Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections
University of Bologna¦¦Itália ; Swiss Tropical and Public Health Institute (Swiss TPH)¦¦Suiça ; University of Basel¦¦Suiça ; Laboratório Nacional de Biociências (LNBio)¦¦Brasil ; Fraunhofer Institute for Molecular Biology and Applied Ecology IME¦¦Alemanha ; Universidade de Módena e Reggio Emília¦¦Itália ; Universidade de São Paulo (USP)¦¦Brasil
Appears in Collections:
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 IC50 values of 1.8 and 1.9gmL(-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.
Uliassi E, Piazzi L, Mazzanti A, Kaiser M, Brun R, Moraes CB, et al. Development of a focused library of triazole-linked privileged-structure-based conjugates leading to the discovery of novel phenotypic hits against protozoan parasitic infections. ChemMedChem. 2018 Apr;13(7):678-83. doi:10.1002/cmdc.201700786.
Link to cite this reference
The access to the publications deposited in this repository respects the licenses from journals and publishers.