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Development of a Focused Library of Triazole‐Linked Privileged‐Structure‐Based Conjugates Leading to the Discovery of Novel Phenotypic Hits against Protozoan Parasitic Infections
Author(s) -
Uliassi Elisa,
Piazzi Lorna,
Belluti Federica,
Mazzanti Andrea,
Kaiser Marcel,
Brun Reto,
Moraes Carolina B.,
FreitasJunior Lucio H.,
Gul Sheraz,
Kuzikov Maria,
Ellinger Bernhard,
Borsari Chiara,
Costi Maria Paola,
Bolognesi Maria Laura
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700786
Subject(s) - adme , phenothiazine , triazole , drug discovery , biphenyl , drug , chemistry , combinatorial chemistry , biology , pharmacology , stereochemistry , computational biology , biochemistry , organic chemistry
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, h ERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10‐((1‐(3‐([1,1′‐biphenyl]‐3‐yloxy)propyl)‐1 H ‐1,2,3‐triazol‐5‐yl)methyl)‐10 H ‐phenothiazine ( 7 ) and 10‐(3‐(1‐(3‐([1,1′‐biphenyl]‐3‐yloxy)propyl)‐1 H ‐1,2,3‐triazol‐4‐yl)propyl)‐10 H ‐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.