LAUSR

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3b/c and 4b/c showed strong activity against L. major promastigotes (IC50 = 4.5-5.8 µM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3b, 3c, and 4a-c exhibited high activity against T. gondii parasites (IC50 = 2.0-3.5 µM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4b. Antifungal activity against Madurellamycetomatis was observed for compound 4c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4b in T. b. brucei cells.