title: Preparation of transition-state analogues of sterol 24-methyl transferase as potential anti-parasitics.
abstract: There is an urgent need for new drugs to treat leishmaniasis and Chagas disease. One important drug target in these organisms is sterol biosynthesis. In these organisms the main endogenous sterols are ergosta- and stigmata-like compounds in contrast to the situation in mammals, which have cholesterol as the sole sterol. In this paper we discuss the design, synthesis and evaluation of potential transition state analogues of the enzyme Delta24(25)-methyltransferase (24-SMT). This enzyme is essential for the biosynthesis of ergosterol, but not required for the biosynthesis of cholesterol. A series of compounds were successfully synthesised in which mimics of the S-adenosyl methionine co-factor were attached to the sterol nucleus. Compounds were evaluated against recombinant Leishmania major 24-SMT and the parasites L. donovani and Trypanosoma cruzi in vitro, causative organisms of leishmaniasis and Chagas disease, respectively. Some of the compounds showed inhibition of the recombinant Leishmania major 24-SMT and induced growth inhibition of the parasites. Some compounds also showed anti-parasitic activity against L. donovani and T. cruzi, but no inhibition of the enzyme. In addition, some of the compounds had anti-proliferative activity against the bloodstream forms of Trypanosoma brucei rhodesiense, which causes African trypanosomiasis.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
authors.forename: Silvia Orenes
authors.initials: SO
authors.lastname: Lorente
authors.forename: Carmen Jimenez
authors.initials: CJ
authors.lastname: Jimenez
authors.forename: Ludovic
authors.initials: L
authors.lastname: Gros
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Kate
authors.initials: K
authors.lastname: de Luca-Fradley
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Julio
authors.initials: J
authors.lastname: A Urbina
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz-Perez
authors.forename: Dolores Gonzalez
authors.initials: DG
authors.lastname: Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology; D008055:Lipids / Q000737:chemistry; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D018716:Molecular Mimicry; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013261:Sterols / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects*
chemical_list: D008055:Lipids; D013261:Sterols; D014344:Trypanocidal Agents; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase