Design, synthesis and biological evaluation of benzimidazole/bis-imine derivatives as glyoxalase I inhibitors

Abstract

Glyoxalase I (Glo-I), a key enzyme involved in cellular detoxification, overexpression of which is implicated in cancer cell survival and proliferation, is a promising therapeutic target. Al-Balas et al. discovered NSCI153166 (IC₅₀ = 0.97 μM) as a potent Glo-I inhibitor through virtual screening of the NCI database. The compound was previously reported as a bis-imine derivative 1; however, structural elucidation for the in-house synthesized compound revealed it to be a 1,2-disubstituted benzimidazole 2. Surprisingly, both compounds exhibited comparable inhibitory activities. To explore structure-activity relationships, 31 analogues of both scaffolds were synthesized and evaluated against Glo-I. Key findings demonstrated that in the benzimidazole series, both aromatic rings and hydroxyl groups are essential for activity, as removal of the substituted benzyl ring and variations in the phenyl ring substituents led to a complete loss of activity, highlighting the importance of both aromatic rings and the hydroxyl groups, confirmed by docking studies showing crucial interactions of these groups with the Glo-I active site. In the bis-imine series, while modifications to the linker and phenyl rings were tolerated, the scaffold proved to be more fruitful. Notably, meta- and para-substituted bis-imines 22 (IC₅₀ = 0.86 μM) and 23 (IC₅₀ = 0.89 μM) exhibited potent activity, comparable to NSCI153166. However, docking studies of 23 indicated a lack of zinc chelation, suggesting potential for optimization through zinc-chelating substituents. The phenyl linker proved superior to the aliphatic ethylene linker. While both scaffolds show promise as Glo-I inhibitors, further optimization is necessary to enhance potency by exploring alternative linker groups and structural modifications to improve zinc binding affinity, ultimately leading to the development of novel Glo-I inhibitors for cancer therapy.