Pharmaceutical Chemistry

Type 2 diabetes (T2D) is characterized by impaired insulin secretion and peripheral insulin resistance. Despite many classes of drugs available, T2D is still projected to increase by 55% in 2035. Citrus fruit-derived flavonoid, naringenin has been reported to have antidyslipidemic, anti-oxidant and more recently metformin-like antidiabetic effects. Metformin, the most commonly used drug for T2D management acts by activating adenosine monophosphate activated protein kinase (AMPK). Naringenin’s anti-diabetic effects could be mediated by AMPK activation. Although naringenin has been shown to have anti-diabetic properties, it is less lipophilic and has poor water solubility hence chalco-naringenin analogs with enhanced pharmacological activities were synthesized. A series of 11 compounds of 4-[(cyclopropylcarbonyl) amino] chalco-naringenin analouges were synthesized using Claisen-Schmidt and characterized by IR, 1H-NMR and 13 C-NMR. An intermediate compound, N-(3-acetylphenyl) cyclopropanecarboxamide synthesized was reacted with commercially available aldehydes to yield the final amnio-chalco-naringenin series. The synthesized compounds showed characteristic peaks on IR, 1H-NMR and 13 C-NMR and fit very well in the hydrophobic binding pockets of AMPK. They also presented good binding affinity to the enzyme as shown by computer simulation suggesting potential metformin-like antidiabetic effects.

Further in vitro and in vivo antidiabetic studies are suggested to elucidate the molecular mechanisms of these compounds.