Bioactivity-guided isolation of trypanocidal coumarins and dihydro-pyranochromones from selected Apiaceae plant species.

Autor: Krishnan SR; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland., Skiba A; Department of Chemistry of Natural Products, Medical University of Lublin, 20-093, Lublin, Poland., Luca SV; Biothermodynamics, TUM School of Life Sciences, Technical University of Munich, 85354, Freising, Germany; Department of Pharmacognosy, Grigore T. Popa University of Medicine and Pharmacy Iasi, 700115, Iasi, Romania., Marcourt L; School of Pharmaceutical Sciences, University of Geneva, CMU, Rue Michel Servet 1, 1211 Geneva 4, Switzerland., Wolfender JL; School of Pharmaceutical Sciences, University of Geneva, CMU, Rue Michel Servet 1, 1211 Geneva 4, Switzerland., Skalicka-Woźniak K; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland; Department of Chemistry of Natural Products, Medical University of Lublin, 20-093, Lublin, Poland. Electronic address: kskalicka@pharmacognosy.org., Gertsch J; Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland. Electronic address: juerg.gertsch@unibe.ch.
Jazyk: angličtina
Zdroj: Phytochemistry [Phytochemistry] 2023 Sep; Vol. 213, pp. 113770. Date of Electronic Publication: 2023 Jun 16.
DOI: 10.1016/j.phytochem.2023.113770
Abstrakt: Bioactivity-guided isolation of natural products from plant matrices is widely used in drug discovery. Here, this strategy was applied to identify trypanocidal coumarins effective against the parasite Trypanosoma cruzi, the etiologic agent of Chagas disease (American trypanosomiasis). Previously, phylogenetic relationships of trypanocidal activity revealed a coumarin-associated antichagasic hotspot in the Apiaceae. In continuation, a total of 35 ethyl acetate extracts of different Apiaceae species were profiled for selective cytotoxicity against T. cruzi epimastigotes over host CHO-K1 and RAW264.7 cells at 10 μg/mL. A flow cytometry-based T. cruzi trypomastigote cellular infection assay was employed to measure toxicity against the intracellular amastigote stage. Among the tested extracts, Seseli andronakii aerial parts, Portenschlagiella ramosissima and Angelica archangelica subsp. litoralis roots exhibited selective trypanocidal activity and were subjected to bioactivity-guided fractionation and isolation by countercurrent chromatography. The khellactone ester isosamidin isolated from the aerial parts of S. andronakii emerged as a selective trypanocidal molecule (selectivity index ∼9) and inhibited amastigote replication in CHO-K1 cells, though it was significantly less potent than benznidazole. The khellactone ester praeruptorin B and the linear dihydropyranochromones 3'-O-acetylhamaudol and ledebouriellol isolated from the roots of P. ramosissima were more potent and efficiently inhibited the intracellular amastigote replication at < 10 μM. The furanocoumarins imperatorin, isoimperatorin and phellopterin from A. archangelica inhibited T. cruzi replication in host cells only in combination, indicative of superadditive effects, while alloimperatorin was more active in fractions. Our study reports preliminary structure-activity relationships of trypanocidal coumarins and shows that pyranocoumarins and dihydropyranochromones are potential chemical scaffolds for antichagasic drug discovery.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Jürg Gertsch ic co-guest editor of this Special Issue.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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