1,3,5-Triazepane-2,6-diones as structurally diverse and conformationally constrained dipeptide mimetics: identification of malaria liver stage inhibitors from a small pilot library.
The development of the 1,3,5-triazepane-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-triazepane-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-triazepane-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-triazepane-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.
Lena
Gersande
G
Immunologie et Chimie Thérapeutiques (ICT), UPR CNRS 9021, Institut de Biologie Moléculaire et Cellulaire, 15 rue Descartes, 67084 Strasbourg, France.
Lallemand
Eliette
E
Gruner
Anne Charlotte
AC
Boeglin
Joel
J
Roussel
Solveig
S
Schaffner
Arnaud-Pierre
AP
Aubry
André
A
Franetich
Jean-François
JF
Mazier
Dominique
D
Landau
Irène
I
Briand
Jean-Paul
JP
Didierjean
Claude
C
Rénia
Laurent
L
Guichard
Gilles
G
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004151:Dipeptides / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000032:analysis; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D008099:Liver / Q000469:parasitology / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008288:Malaria / Q000473:pathology; D008968:Molecular Conformation; D018716:Molecular Mimicry; D019151:Peptide Library; D010865:Pilot Projects; D014961:X-Ray Diffraction
D004151:Dipeptides; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D019151:Peptide Library