title: Evaluation of azasterols as anti-parasitics.
abstract: In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti-parasitic activity. In particular, a number of compounds appeared to very potently inhibit the growth of the blood stream form T. b. rhodesiense, with one compound giving an IC50 value of 12 nM. Clear structure activity relationships could be discerned. These compounds represent important leads for further optimization. Azasterols have previously been shown to inhibit sterol biosynthesis in T. cruzi and L. donovani by the inhibition of the enzyme sterol 24-methyltransferase. However, in this case, none of the compounds showed inhibition of the enzyme. Therefore, these compounds have an unknown mode of action.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Gros
authors.forename: Silvia Orenes
authors.initials: SO
authors.lastname: Lorente
authors.forename: Carmen Jimenez
authors.initials: CJ
authors.lastname: Jimenez
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Lauren
authors.initials: L
authors.lastname: Rattray
authors.forename: Hayley
authors.initials: H
authors.lastname: Wharton
authors.forename: Susan
authors.initials: S
authors.lastname: Little
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz-Perez
authors.forename: Dolores
authors.initials: D
authors.lastname: Gonzalez-Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001378:Azasteroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D010963:Plasmodium falciparum / Q000187:drug effects; D013237:Stereoisomerism; D013261:Sterols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000962:Antimalarials; D001378:Azasteroids; D013261:Sterols; D014344:Trypanocidal Agents; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase