title: Azasterols as inhibitors of sterol 24-methyltransferase in Leishmania species and Trypanosoma cruzi.
abstract: This paper describes the synthesis of some novel azasterols based on (20R,22xi)-5alpha-pregnan-20-(piperidin-2-yl)-3beta,20-diol. These compounds are potential inhibitors of the enzyme sterol 24-methyltransferase (24-SMT), which is a vital enzyme in the biosynthesis of ergosterol and related 24-alkyl sterols. Structure-activity studies were undertaken to understand the important features for activity against the enzyme, with the aim of increasing activity and selectivity. The compounds were evaluated for inhibition of recombinant Leishmania major 24-SMT and the effect of compounds on sterol composition and parasite proliferation. Essentially, compounds which showed good activity against the recombinant enzyme had a significant effect on the sterol composition and growth of parasites. The activity of compounds was found to be related to the basicity and stereochemical location of the nitrogen. Also, presence of an unprotected 3beta-OH seemed to be important for activity. However, some azasterols which were not good inhibitors of 24-SMT also showed antiproliferative activity, suggesting that there may be other modes of actions of these compounds.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
authors.forename: Filippo
authors.initials: F
authors.lastname: Magaraci
authors.forename: Carmen Jimenez
authors.initials: CJ
authors.lastname: Jimenez
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodrigues
authors.forename: Juliany C F
authors.initials: JC
authors.lastname: Rodrigues
authors.forename: Marina Vianna
authors.initials: MV
authors.lastname: Braga
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: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz-Perez
authors.forename: Julio
authors.initials: J
authors.lastname: Urbina
authors.forename: Dolores
authors.initials: D
authors.lastname: Gonzalez Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007891:Leishmania / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011276:Pregnanediol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D013045:Species Specificity; D013261:Sterols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014345:Trypanosoma / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure
chemical_list: C443579:20-piperidin-2-yl-5-pregnan-3,20-diol; D001372:Aza Compounds; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013261:Sterols; D014344:Trypanocidal Agents; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase; D011276:Pregnanediol