Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents

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 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50=4.5-5.8 mu M). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50=2.0-3.5 mu M) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c 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 4 b in T. b. brucei cells.

Automated summary

Synthetic derivatives of the natural alkaloid piperlongumine, N-acylpyrrolidones and -piperidones, were prepared and tested against Leishmania major and Toxoplasma gondii parasites. Replacement of an aryl meta-methoxy group with halogens increased antiparasitic activities. Some compounds showed strong activity against L. major promastigotes and high activity against T. gondii parasites. QSAR studies and docking calculations revealed binding differences between 2-pyrrolidone and 2-piperidone derivatives. Compound 4 b exhibited microtubules-destabilizing effects in T. b. brucei cells.