 10a showed the most stabilizing interaction energy (-134.36 kcal mol-1) with the active cavity. For the first time, derivatives based in 2-amino-1,3,4-oxadiazole scaffolds were evaluated, and the results suggested that this core displays a remarkable potential as a building block for Cat K inhibitors.


Subject(s)
Cathepsin K/antagonists & inhibitors , Dipeptides/pharmacology , Oxadiazoles/pharmacology , Binding Sites , Cell Survival/drug effects , Computer Simulation , Dipeptides/chemical synthesis , Dipeptides/chemistry , Drug Design , Human Umbilical Vein Endothelial Cells , Humans , Models, Molecular , Molecular Structure , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Protein Binding , Protein Conformation , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 27(18): 4446-4456, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28818447

ABSTRACT

Fluorescent quinone-based BODIPY hybrids were synthesised and characterised by NMR analysis and mass spectrometry. We measured their cytotoxic activity against cancer and normal cell lines, performed mechanistic studies by lipid peroxidation and determination of reduced (GSH) and oxidized (GSSG) glutathione, and imaged their subcellular localisation by confocal microscopy. Cell imaging experiments indicated that nor-ß-lapachone-based BODIPY derivatives might preferentially localise in the lysosomes of cancer cells. These results assert the potential of hybrid quinone-BODIPY derivatives as promising prototypes in the search of new potent lapachone antitumor drugs.


Subject(s)
Antineoplastic Agents/pharmacology , Benzoquinones/pharmacology , Boron Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzoquinones/chemical synthesis , Benzoquinones/chemistry , Boron Compounds/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship
4.
Chem Commun (Camb) ; 52(90): 13281-13284, 2016 Nov 03.
Article in English | MEDLINE | ID: mdl-27775736

ABSTRACT

For the first time, a fluorescent lapachone-based BODIPY was synthesised and characterised by NMR and mass spectrometry. Computational and electrochemical aspects, as well as cytotoxic activity and subcellular localisation, were studied. Confocal microscopy experiments indicated that the probe was a specific mitochondria-staining agent. These in-detail analyses were useful in understanding the cytotoxic effects and mechanism of action of this novel hybrid compound. This molecule constitutes a promising prototype owing to its potential biological activities and the new strategies aimed at mechanistic investigations in cells and in vivo, and opens up an interesting avenue of research.

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