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

Tariq Khan, Ibrahim Al Nasr, Waleed Koko, MA Jingyi, Simon Eckert, Lucas Brehm, Ridha Ben Said, Ismail Daoud, Riadh Hanachi, Seyfeddine Rahali, Wendy van de Sande, klaus Ersfeld, Rainer Schobert, Bernhard Biersack*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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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.
Original languageEnglish
Article numbere202300132
JournalChemMedChem
Volume18
Issue number12
Early online date6 Apr 2023
DOIs
Publication statusPublished - 15 Jun 2023

Bibliographical note

Funding Information:
We are grateful to Prof. Ahmed Fahal of the Mycetoma Research Center in Sudan for providing M. mycetomatis strain MM55 for the in vitro antifungal susceptibility testing, and to the College of Applied Health Sciences at Ar Rass, Qassim University. Open Access funding enabled and organized by Projekt DEAL.

Publisher Copyright:
© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.

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