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

Abstract

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.

Synthetic Methods for the Preparation of Triazepandiones and Review of their Applications

“…A variety of synthetic methods have been employed, most of them involving cyclization of a linear fragment. It is worth mentioning that crystallographic analysis of 1,2,5-Triazepan-3,6-dione [26] and 1,3,5-triazepan-2,6-diones [43] revealed a Fig. (6).…”

“…Crystal structures have been reported for compounds 118a,m [46], 118c [47], 118h [48], 118k,l,n,p,r, 120a,i, 121a and 122c [43]. Supramolecular organization of compounds 118a and 118m showed a remarkable formation of helical H-bonded molecular tapes that Scheme 23.…”

“…The reaction is supposed to proceed through photochemical nitrogen elimination and ring expansion. The preparation, characterization and preliminary biological evaluation of 1,3,5-triazepan-3,6-diones has been the object of our work [43]. The solution synthesis of 1,3,5-triazepan-2,6-diones was readily completed in four steps by head-to-tail cyclization of simple activated dipeptide derivatives (Scheme 23).…”

“…A first biological screening of 1,3,5-triazepan-2,6-diones have permitted to identify that these compounds have inhibitory activity of the Malaria liver stage [43], which represents an early step in the life cycle of the malaria parasite. Sporoaction on the pancreas.…”

In Silico-Guided Target Identification of a Scaffold-Focused Library: 1,3,5-Triazepan-2,6-diones as Novel Phospholipase A2 Inhibitors

“…Compounds were built and docked as described for compounds 1, 5, 16, 29, and 36 in the Experimental Section, with the exception that both axial and equatorial positions were allowed at substituents R 3 and R 4 , as recently exemplified by the X-ray structure of compound 21. 32 The main chain of sPLA2 is traced by red helices, yellow strands, and white loops. The ligand binding site is delimited by a solid surface.…”