Sova M

References (3)

Title : 4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B - Mazej_2021_Molecules_26_
Author(s) : Mazej T , Knez D , Meden A , Gobec S , Sova M
Ref : Molecules , 26 : , 2021
Abstract : The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer's disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13-15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC(50) of 4.3 microM) and hBChE (IC(50) of 8.5 microM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs.
ESTHER : Mazej_2021_Molecules_26_
PubMedSearch : Mazej_2021_Molecules_26_
PubMedID: 34299393

Title : Multi-target-directed ligands for treating Alzheimer's disease: Butyrylcholinesterase inhibitors displaying antioxidant and neuroprotective activities - Knez_2018_Eur.J.Med.Chem_156_598
Author(s) : Knez D , Coquelle N , Pislar A , Zakelj S , Jukic M , Sova M , Mravljak J , Nachon F , Brazzolotto X , Kos J , Colletier JP , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 156 :598 , 2018
Abstract : The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay. The crystal structure of compound 11 in complex with butyrylcholinesterase revealed the molecular basis for its low nanomolar inhibition of butyrylcholinesterase (Ki=1.09+/-0.12nM). In addition, compounds 8 and 11 show metal-chelating properties, and reduce the redox activity of chelated Cu(2+) ions in a Cu-ascorbate redox system. Compounds 8 and 11 decrease intracellular levels of reactive oxygen species, and are not substrates of the active efflux transport system, as determined in Caco2 cells. Compound 11 also protects neuroblastoma SH-SY5Y cells from toxic Abeta1-42 species. These data indicate that compounds 8 and 11 are promising multifunctional lead ligands for treatment of Alzheimer's disease.
ESTHER : Knez_2018_Eur.J.Med.Chem_156_598
PubMedSearch : Knez_2018_Eur.J.Med.Chem_156_598
PubMedID: 30031971
Gene_locus related to this paper: human-BCHE

Title : Dual inhibitors of cholinesterases and monoamine oxidases for Alzheimer's disease - Knez_2017_Future.Med.Chem_9_811
Author(s) : Knez D , Sova M , Kosak U , Gobec S
Ref : Future Med Chem , 9 :811 , 2017
Abstract : Accumulating evidence indicates a solid relationship between several enzymes and Alzheimer's disease. Cholinesterases and monoamine oxidases are closely associated with the disease symptomatology and progression and have been tackled simultaneously using several multifunctional ligands. This design strategy offers great chances to alter the course of Alzheimer's disease, in addition to alleviation of the symptoms. More than 15 years of research has led to the identification of various dual cholinesterase/monoamine oxidase inhibitors, while some showing positive outcomes in clinical trials, thus giving rise to additional research efforts in the field. The aim of this review is to provide an update on the novel dual inhibitors identified recently and to shed light on their therapeutic potential.
ESTHER : Knez_2017_Future.Med.Chem_9_811
PubMedSearch : Knez_2017_Future.Med.Chem_9_811
PubMedID: 28504893