Influence of N-Methylation and Conformation on Almiramide Anti-Leishmanial Activity

Autor: Anh Minh Thao Nguyen, Skye Brettell, Noélie Douanne, Claudia Duquette, Audrey Corbeil, Emanuella F. Fajardo, Martin Olivier, Christopher Fernandez-Prada, William D. Lubell
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Molecules, Vol 26, Iss 12, p 3606 (2021)
Druh dokumentu: article
ISSN: 26123606
1420-3049
DOI: 10.3390/molecules26123606
Popis: The almiramide N-methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure–activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on either the first or fifth residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide, by turn inducing α amino γ lactam (Agl) and N-aminoimidazalone (Nai) counterparts, reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues, and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides.
Databáze: Directory of Open Access Journals
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