Data Entry: Please note that the research database will be replaced by UNIverse by the end of October 2023. Please enter your data into the system https://universe-intern.unibas.ch. Thanks
Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4481970
Author(s)
Uliassi, Elisa; Piazzi, Lorna; Belluti, Federica; Mazzanti, Andrea; Kaiser, Marcel; Brun, Reto; Moraes, Carolina B.; Freitas-Junior, Lucio H.; Gul, Sheraz; Kuzikov, Maria; Ellinger, Bernhard; Borsari, Chiara; Costi, Maria Paola; Bolognesi, Maria Laura
Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections
Journal
ChemMedChem
Volume
13
Number
7
Pages / Article-Number
678-683
Abstract
Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC; 50; values of 1.8 and 1.9 μg mL; -1; against T. cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.
