Evaluation of honokiol, magnolol and of a library of new nitrogenated neolignans as pancreatic lipase inhibitors

Obesity is a complex disease defined as an excessive amount of body fat. It is considered a risk factor for several pathologies; therefore, there is an increasing interest in its treatment. Pancreatic lipase (PL) plays a key role in fat digestion, and its inhibition is a preliminary step in the search for anti-obesity agents. For this reason, many natural compounds and their derivatives are studied as new PL inhibitors. This study reports the synthesis of a library of new compounds inspired by two natural neolignans, honokiol (1) and magnolol (2) and bearing amino or nitro groups linked to a biphenyl core. The synthesis of unsymmetrically substituted biphenyls was achieved through an optimisation of the Suzuki-Miyaura cross-coupling reaction followed by the insertion of allyl chains, thus furnishing the O- and/or N-allyl derivatives, and finally, a sigmatropic rearrangement yielding in some cases, the C-allyl analogues. Magnolol, honokiol and the twenty-one synthesised biphenyls were evaluated for their in vitro inhibitory activity toward PL. Three compounds (15b, 16 and 17b) were more effective inhibitors than the natural neolignans (magnolol IC50 = 158.7 mu M and honokiol IC50 = 115.5 mu M) with IC50 of 41-44 mu M. Detailed studies through kinetics suggested better inhibitory activity of the synthetic analogues compared with the natural 1 and 2. Magnolol (Ki = 614.3 mu M; K ' i of 140.9 mu M) and the synthetic biphenyls 15b (Ki = 286.4 mu M; K ' i = 36.6 mu M) and 16 (Ki = 176.2 mu M; K ' i = 6.4 mu M) are mixed-type inhibitors, whereas honokiol (Ki = 674.8 mu M) and 17b (Ki = 249 mu M) are competitive inhibitors. Docking studies corroborated these findings, showing the best fitting for intermolecular interaction between biphenyl neolignans and PL. The above outcomes highlighted how the proposed structures could be considered interesting candidates for future studies for the development of more effective PL inhibitors.