2‐Phenyloxazole‐4‐carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B

Abstract

A series of 2‐phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO‐B isoform. The most potent and selective derivatives are characterized by inhibition constant (Ki) values in the sub‐micromolar range and a good selectivity index (Ki MAO‐A/Ki MAO‐B>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)‐differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2‐(2‐hydroxyphenyl)‐N‐phenyloxazole‐4‐carboxamide (compound 4 a) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF‐differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity.

Promising Non-cytotoxic Monosubstituted Chalcones to Target Monoamine Oxidase-B

“…Moreover, the carbonyl group of 13 did not establish hydrogen bonds with MAO-A residues. Interestingly, the lack of a hydrogen bond with residues in this region of the MAO-A binding pocket, like those previously observed with Cys172 or Tyr326 into MAO-B, has been reported to play an important role in isoform selectivity for the MAO proteins. ,, The B phenyl ring is accommodated close to the Tyr60 and Tyr407 side chains and FAD, similar to what was observed in MAO-B. Altogether, these differences help explain the experimentally observed selectivity of compound 13 for MAO-B over MAO-A.…”

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

“…We have previously identified 2-phenyloxazole (PHOX) derivatives as selective monoamine oxidase B (MAO-B) inhibitors (Di Paolo et al, 2019) ( Figure 2A ). MAO-B inhibitors are used to treat Parkinson’s disease and are also considered potential drug candidates for the treatment of AD (Jost, 2022; Park et al, 2019).…”

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

“…Introduction of substituents at positions 3, 4 and 7 was selected based on previously described coumarins with interesting hMAO-B inhib-itory profiles. All the derivatives were prepared by alkylation of one of the above-mentioned aminocoumarins and the corresponding alkynyl bromide, in tetrahydrofuran (THF), with potassium carbonate (K 2 CO 3 ), at reflux, for approximately 18 h. This methodology allowed obtaining the differently substituted alkynylaminocoumarins (1)(2)(3)(4)(5)(6)(7)(8)(9)(10) in yields between 42-58 % (purified by flash chromatography using n-hexane/ethyl acetate, 9 : 1). In the case of compound 4, the monosubstituted propargyl derivative couldn't be isolated from the reaction mixture.…”

“…In addition, the development of multitarget hybrids based on well‐known bioactive molecules is becoming a widely used strategy in Medicinal Chemistry . Complex compounds presenting different scaffolds can be especially interesting when searching for new therapeutic solutions for multifactorial diseases, as Parkinson's disease …”

“…[5][6][7] In addition, the development of multitarget hybrids based on well-known bioactive molecules is becoming a widely used strategy in Medicinal Chemistry. [8,9] Complex compounds presenting different scaffolds can be especially interesting when searching for new therapeutic solutions for multifactorial diseases, [10,11] as Parkinson's disease. [12,13] Coumarins are ubiquitous in nature and have relevant pharmacological properties such as anti-inflammatory, antioxidant and cardioprotective effects, depending on their substitution patterns.…”