Coumarin‐Rasagiline Hybrids as Potent and Selective hMAO‐B Inhibitors, Antioxidants, and Neuroprotective Agents

Abstract

The frequency, complexity and morbidity of neurodegenerative diseases make them a great challenge for nowadays medicine. Most of the treatments currently used for Parkinson's disease – the second most prevalent – are only symptomatic. Therefore, it is urgent to develop drugs that are able to act simultaneously on different targets, being able to stop neuronal death and promote the recovery of neuronal populations already affected. In this work, we studied the activity of a series of hybrid molecules, which combine the structure of both coumarin and an alkynylamine group inspired on rasagiline, as MAO inhibitors, antioxidants and neuroprotective agents. Half of the studied hybrids turned out to be selective monoamine oxidase B (hMAO‐B) inhibitors in the low micro/nanomolar range, demonstrating that positions 3 (compounds 1–3) and 7 (compounds 8 and 10) of the coumarin scaffold are the most suitable for the incorporation of the alkynylamine chain. All the studied compounds proved to be capable of neutralizing free radicals (DPPH). Finally, the 4‐(but‐2‐yn‐1‐ylamino)coumarin (5) showed neuroprotective effects on glial cells and the 4‐methyl‐7‐(pent‐2‐yn‐1‐ylamino)coumarin (8) inhibited intraneuronal ROS production as well.

7‐Amidocoumarins as Multitarget Agents against Neurodegenerative Diseases: Substitution Pattern Modulation

“…Some 3‐amidocoumarins already reported by the group were described as reversible h MAO‐B inhibitors [23] . Recently, a coumarin derivative bearing a pent‐2‐yn‐1‐amine group at position 7, the same position under study in this project, was reported as a partially reversible MAO‐B inhibitor [26] …”

“…Their multitarget profile, especially regarding neurodegenerative disease, has already been described by several groups working in the field [12–15] . For more than ten years, our research group has been reporting differently substituted coumarins as monoamine oxidase (MAO), [16–20] acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors, as well as neuroprotective agents (Figure 1A–D) [21–26] . Furthermore, 7‐substituted coumarins have been raised as potent multitarget molecules [27–31] .…”

Deciphering the detailed structure–activity relationship of coumarins as Monoamine oxidase enzyme inhibitors—An updated review

“…The propargyl group is an alkylamine which is a bioactive moiety present in irreversible MAO‐B inhibitors rasagiline and selegiline. An effort was made by (Matos et al., 2020) to join the propargyl group of rasagiline with the coumarin nucleus (Figure 16). Compounds with the propargyl group being substituted at position 3 of coumarin ( 35a ) and position 7 ( 35b and 35c ) were found to be selective MAO‐B inhibitors.…”

Curcumin–Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders

“…Some of these compounds display potent antioxidant activity and, therefore, could protect cells from neurodegeneration [ 10 ]. In the last few years, our group has described different series of 3-substituted coumarins displaying these properties [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

“…4.2.13. Synthesis of 6,7-Dihydroxy-3-(7-(2 ,4 ,5 -trihydroxyphenyl)-3,5-dioxohepta-1,6dien-1-yl)coumarin(16)…”