2-[(2,6-Dimethylmorpholin-4-yl)methyl]-4-[(E)-2-{3-[(E)-2-{3-[(2,6-dimethylmorpholin-4-yl)methyl]-4-hydroxy-5-methoxyphenyl}ethenyl]-1H-pyrazol-5-yl}ethenyl]-6-methoxyphenol

Joko Untung,Iskandarsyah Iskandarsyah,Hayun Hayun

doi:10.3390/m949

Abstract

A novel di-Mannich derivative of curcumin pyrazole, 2-[(2,6-dimethyl morpholin-4-yl)methyl]-4-[(E)-2-{3-[(E)-2-{3-[(2,6-dimethylmorpholin-4-yl)methyl]-4-hydroxy-5-methoxyphenyl}ethenyl]-1H-pyrazol-5-yl}ethenyl]-6-methoxyphenol (2), has been synthesized through a Mannich reaction of curcumin pyrazole (1), formaldehyde, and 2,6-dimethylmorpholine. The structure of the synthesized compound was confirmed on the basis of FTIR, 1H-NMR, 13C-NMR, 2D Heteronuclear Single-Quantum Correlation (HSQC) and 2D Heteronuclear Multiple Bond Correlation (HMBC), and mass spectral data. The water solubility was evaluated and the result showed that compound 2 was three times more soluble than that of curcumin pyrazole (1) and curcumin.

Highlights

Several curcuminoids bearing a pyrazole ring showed enhancement in the potency of their biological activity as anti-malarials, anti-proliferates, antiplatelet inhibitors, anti-inflammatory agents, antiviral agents, and NOS inhibitors, in comparison with curcumin [1,2,3,4,5,6,7]
We report the aminomethylation of curcumin pyrazole
The aminoalkylation of compound 1 was achieved through a Mannich reaction using formaldehyde solution and 2,6-dimethylmorpholine at a reflux temperature for 8 h, to give the title compound, 2-[(2,6-dimethylmorpholin-4-yl)methyl]-4-[(E)-2-{3-[(E)-2-{3-[(2,6-dimethylmorpholin-4-yl)methyl]-4hydroxy-5-methoxyphenyl}ethenyl]-1H-pyrazol-5-yl}ethenyl]-6-methoxyphenol (2) (Scheme 1)

Summary

Introduction

Several curcuminoids bearing a pyrazole ring showed enhancement in the potency of their biological activity as anti-malarials, anti-proliferates, antiplatelet inhibitors, anti-inflammatory agents, antiviral agents, and NOS inhibitors, in comparison with curcumin [1,2,3,4,5,6,7]. The water solubility prediction (log S) of curcumin pyrazole is not different enough from curcumin [10]. A Mannich reaction provides a suitable method to introduce an aminoalkyl substituent into a molecule. The Mannich derivatives exhibit better activity than the corresponding parent analogs. The presence of a Mannich side chain increases the solubility and the bioavailability of the drug molecule [11,12,13]. The substitution of aminomethyl into curcumin and into 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one by means of the Mannich reaction was reported [14,15]. We report the aminomethylation of curcumin pyrazole (1) with 2,6-dimethylmorpholine as an amine reagent

Chemistry

Solubility Evaluation

General