Identification of Metabolites Derived from the Anti-trypanosomal Drug Megazol
Abstract
Background: African Trypanosomiasis is an endemic vector-borne parasitic disease in sub-Saharan Africa. It is caused by different parasites of the genus Trypanosoma and is transmitted through a tsetse fly (Glossina sp.) bite during a blood meal. This neglected tropical disease remains difficult to control due to the complexity of treatment protocols and use of toxic drugs. Over the decades, nitroimidazole compounds have been promising molecules for anti-parasite therapy. One of them, megazol, has proven to be an effective anti-trypanosomal drug, but interest dropped after reports were published concerning its mutagenic properties. Objectived: We therefore decided to characterize and identify megazol metabolites, with the hypothesis that they could be less toxic. Methods: We treated groups of mice with different derivatives and then detected metabolites by high performance liquid chromatography combined with mass spectrometry in urine, feces, and plasma samples from mice. Results: In vivo results showed that eleven metabolites were detected in urine (M1 to M11); six metabolites were detected in plasma (M1a/b, M2a/b, M5, M7a/b M9, andM10a/b) and in feces, only two (M1 a/b and M5) were found. Conclusions: The structures of metabolites were deduced using chromatograms and mass spectra data combined with usual metabolic patterns.
Â
Keywords
References
About Sleeping Sickness | DNDi, Drugs Neglected Dis. Initiat. DNDi. (n.d.). Accessed April 9, 2019. https://www.dndi.org/diseases-projects/hat/
Büscher P, Cecchi G, Jamonneau V & Priotto G 2017 Human African trypanosomiasis. Lancet 390 2397-2409
Chauvière G, Bouteille B, Enanga B, de Albuquerque C, Croft SL, Dumas M & Périé J 2003 Synthesis and biological activity of nitro heterocycles analogous to megazol, a trypanocidal lead. J Med Chem 46 427-440
Chauviere G, Rousseau B, Pillon F & Perie J 1998 Synthesis of 2-amino-5-(1-methyl-5-nitro-[4-3H]-2-imidazolyl)-1,3,4-thiadiazole. J Label Comp Radiopharm 41 47–51
de Morais Jr. MA, de Cássia Café Ferreira R & Carlos de Souza Ferreira L 1998 Mutagenic activation of CL64,855, an anti-Trypanosoma cruzi nitroderivant, by bacterial nitroreductases. Genet Mol Biol 21 S1415
Enanga B, Labat C, Boudra H, Chauvière G, Keita M, Bouteille B, Dumas M & Houin G 1997 Simple high-performance liquid chromatographic method to analyse megazol in human and rat plasma. J Chromatogr B Biomed Sci Appl 696 261-266
Enanga B, Ndong JM, Boudra H, Debrauwer L, Dubreuil G, Bouteille B, Chauvière G, Labat C, Dumas M, Périé J & Houin G 2000 Pharmacokinetics, metabolism and excretion of megazol in a Trypanosoma brucei gambiense primate model of human African trypanosomiasis. Preliminary study. Arzneimittelforschung 50 158-162
Ferreira RC & Ferreira LC 1986 CL 64,855, a potent anti-Trypanosoma cruzi drug, is also mutagenic in the Salmonella/microsome assay. Mem Inst Oswaldo Cruz 81 49-52
Franco JR, Cecchi G, Priotto G, Paone M, Diarra A, Grout L, Mattioli RC & Argaw D 2017 Monitoring the elimination of human African trypanosomiasis: Update to 2014. PLoS Negl Trop Dis 11 e0005585
Jacobs RT, Nare B, Wring SA, Orr MD, Chen D, Sligar JM, Jenks MX, Noe RA, Bowling TS, Mercer LT, Rewerts C, Gaukel E, Owens J, Parham R, Randolph R, Beaudet B, Bacchi CJ, Yarlett N, Plattner JJ, Freund Y, Ding C, Akama T, Zhang YK, Brun R, Kaiser M, Scandale I & Don R 2011 SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Negl Trop Dis 5 e1151
Kaiser M, Bray MA, Cal M, Bourdin Trunz B, Torreele E & Brun R 2011 Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness. Antimicrob Agents Chemother 55 5602-5608
Nesslany F, Brugier S, Mouriès MA, Le Curieux F & Marzin D 2004 In vitro and in vivo chromosomal aberrations induced by megazol. Mutat Res 560 147-158
Picard N, Dridi D, Sauvage FL, Boughattas NA & Marquet P 2009 General unknown screening procedure for the characterization of human drug metabolites: Application to loratadine phase I metabolism. J Sep Sci 32 2209-2217
Poli P, Aline de Mello M, Buschini A, Mortara RA, Northfleet de Albuquerque C, da Silva S, Rossi C & Zucchi TM 2002 Cytotoxic and genotoxic effects of megazol, an anti-Chagas' disease drug, assessed by different short-term tests. Biochem Pharmacol 64 1617-1627
Sauvage FL, Picard N, Saint-Marcoux F, Gaulier JM, Lachâtre G & Marquet P 2009 General unknown screening procedure for the characterization of human drug metabolites in forensic toxicology: applications and constraints. J Sep Sci 32 3074-3083
Sauvage FL, Saint-Marcoux F, Duretz B, Deporte D, Lachatre G & Marquet P 2006 Screening of drugs and toxic compounds with liquid chromatography-linear ion trap tandem mass spectrometry. Clin Chem 52 1735-1742
Torreele E, Bourdin Trunz B, Tweats D, Kaiser M, Brun R, Mazué G, Bray MA & Pécoul B 2010 Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness. PLoS Negl Trop Dis 4 e923
WHO | Human African trypanosomiasis, WHO. (n.d.). Accessed April 9, 2019. http://www.who.int/trypanosomiasis_african/en/
Refbacks
- There are currently no refbacks.
Copyright © 2021 Journal of Molecular Biochemistry