Structural Studies of Piperine Inclusion Complexes in Native and Derivative β-Cyclodextrins

Piperine (PN), the primary pungent alkaloid in black pepper shows several biological activities such as antioxidant, antimicrobial and anti-cancerogenic effects. Similar to other alkaloids, PN is characterized by poor water solubility. One way to improve its solubility and thus its biological activities is by forming inclusion complexes with suitable cyclodextrins. In this work PN inclusion complexes in native β-cyclodextrin (β-CD), its methylated (randomly methylated (RM-β-CD), heptakis-(2,6-di-O-methyl)-β-CD (DM-β-CD) and heptakis-(2,3,6-tri-O-methyl)-β-CD (TM-β-CD)) and 2-hydroxypropylated (HP-β-CD) derivatives are investigated using physicochemical methods, such as phase solubility study and X-ray crystallography complemented by theoretical (molecular dynamics simulations) studies. The determination of the crystal structure of the PN inclusion complexes in β-CD, DM-β-CD and TM-β-CD, reveals the formation of 1:2 guest:host inclusion complexes in the crystalline state. The guest PN molecule threads the hydrophobic cavities of the hosts which are arranged as couples in a tail-to-tail mode in the case of PN/β-CD and in a head-to-tail mode in the cases of PN/DM-β-CD and PN/TM-β-CD. MD studies based on the crystallographically determined structures and docked models show the stability of the examined complexes in an aqueous environment whereas the binding affinity of PN for the host molecules is calculated by the MM/GBSA method. Finally, phase-solubility studies of PN with β-CD, RM-β-CD and HP-β-CD are presented, indicating a B_s-type for the PN/β-CD complex and an A_L-type for the PN/RM-β-CD and PN/HP-β-CD complexes with 1:1 guest:host stoichiometry.