Curcumin-Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders

Abstract

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H₂O₂ in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.

Keywords: cholinesterase inhibition; curcumin; curcumin–coumarin hybrids; monoamine oxidase inhibition; neuroprotection; scavenging activity.

Figure 1

Overview of design of new curcumin–coumarin hybrid analogues.

Scheme 1

(a) dichlorodiphenylmethane, (Ph)₂O, 180 °C, 30 min; (b) MgCl₂, Et₃N, (CH₂O)_n, THF reflux, 4 h; (c) (trimethylsilyl)propioloyl chloride, NaH, THF, reflux, 10 h; (d) DABCO, THF, reflux, 12 h.

Scheme 2

(a) i: 2,4-Pentanedione, B₂O₃, EtOAc, 40 °C, 2 h; (BuO)₃B; nBuNH₂, EtOAc, 25–40 °C 22 h; ii: HCl, 60 °C, 1 h; iii: H₂, Pd/C, EtOH, rt, 48 h.

Figure 2

Percentage of neutralization of radical DPPH^. by curcumin, curcumin–coumarin hybrid analogues 11–18 (100 µM) and vitamin C used as reference (100 µM). Each value is the mean ± s.e.m. of 3 experiments (n = 3).

Figure 3

Neuroprotective effects of curcumin and curcumin–coumarin hybrid analogues 11–18 (10 µM) on SH-SY5Y cells. The results are expressed as % viability versus the control group (treated with DMSO 1%, or DMSO 1%, and H₂O₂ 100 µM). Each value is the mean ± s.e.m of at least five experiments. # p < 0.0001 versus the control group without H₂O₂ treatment. * p < 0.05, ** p < 0.005 versus DMSO + H₂O₂ treated group.

Figure 4

Neuroprotective effects on SH-SY5Y cells of different concentrations of curcumin and curcumin–coumarin hybrid analogues 14 and 16 and their nanoparticle formulations (NC). Each value is the mean ± s.e.m of at least 5 experiments. # p < 0.0001 versus the control group (without H₂O₂ treatment), ** p < 0.005, *** p < 0.001, **** p < 0.0001 versus cells treated with H₂O₂.