Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies

Abstract

Cholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood‐brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.

Azole derivatives inhibit wildtype butyrylcholinesterase and its common mutants

“…Although the realization of cholinesterase inhibitory effects of azoles dates back to the beginning of 2000s, it was the discovery of miconazole's effects that brought the subject to the awareness of many research (Chen et al, 2015). The discovery was followed by a number of studies proving anticholinesterase properties of miconazole derivatives and other azoles (Barut et al, 2021; Lu et al, 2018; Sari et al, 2022, 2022) (Figure 1).…”