Rapid synthesis of flavone‐based monoamine oxidase (MAO) inhibitors targeting two active sites using click chemistry

Abstract

A new library of flavone derivatives targeting two active sites of monoamine oxidases ("aromatic cage" and substrate cavity) were designed and synthesized using click chemistry (CuAAC reaction) between 6-N -2-phenyl chromones (Az1-Az2) and a series of alkynes (k1-k20). Their inhibitory activities against MAO isoforms (MAO-A and MAO-B) are evaluated. Compounds with fluorine, amide bonds, or amino bonds have shown better inhibition. The most potent flavone MAO inhibitor studied is Az2k19 (1.6 μm for MAO-A, 2.1 μm for MAO-B), while Az1k15 and Az2k15 displayed better selectivity toward MAO-B (SI > 10). Docking studies are in accordance with our hypothesis that these inhibitors are most likely located at both the substrate cavity and the "aromatic cage". Our results show that it is considerable to develop new MAO inhibitors from C6 substitution of flavone derivatives and that these compounds are also potential for the treatment of diseases associated with MAOs.

Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics

“…Jia et al 82 explored flavone-based MAO inhibitors with structural versatility by retaining the core chromone scaffold using click chemistry (CuAAC reaction) between 6-N 3 -2-phenyl chromones and alkynes, shown in Scheme 5. The study indicated that compound 13 was the best compound with inhibitory activity IC 50 = 1.6 μm for MAO-A and 2.1 μm for MAO-B, while the compound with better selectivity (SI >14.0) towards MAO-B was 14 .…”

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…Jia et al designed and synthesized a new library of flavone derivatives ( 62 ‐ 64 and 64a ) using click chemistry (CuAAC reaction) by reaction between 6‐ N 3 ‐2‐phenyl chromones and a series of alkynes and investigated them for their potential to inhibit MAO‐B (Figure ). Compounds with fluorine, amide bonds, or amino bonds have shown better inhibition.…”

“…Flavones ( 62 ‐ 64 and 64a ) and homoisoflavonoids ( 65 ‐ 94 ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

“…Jia et al 181 From the inhibition data, it was evident that the derivatives 97-99 (97a-l, 98a-k, and 99a-k) were selective inhibitors of MAO-B, with SI > 2.7. Compound 98i was found to be a particularly selective inhibitor, with 1348-fold more selective for MAO-B over the MAO-A isoform.…”

“…Ferulic acid amides (61a-m).180 hMAO, human monoamine oxidase F I G U R E 4 1 Flavones (62-64 and 64a)181 and homoisoflavonoids 182. hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration TRIPATHI AND AYYANNAN | 1639 4.12 | 4-Hydroxyl auronesLi et al 183 synthesized a series of 4-hydroxyl aurone derivatives (95-96) and investigated their potential to inhibit rhMAO-B isozyme (Figure 42).…”