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

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Khan, Tariq A. ; Al Nasr, Ibrahim S. ; Koko, Waleed S. ; Ma, Jingyi ; Eckert, Simon ; Brehm, Lucas ; Ben Said, Ridha ; Daoud, Ismail ; Hanachi, Riadh ; Rahali, Seyfeddine ; van de Sande, Wendy W. J. ; Ersfeld, Klaus ; Schobert, Rainer ; Biersack, Bernhard:
Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives : Booster Effect by Halogen Substituents.
In: ChemMedChem. Bd. 18 (2023) Heft 12 . - e202300132.
ISSN 1860-7187
DOI: https://doi.org/10.1002/cmdc.202300132

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Abstract

Abstract 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 μM). 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 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 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.