Tasqiah Julianti1, Maria De Mieri2, Stefanie Zimmermann3, Samad N Ebrahimi4, Marcel Kaiser5, Markus Neuburger6, Melanie Raith2, Reto Brun5, Matthias Hamburger7. 1. Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Faculty of Pharmacy, Pancasila University, Jakarta 12640, Indonesia. 2. Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland. 3. Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Swiss Tropical and Public Health Institute, Basel 4051, Switzerland. 4. Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland; Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, Tehran, Iran. 5. Swiss Tropical and Public Health Institute, Basel 4051, Switzerland. 6. Inorganic Chemistry, Department of Chemistry, University of Basel, Basel 4056, Switzerland. 7. Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel 4056, Switzerland. Electronic address: matthias.hamburger@unibas.ch.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Leaf decoctions of Carica papaya have been traditionally used in some parts of Indonesia to treat and prevent malaria. Leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo. MATERIALS AND METHODS: Antiplasmodial activity of extracts was confirmed and the active fractions in the extract were identified by HPLC-based activity profiling, a gradient HPLC fractionation of a single injection of the extract, followed by offline bioassay of the obtained microfractions. For preparative isolation of compounds, an alkaloidal fraction was obtained via adsorption on cationic ion exchange resin. Active compounds were purified by HPLC-MS and MPLC-ELSD. Structures were established by HR-ESI-MS and NMR spectroscopy. For compounds 5 and 7 absolute configuration was confirmed by comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy data, and by X-ray crystallography. Compounds were tested for bioactivity in vitro against four parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum), and in the Plasmodium berghei mouse model. RESULTS: Profiling indicated flavonoids and alkaloids in the active time windows. A total of nine compounds were isolated. Four were known flavonols--manghaslin, clitorin, rutin, and nicotiflorin. Five compounds isolated from the alkaloidal fraction were piperidine alkaloids. Compounds 5 and 6 were inactive carpamic acid and methyl carpamate, while three alkaloids 7-9 showed high antiplasmodial activity and low cytotoxicity. When tested in the Plasmodium berghei mouse model, carpaine (7) did not increase the survival time of animals. CONCLUSIONS: The antiplasmodial activity of papaya leaves could be linked to alkaloids. Among these, carpaine was highly active and selective in vitro. The high in vitro activity could not be substantiated with the in vivo murine model. Further investigations are needed to clarify the divergence between our negative in vivo results for carpaine, and previous reports of in vivo activity with papaya leaf extracts.
ETHNOPHARMACOLOGICAL RELEVANCE: Leaf decoctions of Carica papaya have been traditionally used in some parts of Indonesia to treat and prevent malaria. Leaf extracts and fraction have been previously shown to possess antiplasmodial activity in vitro and in vivo. MATERIALS AND METHODS: Antiplasmodial activity of extracts was confirmed and the active fractions in the extract were identified by HPLC-based activity profiling, a gradient HPLC fractionation of a single injection of the extract, followed by offline bioassay of the obtained microfractions. For preparative isolation of compounds, an alkaloidal fraction was obtained via adsorption on cationic ion exchange resin. Active compounds were purified by HPLC-MS and MPLC-ELSD. Structures were established by HR-ESI-MS and NMR spectroscopy. For compounds 5 and 7 absolute configuration was confirmed by comparison of experimental and calculated electronic circular dichroism (ECD) spectroscopy data, and by X-ray crystallography. Compounds were tested for bioactivity in vitro against four parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum), and in the Plasmodium bergheimouse model. RESULTS: Profiling indicated flavonoids and alkaloids in the active time windows. A total of nine compounds were isolated. Four were known flavonols--manghaslin, clitorin, rutin, and nicotiflorin. Five compounds isolated from the alkaloidal fraction were piperidine alkaloids. Compounds 5 and 6 were inactive carpamic acid and methyl carpamate, while three alkaloids 7-9 showed high antiplasmodial activity and low cytotoxicity. When tested in the Plasmodium bergheimouse model, carpaine (7) did not increase the survival time of animals. CONCLUSIONS: The antiplasmodial activity of papaya leaves could be linked to alkaloids. Among these, carpaine was highly active and selective in vitro. The high in vitro activity could not be substantiated with the in vivo murine model. Further investigations are needed to clarify the divergence between our negative in vivo results for carpaine, and previous reports of in vivo activity with papaya leaf extracts.
Authors: Mohamed A Dkhil; Saleh Al-Quraishy; Esam M Al-Shaebi; Rewaida Abdel-Gaber; Felwa Abdullah Thagfan; Mahmood A A Qasem Journal: Saudi J Biol Sci Date: 2020-12-19 Impact factor: 4.219
Authors: Bee Ping Teh; Norzahirah Binti Ahmad; Saharuddin Bin Mohamad; Terence Yew Chin Tan; Mohd Ridzuan Bin Mohd Abd Razak; Adlin Binti Afzan; Ami Fazlin Binti Syed Mohamed Journal: Nutrients Date: 2022-04-11 Impact factor: 6.706