title: Screening of agelasine D and analogs for inhibitory activity against pathogenic protozoa; identification of hits for visceral leishmaniasis and Chagas disease.
abstract: There is an urgent need for novel and improved drugs against several tropical diseases caused by protozoa. The marine sponge (Agelas sp.) metabolite agelasine D, as well as other agelasine analogs and related structures were screened for inhibitory activity against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei and T. cruzi, as well as for toxicity against MRC-5 fibroblast cells. Many compounds displayed high general toxicity towards both the protozoa and MRC-5 cells. However, two compounds exhibited more selective inhibitory activity against L. infantum (IC(50) <0.5 microg/mL) while two others displayed IC(50) <1 microg/mL against T. cruzi in combination with relatively low toxicity against MRC-5 cells. According to criteria set up by the WHO Special Programme for Research & Training in Tropical Diseases (TDR), these compounds could be classified as hits for leishmaniasis and for Chagas disease, respectively. Identification of the hits as well as other SAR data from this initial screening will be valuable for design of more potent and selective potential drugs against these neglected tropical diseases.
authors.affiliation: Department of Chemistry, University of Oslo, P.O.Box 1033, Blindern, N-0315 Oslo, Norway. vik.anders@gmail.com
authors.forename: Anders
authors.initials: A
authors.lastname: Vik
authors.forename: Agnes
authors.initials: A
authors.lastname: Proszenyák
authors.forename: Marieke
authors.initials: M
authors.lastname: Vermeersch
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Lise-Lotte
authors.initials: LL
authors.lastname: Gundersen
mesh_terms: D047230:Agelas / Q000737:chemistry; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects; D011687:Purines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D011687:Purines; D014344:Trypanocidal Agents; C509934:agelasine D