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

Abstract

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.

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology

“…We hypothesize that the latter might be the cause of chemical instability in aqueous buffer for these compounds. 55 Compounds were also tested for their turbidimetric solubility to establish the maximum concentrations at which each compound could be evaluated in vitro. As shown in Table S2, the solubility of the whole class is good overall; compounds 1−4, 6−8, and 10 did not precipitate at the maximal concentration tested.…”

“…Inspection of the structures reveals that all the unstable compounds (PLZ, SP-2509, and seclidemstat) feature either a hydrazine or an acylhydrazone chemical function. We hypothesize that the latter might be the cause of chemical instability in aqueous buffer for these compounds …”

Comparison of affinity ranking by target-directed dynamic combinatorial chemistry and surface plasmon resonance

“…In summary, as evidenced by antagonist 10, and as described by Jumde et al 41 replacement by an amide provides a good starting point for further optimization of acylhydrazones.…”

“…Jumde et al recently reported on bioisosteric replacement of the acylhydrazone moiety. 41 Therefore, in an effort to improve on stability and reduce toxicity, we generated a small library of bioisosteric analogues.…”

Hit-optimization using target-directed dynamic combinatorial chemistry: development of inhibitors of the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase

“…As compared to acylhydrazones, amides are known to be less prone to hydrolysis and subsequent liberation of potentially toxic hydrazides. 28 Moreover, the milder and simple conditions required for the synthesis of amides make them ideal candidates as bioisosteres of acylhydrazones. Similarly, structurally more rigid and hydrolytically stable 1,3,4-oxadiazoles can directly be synthesized from the building blocks of acylhydrazone formation.…”