Novel indanone derivatives as MAO B/H3R dual-targeting ligands for treatment of Parkinson's disease.

ABSTRACT

The design of multi-targeting ligands was developed in the last decades as an innovative therapeutic concept for Parkinson's disease (PD) and other neurodegenerative disorders. As the monoamine oxidase B (MAO B) and the histamine H3 receptor (H3R) are promising targets for dopaminergic regulation, we synthetized dual-targeting ligands (DTLs) as non-dopaminergic receptor approach for the treatment of PD. Three series of compounds were developed by attaching the H3R pharmacophore to indanone-related MAO B motifs, leading to development of MAO B/H3R DTLs. Among synthesized indanone DTLs, compounds bearing the 2-benzylidene-1-indanone core structure showed MAO B preferring inhibition capabilities along with nanomolar hH3R affinity. Substitution of C5 and C6 position of the 2-benzylidene-1-indanones with lipophilic substituents revealed three promising candidates exhibiting inhibitory potencies for MAO B with IC50 values ranging from 1931 nM to 276 nM and high affinities at hH3R (Ki < 50 nM). Compound 3f ((E)-5-((4-bromobenzyl)oxy)-2-(4-(3-(piperidin-1-yl)propoxy)benzylidene)-2,3-dihydro-1H-inden-1-one, MAO B IC50 = 276 nM, hH3R Ki = 6.5 nM) showed highest preference for MAO B over MAO A (SI > 36). Interestingly, IC50 determinations after preincubation of enzyme and DTLs revealed also nanomolar MAO B potency for 3e (MAO B IC50 = 232 nM), a structural isomer of 3f, and 3d (MAO B IC50 = 541 nM), suggesting time-dependent inhibition modes. Reversibility of inhibition for all three compounds were confirmed by dilution studies in excess of substrate. Thus, indanone-substituted derivatives are promising lead structures for the design of MAO B/hH3R DTLs as novel therapeutic approach of PD therapy.