Expanded use of benzamidines in the Groebke–Blackburn–Bienaymé synthesis of imidazoles and their biological evaluation

Heterocyclic compounds are often considered privileged scaffolds because many bioactive molecules contain these moieties. Several inhibitors of the valosin-containing protein (VCP, also known as p97), a target for cancer therapeutics, contain 5 or 6-membered heterocyclic cores. With the rise of resistance among these VCP inhibitors, we propose a new class of heterocycles as potential cancer therapeutics. The Groebke–Blackburn–Bienaymé (GBB) reaction is a classic method to produce imidazole compounds. In our earlier study, we showed that acyclic amidines can effectively produce trisubstituted imidazoles known as benzyl imine tricyclic imidazoles (BITIs) via this multicomponent reaction. Herein, we report the first systematic evaluation of para -substituted benzamidines produced via the microwave-assisted GBB reaction, which enables the tuning of trisubstituted imidazole compounds and their application as VCP inhibitors. Several of the newly developed compounds inhibit VCP activity, with one amidinopyridine derivative showing low-micromolar, cancer-selective cytotoxicity. This establishes a new scaffold for VCP inhibitor development.