Azole derivatives inhibit wildtype butyrylcholinesterase and its common mutants


SARI S., Onder S., AKKAYA D., SABUNCUOĞLU S., ZENGİN M., BARUT B., ...More

DRUG DEVELOPMENT RESEARCH, vol.84, pp.1018-1028, 2023 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 84
  • Publication Date: 2023
  • Doi Number: 10.1002/ddr.22071
  • Journal Name: DRUG DEVELOPMENT RESEARCH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, Veterinary Science Database
  • Page Numbers: pp.1018-1028
  • Karadeniz Technical University Affiliated: Yes

Abstract

Azoles, which have been used for antifungal chemotherapy for decades, have recently been of interest for their efficacy against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). There is little known about the potential of azoles against BChE, however there is none regarding their inhibitory effects against mutants of BChE. In the current study, an azole library of 1-aryl-2-(1H-imidazol-1-yl)ethanol/ethanone oxime esters were tested against AChE and BChE, which yielded derivates more potent than the positive control, galantamine, against both isoforms. Kinetic analyses were performed for wildtype and mutant (A328F and A328Y) inhibition for the two most potent BChE inhibitors, pivalic and 3-bezoylpropanoic acid esters of 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethanol, which were found to have great affinity to the wildtype and mutant BChE types with K-i values as low as 0.173 +/- 0.012 mu M. The compounds were identified to show linear competitive or mixed type inhibition. Molecular modeling confirmed these kinetic data and provided further insights regarding molecular basis of BChE inhibition by the active derivatives. Thus, current study suggests new azole derivatives with promising cholinesterase inhibitory effects and reveals the first set of information to promote our understanding for the inhibitory behavior of this class against the mutant BChE forms.