Antitrypanosomal Isothiocyanate and Thiocarbamate Glycosides from
                        Moringa peregrina

Mahdi Ayyari; Peyman Salehi; Samad Nejad Ebrahimi; Stefanie Zimmermann; Lena Portmann; R. Luise Krauth-Siegel; Marcel Kaiser; Reto Brun; Hassan Rezadoost; Shamsali Rezazadeh; Matthias Hamburger

doi:10.1055/s-0033-1351102

Planta Medica, Table of Contents

Planta Med 2014; 80(01): 86-89
DOI: 10.1055/s-0033-1351102

Biological and Pharmacological Activity

Letters

Georg Thieme Verlag KG Stuttgart · New York

Antitrypanosomal Isothiocyanate and Thiocarbamate Glycosides from Moringa peregrina

Mahdi Ayyari

¹Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, Tehran, Iran

,

Peyman Salehi

¹Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, Tehran, Iran

,

Samad Nejad Ebrahimi

¹Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, Tehran, Iran

²Department of Pharmaceutical Sciences, Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland

,

Stefanie Zimmermann

²Department of Pharmaceutical Sciences, Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland

³Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

,

Lena Portmann

²Department of Pharmaceutical Sciences, Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland

,

R. Luise Krauth-Siegel

⁴Center of Biochemistry, Heidelberg University, Heidelberg, Germany

,

Marcel Kaiser

³Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

⁵University of Basel, Basel, Switzerland

,

Reto Brun

³Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland

⁵University of Basel, Basel, Switzerland

,

Hassan Rezadoost

¹Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, Tehran, Iran

,

Shamsali Rezazadeh

⁶Department of Pharmacognosy and Phytochemistry, Institute of Medicinal Plants, ACECR, Karaj, Iran

,

Matthias Hamburger

²Department of Pharmaceutical Sciences, Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland

› Author Affiliations

Abstract

O-Methyl (1), O-ethyl (2), and O-butyl (3) 4-[(α-L-rhamnosyloxy) benzyl] thiocarbamate (E), along with 4-(α-L-rhamnosyloxy) benzyl isothiocyanate (4) have been isolated from the aerial parts of Moringa peregrina. The compounds were tested for in vitro activity against Trypanosoma brucei rhodesiense and cytotoxicity in rat skeletal myoblasts (L6 cells). The most potent compound was 4 with an IC₅₀ of 0.10 µM against T. b. rhodesiense and a selectivity index of 73, while the thiocarbamate glycosides 1, 2, and 3 showed only moderate activity. Intraperitoneal administration of 50 mg/kg body weight/day of 4 in the T. b. rhodesiense STIB 900 acute mouse model revealed significant in vivo toxicity. Administration of 10 mg/kg body weight/day resulted in a 95 % reduction of parasitemia on day 7 postinfection, but did not cure the animals. Because of its high in vitro activity and its ability to irreversibly inhibit trypanothione reductase, an attractive parasite-specific target enzyme, 4-[(α-L-rhamnosyloxy) benzyl] isothiocyanate (4), can be considered as a lead structure for the development and characterization of novel antitrypanosomal drugs.

Key words

isothiocyanate - Moringa peregrina - Moringaceae - Trypanosoma brucei rhodesiense - thiocarbamate glycoside

Full Text

References

References
1 Brun R, Blum J, Chappuis F, Burri C. Human African trypanosomiasis. Lancet 2009; 375: 148-159
2 Burri C, Brun R. Human African trypanosomiasis. In: Gordon CC, Zumla AI, editors Mansonʼs Tropical diseases. 22nd edition. Amsterdam: Saunders Elsevier; 2009: 1307-1325
3 Dastan D, Salehi P, Reza Gohari A, Zimmermann S, Kaiser M, Hamburger M, Reza Khavasi H, Ebrahimi SN. Disesquiterpene and sesquiterpene coumarins from Ferula pseudalliacea, and determination of their absolute configurations. Phytochemistry 2012; 78: 170-178
4 Zimmermann S, Kaiser M, Brun R, Hamburger M, Adams M. Cynaropicrin: the first plant natural product with in vivo activity against Trypanosoma brucei . Planta Med 2012; 78: 553-556
5 Adams M, Zimmermann S, Kaiser M, Brun R, Hamburger M. A protocol for HPLC-based activity profiling for natural products with activities against tropical parasites. Nat Prod Commum 2009; 4: 1377
6 Mekonnen Y, Yardley V, Rock P, Croft S. In vitro antitrypanosomal activity of Moringa stenopetala leaves and roots. Phytother Res 1999; 13: 538-539
7 Elbatran SA, Abdel-Salam OM, Abdelshfeek KA, Nazif NM, Ismail SI, Hammouda FM. Phytochemical and pharmacological investigations on Moringa peregrina (Forssk) Fiori. Nat Prod Sci 2005; 11: 1-8
8 Bennett RN, Mellon FA, Foidl N, Pratt JH, Dupont MS, Perkins L, Kroon PA. Profiling glucosinolates and phenolics in vegetative and reproductive tissues of the multi-purpose trees Moringa oleifera L. (horseradish tree) and Moringa stenopetala L. J Agric Food Chem 2003; 51: 3546-3553
9 Anwar F, Latif S, Ashraf M, Gilani AH. Moringa oleifera: a food plant with multiple medicinal uses. Phytother Res 2007; 21: 17-25
10 Fahey JW, Zalcmann AT, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 2001; 56: 5-51
11 Faizi S, Siddiqui BS, Saleem R, Siddiqui S, Aftab K. Isolation and structure elucidation of novel hypotensive agents, niazinin A, niazinin B, niazimicin and niaziminin A+ B from Moringa oleifera: the first naturally occurring thiocarbamates. J Chem Soc [Perkin I] 1992; 3237-3241
12 Krauth-Siegel RL, Comini MA. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta 2008; 1780: 1236-1248
13 Kjær A, Malver O, El-menshawi B, Reischt J. Isothiocyanates in myrosinase-treated seed extracts of Moringa peregrina . Phytochemistry 1979; 18: 1485-1487
14 Eilert U, Wolters B, Nahrstedt A. The antibiotic principle of seeds of Moringa oleifera and Moringa stenopetala . Planta Med 1981; 42: 55-61
15 Shikita M, Fahey JW, Golden TR, Holtzclaw WD, Talalay P. An unusual case of ʼuncompetitive activationʼ by ascorbic acid: purification and kinetic properties of a myrosinase from Raphanus sativus seedlings. Biochem J 1999; 341: 725-732
16 Zhang Y, Talalay P. Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes. Cancer Res 1998; 58: 4632-4639
17 Mahéo K, Morel F, Langouët S, Kramer H, Le Ferrec E, Ketterer B, Guillouzo A. Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res 1997; 57: 3649-3652
18 Saleem R, Meinwald J. Synthesis of novel hypotensive aromatic thiocarbamate glycosides. J Chem Soc [Perkin I] 2000; 391-394
19 Faizi S, Siddiqui BS, Saleem R, Siddiqui S, Aftab K, Gilani AH. Novel hypotensive agents, niazimin A, niazimin B, Niazicin A and Niazicin B from Moringa oleifera: isolation of first naturally occurring carbamates. J Chem Soc [Perkin I] 1994; 3035-3040
20 Leuck M, Kunz H. Synthesis of active principles from the leaves of Moringa oleifera using S-pent-4-enyl thioglycosides. Carbohydr Res 1998; 312: 33-44
21 Bauman RA. Cis-trans isomerism of thionocarbamate esters. J Org Chem 1967; 32: 4129-4132
22 Fueller F, Jehle B, Putzker K, Lewis JD, Krauth-Siegel RL. High throughput screening against the peroxidase cascade of African trypanosomes identifies antiparasitic compounds that inactivate tryparedoxin. J Biol Chem 2012; 287: 8792-8802
23 Nibret E, Wink M. Trypanocidal and antileukaemic effects of the essential oils of Hagenia abyssinica, Leonotis ocymifolia, Moringa stenopetala, and their main individual constituents. Phytomedicine 2010; 17: 911-920
24 Hannaert V. Sleeping sickness pathogen (Trypanosoma brucei) and natural products: therapeutic targets and screening systems. Planta Med 2011; 77: 586-597
25 Schmidt TJ, Khalid SA, Romanha AJ, Alves TM, Biavatti MW, Brun R, Da Costa FB, de Castro SL, Ferreira VF, de Lacerda MV, Lago JH, Leon LL, Lopes NP, das Neves Amorim RC, Niehues M, Ogungbe IV, Pohlit AM, Scotti MT, Setzer WN, Soeiro MDNC, Steindel M, Tempone AG. The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases – part I. Curr Med Chem 2012; 19: 2128-2175
26 Schmidt TJ, Khalid SA, Romanha AJ, Alves TM, Biavatti MW, Brun R, Da Costa FB, De Castro SL, Ferreira VF, De Lacerda MVG, Lago JHG, Leon LL, Lopes NP, Amorim RCDN, Niehues M, Ogungbe IV, Pohlit AM, Scotti MT, Setzer WN, Soeiro MDNC, Steindel M, Tempone AG. The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases – part II. Curr Med Chem 2012; 19: 2176-2228
27 Jockers-Scherübl MC, Schirmer RH, Krauth-Siegel RL. Trypanothione reductase from Trypanosoma cruzi, catalytic properties of the enzyme and inhibition studies with trypanocidal compounds. Eur J Biochem 1989; 180: 267-272

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