Départements de chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada.
Département de Pathologie et Microbiologie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada.
Molecules. 2021 Jun 12;26(12):3606. doi: 10.3390/molecules26123606.
The almiramide -methylated lipopeptides exhibit promising activity against trypanosomatid parasites. A structure-activity relationship study has been performed to examine the influences of -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 -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.
阿米拉米德-甲基化脂肽对原生动物寄生虫表现出有希望的活性。已经进行了构效关系研究，以检查甲基化和构象对针对各种利什曼原虫和细胞毒性的活性的影响。二十五种类似物的合成和生物学分析表明，在第一个或第五个残基酰胺氮上具有单个甲基的衍生物比全甲基化肽具有更高的活性，并且对耐药株具有相对高的效力。在肽中取代氨基酰胺残基，依次诱导α-氨基γ-内酰胺（Agl）和β-氨基咪唑啉（Nai）对应物，通常会降低抗寄生虫活性；然而，在未甲基化和全甲基化系列中，具有 Agl 残基的第二残基的肽酰胺仍然保持显著的效力。对甲基化和构象对抗寄生虫活性的影响的系统研究表明，关于中心残基的扩展构象以及通过三级酰胺异构化和末端的构象流动性的相关重要性在活性肽中。
