Enzymatic synthesis and antibacterial activity of andrographolide derivatives

A series of andrographolide derivatives have been synthesized through enzymatic acylation reactions. Immobilized Candida antarctica lipase B (Novozym 435) was found to be a useful biocatalyst for the 35-gram scale syntheses of these acylated derivatives, and the biocatalyst displayed excellent regioselectivity and high operational stability during the transformation. The 14-substituted andrographolide derivative was the sole detectable product from each acylation reaction. The acylated andrographolides showed antibacterial activity against representative Gram-positive and Gram-negative bacteria [with minimal inhibitory concentrations (MICs) as low as 4 μg/mL], whereas andrographolide exhibited no such activity. Chain length of acyl moiety on the lactone-ring at the C-14 position plays an important role in determining the potency of the antibacterial activity. These results indicate an enzymatic modification was not only facile and green, but an effective method for the preparation of an andrographolide monoester.