Expanded use of benzamidines in the Groebke–Blackburn–Bienaymé synthesis of imidazoles and their biological evaluation
Abstract
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.
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BibTeX
@article{walker2026expanded,
title = {{Expanded use of benzamidines in the Groebke–Blackburn–Bienaymé synthesis of imidazoles and their biological evaluation}},
author = {Kamryn Walker and Sydney Rivas and Erik Tillman-Smith and Kayla McLeod and Jeanee Bullock and Jacqueline Smith},
journal = {Beilstein Journal of Organic Chemistry},
year = {2026},
month = sep,
doi = {10.3762/bjoc.22.108},
url = {https://www.beilstein-journals.org/bjoc/articles/22/108},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Expanded use of benzamidines in the Groebke–Blackburn–Bienaymé synthesis of imidazoles and their biological evaluation
AU - Kamryn Walker
AU - Sydney Rivas
AU - Erik Tillman-Smith
AU - Kayla McLeod
AU - Jeanee Bullock
AU - Jacqueline Smith
PY - 2026
DA - 2026/09/30
JO - Beilstein Journal of Organic Chemistry
DO - 10.3762/bjoc.22.108
UR - https://www.beilstein-journals.org/bjoc/articles/22/108
AB - 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.
SN - 1860-5397
ER -