9β-Hydroxyparthenolide Esters from Inula montbretiana and Their Antiprotozoal Activity

Abstract

In continuation of ongoing studies on the potential of natural products as antiprotozoal leads or drugs, it was found that the CH₂Cl₂ extract obtained from the flowering aerial parts of Inula montbretiana DC. (Asteraceae, tribe Inuleae) displays antiprotozoal activity, especially against Trypanosoma brucei rhodesiense (IC₅₀: 3.38 µg/mL). Isolation of the possible active constituents led to the identification of six sesquiterpene lactones, all esters of 9β-hydroxyparthenolide. Two isolates, namely, 9β-(3′,4′-epoxy-3′-methylpentanoyloxy)-parthenolide and 9β-(3′-oxo-2′-methylbutanoyloxy)-parthenolide, represented diastereomeric mixtures differing only in the configuration within the acyl moieties. According to in vitro test results, the mixture of esters with diastereomeric 3,4-epoxy-3-methylpentanoic acid was the most active constituent against Trypanosoma brucei rhodesiense (IC₅₀: 0.26 µg/mL) and was less cytotoxic against rat skeletal myoblasts (L6 cell line) with a selectivity index of about 9. The mixture of diastereomeric 2-methyl-3-oxobutyric acid esters was the most potent against Plasmodium falciparum (IC₅₀: 1.48 µg/mL) and displayed a selectivity index of about 35.

Key words

Inula montbretiana DC. - Asteraceae - sesquiterpene lactone - 9-β-acyloxyparthenolide - antiprotozoal activity - Trypanosoma - Leishmania - Plasmodium

References

• 1 Topçu G, Öksüz S, Shieh H-L, Cordell G A, Pezzuto J M, Bozokjohansson C. Cytotoxic and antibacterial sesquiterpenes from Inula graveolens.  Phytochemistry. 1993;  33 407-410
• 2 Song Q H, Kobayashi T, Iijima K, Hong T, Cyong J C. Hepatoprotective effects of Inula britannica on hepatic injury in mice.  Phytother Res. 2000;  14 180-186
• 3 Zhao Y-M, Zhang M-L, Shi Q-W, Kiyota H. Chemical constituents of plants from the genus Inula.  Chem Biodivers. 2006;  3 371-384
• 4 Marco J A, Sanz-Cervera J F, Manglano E. Chlorinated thymol derivatives from Inula crithmoides.  Phytochemistry. 1993;  33 875-878
• 5 Shao Y, Bai N-S, Zhou B-N. Kaurane glycosides from Inula britannica.  Phytochemistry. 1996;  42 783-786
• 6 Zarga M H A, Hamed E M, Sabri S S, Voelter W, Zeller K-P. New sesquiterpenoides from the Jordanian medicinal plant Inula viscosa.  J Nat Prod. 1998;  61 798-800
• 7 Su B-N, Takaishi Y, Yabuuchi T, Kusumi T, Tori M, Takaoka S, Honda G, Ito M, Takeda Y, Kodzhımatov O K, Ashurmetov O. Sesquiterpenes and monoterpenes from the bark of Inula macrophylla.  Chem Nat Prod. 2001;  64 466-471
• 8 Kalsi P S, Goyal R, Talwar K K, Chhabra B R. Stereostructures of two biologically active sesquiterpene lactones from Inula racemosa.  Phytochemistry. 1989;  28 2093-2096
• 9 Yang C, Wang C-M, Jia Z-J. Sesquiterpenes and other constituents from the aerial parts of Inula japonica.  Planta Med. 2003;  69 662-666
• 10 Xie H-G, Chen H, Cao B, Zhang H-W, Zou Z M. Cytotoxic germacranolide sesquiterpene from Inula cappa.  Chem Pharm Bull. 2007;  55 1258-1260
• 11 Nour A M M, Khalid S A, Kaiser M, Brun R, Abdallah W E, Schmidt T J. The antiprotozoal activity of sixteen Asteraceae species native to Sudan and bioactivity-guided isolation of xanthanolides from Xanthium brasilicum.  Planta Med. 2009;  75 1363-1368
• 12 Schmidt T J, Nour A M M, Khalid S A, Kaiser M, Brun R. Quantitative structure-antiprotozoal activity relationships of sesquiterpene lactones.  Molecules. 2009;  14 2062-2076
• 13 Maas M, Hensel A, da Costa F B, Brun R, Kaiser M, Schmidt T J. An unusual dimeric guaianolide with antiprotozoal activity and further sesquiterpene lactones from Eupatorium perfoliatum.  Phytochemistry. 2011;  72 635-644
• 14 Harvala E, Aligiannis N, Skaltsounis A-L, Pratsinis H, Lambrinidis G, Harvala C, Chinou I. Cytotoxic germacranolides from Inula verbascifolia subsp. methanea.  J Nat Prod. 2002;  65 1045-1048
• 15 Stöcklin W, Waddell T G, Geissman T A. Circular dichroism and optical rotatory dispersion of sesquiterpene lactones.  Tetrahedron. 1970;  26 2397-2410
• 16 Ahmed A A, Mohamed Ael-H, Tzakouc O, Petropoulou A, Hassan M E, El-Maghraby M A, Zeller K-P. Terpenes from Inula verbascifolia.  Phytochemistry. 2003;  62 1191-1194

1 Part of thesis. The phytochemical part of this work was performed at the Institute of Pharmaceutical Biology and Phytochemistry, Münster, in March – May 2010.

2 In memory of Dr. rer. nat. Detlef A. W. Wendisch, formerly Abt. ZF-DZA Strukturforschung, Bayer AG, Leverkusen, deceased on July 24, 2011.