Nguyen, A. M. T., Brettell, S., Douanne, N., Duquette, C., Corbeil, A., Fajardo, E. F., Olivier, M., Fernandez-Prada, C. and Lubell, W. D. (2021) Influence of N- methylation and conformation on almiramide anti-leishmanial activity. Molecules, 26(12), 3606. (doi: 10.3390/molecules26123606)
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Publisher's URL: https://www.mdpi.com/1420-3049/26/12/3606
Abstract
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.
Item Type: | Articles |
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Additional Information: | This work was supported by a New Frontiers in Research Fund Exploration Grant NFRFE2018-00766 awarded to CFP, MO and WL; the Natural Sciences and Engineering Research Council (NSERC) of Canada Discovery Grant Program Projects #06647 (WL) and RGPIN-2017-04480 (CFP); the FRQNT Centre in Green Chemistry and Catalysis, Project #171310 (WL). The Canada Foundation for Innovation, grant number 37324 (CFP). AC and ND were supported by the Fonds de recherche du Québec—Nature et technologies (FRQNT). |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Brettell, Ms Skye |
Creator Roles: | |
Authors: | Nguyen, A. M. T., Brettell, S., Douanne, N., Duquette, C., Corbeil, A., Fajardo, E. F., Olivier, M., Fernandez-Prada, C., and Lubell, W. D. |
College/School: | College of Science and Engineering > School of Chemistry |
Journal Name: | Molecules |
Publisher: | MDPI |
ISSN: | 1420-3049 |
ISSN (Online): | 1420-3049 |
Published Online: | 12 June 2021 |
Copyright Holders: | Copyright © 2021 The Authors |
First Published: | First published in Molecules 26(12): 3606 |
Publisher Policy: | Reproduced under a Creative Commons License |
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