TY - JOUR
T1 - Evaluation of azasterols as anti-parasitics
AU - Gros, Ludovic
AU - Lorente, Silvia Orenes
AU - Jimenez, Carmen Jimenez
AU - Yardley, Vanessa
AU - Rattray, Lauren
AU - Wharton, Hayley
AU - Little, Susan
AU - Croft, Simon L.
AU - Ruiz-Perez, Luis M.
AU - Gonzalez-Pacanowska, Dolores
AU - Gilbert, Ian H.
N1 - dc.publisher: American Chemical Society
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see [doi:10.1021/jm060290f , see http://pubs.acs.org/page/policy/articlesonrequest/index.html].
dc.description.sponsorship: UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases (TDR)
Plan Nacional de Investigación
SAF2004-03828
FIS Network RICET/C03
PY - 2006/10
Y1 - 2006/10
N2 - NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR ACCURATE DISPLAY. 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.
AB - NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR ACCURATE DISPLAY. 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.
U2 - 10.1021/jm060290f
DO - 10.1021/jm060290f
M3 - Article
C2 - 17004723
SN - 0022-2623
VL - 49
SP - 6094
EP - 6103
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -
