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. 2018 Nov 6;13(21):2266-2270.
doi: 10.1002/cmdc.201800446. Epub 2018 Oct 9.

Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin

Free PMC article

Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin

Varsha R Jumde et al. ChemMedChem. .
Free PMC article


Acylhydrazone-based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone-based inhibitors of the aspartic protease endothiapepsin as a follow-up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X-ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit-to-lead optimization in future acylhydrazone-based DCC projects.

Keywords: acylhydrazones; aspartic proteases; bioisosteres; drug design; dynamic combinatorial chemistry.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
a) Previous examples of bioisosteres and b) proposed bioisosteres (24) of the acylhydrazone 1 as stable inhibitors of endothiapepsin.
Scheme 1
Scheme 1
Synthesis of bioisosteres: a) ClCO2Et, Et3N, dry THF, aq. NH3; b) Lawesson's reagent, dry CH2Cl2; c) EtOH, reflux, 4 h; d) TFA, CH2Cl2; e) 2‐mesitylethanamine hydrochloride (10), 1,1′‐carbonyldiimidazole, THF, RT, 15 h; f) TFA, CH2Cl2, 0 °C→RT, 1.5 h; g) 2‐mesitylethanol (11), DCC, DMAP (5 %) CH2Cl2, 8 h; h) HCl/Et2O 1 m, 24 h; i) SOCl2, dry toluene, reflux, 3 h; j) a) TMS‐diazomethane, Et2O, b) 47.5 % aq. HBr.
Figure 2
Figure 2
a) Zoomed‐out view of the protein shown as surface. b) Electron density omit‐map of the crystal structure of endothiapepsin in complex with compound (S)‐2 and a coordinated DMSO molecule. F oF c map contoured at 3.3 σ (color code: protein cartoon: light blue, C: green, O: red, N: blue, S: yellow).
Figure 3
Figure 3
Superimposition of the acylhydrazone inhibitor (S)‐1 (cyan) and the amide bioisostere (S)‐2 (green). H bonds below 3.0 Å are shown as black dashed lines (color code: protein backbone: C: gray, O: red, N: blue, (S)‐1: C: cyan and (S)‐2: C: green).

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