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1,3,5‐Triazepan‐2,6‐diones as Structurally Diverse and Conformationally Constrained Dipeptide Mimetics: Identification of Malaria Liver Stage Inhibitors from a Small Pilot Library
Author(s) -
Lena Gersande,
Lallemand Eliette,
Gruner Anne Charlotte,
Boeglin Joel,
Roussel Solveig,
Schaffner ArnaudPierre,
Aubry André,
Franetich JeanFrançois,
Mazier Dominique,
Landau Irène,
Briand JeanPaul,
Didierjean Claude,
Rénia Laurent,
Guichard Gilles
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200600560
Subject(s) - dipeptide , diketopiperazines , chemistry , stereochemistry , combinatorial chemistry , ring (chemistry) , peptide , biochemistry , organic chemistry
The development of the 1,3,5‐triazepan‐2,6‐dione system as a novel, conformationally restricted, and readily accessible class of dipeptidomimetics is reported. The synthesis of the densely functionalized 1,3,5‐triazepan‐2,6‐dione skeleton was achieved in only four steps from a variety of simple linear dipeptide precursors. To extend the practical value of 1,3,5‐triazepane‐2,6‐diones, a general polymer‐assisted solution‐phase synthesis approach amenable to library production in a multiparallel format was developed. The conformational preferences of the 1,3,5‐triazepan‐2,6‐dione skeleton were investigated in detail by NMR spectroscopy and X‐ray diffraction. The ring exhibits a characteristic folded conformation which was compared to that of related dipeptide‐derived scaffolds including the more planar 2,5‐diketopiperazine (DKP). Molecular and structural diversity was increased further through post‐cyclization appending operations at urea nitrogens. Preliminary biological screens of a small collection of 1,3,5‐triazepan‐2,6‐diones revealed inhibitors of the underexplored malaria liver stage and suggest strong potential for this dipeptide‐derived scaffold to interfere with and to modulate biological pathways.