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

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 (K_i < 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 K_i = 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.