Insight into the Functional and Structural Properties of 3‐Arylcoumarin as an Interesting Scaffold in Monoamine Oxidase B Inhibition

Abstract

The design, synthesis, pharmacological evaluation, and theoretical studies of a new series of halogenated 3-arylcoumarins were carried out with the aim of finding new structural and biological features. This series displays several alkyl, hydroxy, halogen, and/or alkoxy groups in both benzene rings of the 3-arylcoumarin scaffold. Most of the compounds studied show high affinity and selectivity for the human monoamine oxidase B (hMAO-B) isoenzyme, with IC50 values in the low nanomolar and picomolar range. Most of the evaluated compounds display higher MAO-B inhibitory activity and selectivity than selegiline (the reference compound). Coumarin 12 (3-(3-bromophenyl)-6-methylcoumarin) is the most active compound (IC50 =134 pM), being 140-fold more active than selegiline and showing the highest specificity for hMAO-B. To better understand the structure-activity relationships, docking experiments were carried out on human monoamine oxidase (A and B) structures. Finally, the prediction of passive blood-brain partitioning, based on in silico derived physicochemical descriptors, was performed.

Insight into the Interactions between Novel Coumarin Derivatives and Human A3 Adenosine Receptors

“…[19] 3-(3'-Bromophenyl)-6-(2-oxopropoxy)coumarin (4): White solid (80 mg, yield: 83 %): mp: 167-168 8C. [19] General procedure for the synthesis of 6-acetoxy-3-arylcoumarins (6-9): Compounds 6-9 were synthesized under anhydrous conditions, using material previously dried at 60 8C for at least 12 h and at 300 8C during the few minutes immediately prior to use. A solution containing anhydrous CH 3 CO 2 K (2.94 mmol), the phenylacetic acid derivative (1.67 mmol), and the 2,5-dihydroxybenzaldehyde (1.67 mmol) in Ac 2 O (1.2 mL) was held at reflux for 20 h. The reaction mixture was cooled, neutralized with 10 % aqueous NaHCO 3 , and extracted (3 30 mL) with EtOAc.…”

“…[15] 3-(3'-Methylphenyl)-6-(2-oxopropoxy)coumarin (2) 3-(4'-Bromophenyl)-6-(2-oxopropoxy)coumarin (3): White solid (80 mg, yield: 81 %): mp: 157-158 8C. [19] 3-(3'-Bromophenyl)-6-(2-oxopropoxy)coumarin (4): White solid (80 mg, yield: 83 %): mp: 167-168 8C. [19] General procedure for the synthesis of 6-acetoxy-3-arylcoumarins (6-9): Compounds 6-9 were synthesized under anhydrous conditions, using material previously dried at 60 8C for at least 12 h and at 300 8C during the few minutes immediately prior to use.…”

“…The Williamson reaction of the 3-aryl-6-hydroxycoumarins or 3-aryl-8-hydroxycoumarins with chloroacetone, under reflux with acetone for 16 h, gave the corresponding ethers 1-4 and 11-13, respectively, with good yields. [15,18,19] Compounds 6-9 were obtained starting from the 2,5-dihydroxybenzaldehyde and the corresponding phenylacetic acids using potassium acetate in acetic anhydride, under reflux, for 20 h. Acetylation of the hydroxy groups and pyrone ring closure occurred simultaneously under Perkin-Oglialoro conditions. [20] The CuI/DMEDA (N,N'-dimethylethylenediamine) catalytic system was used to promote the amination of compounds 3 and 8 with TFA and potassium carbonate in dioxane at 70 8C to give amino derivatives 5 and 10, respectively.…”

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

“…Different research groups, including ours, have shown that coumarin is a privileged scaffold for the rational discovery and development of new h MAO‐B inhibitors (Figure ) and antioxidant agents . In addition to being very potent and selective MAO inhibitors, several leads previously reported by the group have proven to be reversible inhibitors . Moreover, hybrid molecules bearing the coumarin scaffold have been already reported by the group .…”

“…[15][16][17] In addition to being very potent and selective MAO inhibitors, several leads previously reported by the group have proven to be reversible inhibitors. [18][19][20] Moreover, hybrid molecules bearing the coumarin scaffold have been already reported by the group. [21,22] Therefore, the development of coumarin-rasagiline hybrids, and the methodology and results described in this manuscript, may contribute to a global effort to find efficient molecules as future perspectives for the treatment of Parkinson's disease (Figure 1).…”