Asproni B

References (2)

Title : Novel thienocycloalkylpyridazinones as useful scaffolds for acetylcholinesterase inhibition and serotonin 5-HT(6) receptor interaction - Asproni_2023_Bioorg.Med.Chem_84_117256
Author(s) : Asproni B , Catto M , Loriga G , Murineddu G , Corona P , Purgatorio R , Cichero E , Fossa P , Scarano N , Martinez AL , Brea J , Pinna GA
Ref : Bioorganic & Medicinal Chemistry , 84 :117256 , 2023
Abstract : A library of eighteen thienocycloalkylpyridazinones was synthesized for human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibition and serotonin 5-HT(6) receptor subtype interaction by following a multitarget-directed ligand approach (MTDL), as a suitable strategy for treatment of Alzheimer's disease (AD). The novel compounds featured a tricyclic scaffold, namely thieno[3,2-h]cinnolinone, thienocyclopentapyridazinone and thienocycloheptapyridazinone, connected through alkyl chains of variable length to proper amine moieties, most often represented by N-benzylpiperazine or 1-(phenylsulfonyl)-4-(piperazin-1-ylmethyl)-1H-indole as structural elements addressing AChE and 5-HT(6) interaction, respectively. Our study highlighted the versatility of thienocycloalkylpyridazinones as useful architectures for AChE interaction, with several N-benzylpiperazine-based analogues emerging as potent and selective hAChE inhibitors with IC(50) in the 0.17-1.23 microM range, exhibiting low to poor activity for hBChE (IC(50) = 4.13-9.70 microM). The introduction of 5-HT(6) structural moiety phenylsulfonylindole in place of N-benzylpiperazine, in tandem with a pentamethylene linker, gave potent 5-HT(6) thieno[3,2-h]cinnolinone and thienocyclopentapyridazinone-based ligands both displaying hAChE inhibition in the low micromolar range and unappreciable activity towards hBChE. While docking studies provided a rational structural explanation for AChE/BChE enzyme and 5-HT(6) receptor interaction, in silico prediction of ADME properties of tested compounds suggested further optimization for development of such compounds in the field of MTDL for AD.
ESTHER : Asproni_2023_Bioorg.Med.Chem_84_117256
PubMedSearch : Asproni_2023_Bioorg.Med.Chem_84_117256
PubMedID: 37003157

Title : Multitarget-directed tricyclic pyridazinones as g protein-coupled receptor ligands and cholinesterase inhibitors - Pau_2015_ChemMedChem_10_1054
Author(s) : Pau A , Catto M , Pinna G , Frau S , Murineddu G , Asproni B , Curzu MM , Pisani L , Leonetti F , Loza MI , Brea J , Pinna GA , Carotti A
Ref : ChemMedChem , 10 :1054 , 2015
Abstract : By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein-coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone-based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5-HT1A , adrenergic alpha1A , and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5-HT1A because of its involvement in neuronal deficits typical of Alzheimer's and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of alpha1A and 5-HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.
ESTHER : Pau_2015_ChemMedChem_10_1054
PubMedSearch : Pau_2015_ChemMedChem_10_1054
PubMedID: 25924828