Structure-activity-relationship (SAR) for in vitro antileishmanial activity of maesabalide (PX-6518) analogue natural products

• Published in: Planta medica
• Main Authors: Maes, L, Kuypers, K, Vermeersch, M, Cos, P, Pieters, L, Van Puyvelde, L
• Format: Conference Proceeding
• Language: English
• Published: 24.08.2006
• ISSN: 0032-0943; 1439-0221
• DOI: 10.1055/s-2006-949761

Maesabalides (PX-6518) were isolated from the leaves of Maesa balansae Mez. (Myrsinaceae) and shown to have a strong and selective in vitro and in vivo action against the intracellular protozoan Leishmania [1, 2]. Efforts to establish a SAR by selective chemical derivatisation have been hampered by the complexity of the maesabalide moiety [3]. As an alternative approach exploiting available natural diversity, a literature search for structural analogues was performed based on the sapogenin core, i.e. the triterpenoid skeleton with the presence of the hemi-acetal moiety between C -13 and C -17 . The search produced >200 molecules belonging to a several plant genera: Aegicerus , Atroxima , Anagallis, Anamirta, Androsace, Ardisia, Burseria, Cyclamen, Eleutherococcus, Eucommia, Euptelea, Grindelia, Leucas, Lysimachia, Myrsine, Platycodon, Primula, Polemonium and Thevetia . None of these were ever evaluated for antileishmanial activity. The activity against intracellular amastigotes of L.donovani could be determined for some Ardisia (IC 50 =10µg/mL), Maesa (IC 50 =<0.25µg/mL), Lysimachia (IC 50 =11µg/mL), Anagallis (IC 50 =<0.25µg/mL) and Primula (IC 50 =14µg/mL) species. The IC 50 -values for the measabalide PX-6518 was 0.06µg/mL and for the reference drug Miltefosin 8µM. The fact that several active 'hits' were identified confirms that specific derivatives do indeed retain antileishmania activity. However, the occurrence of several negatives also shows that the active maesabalide moiety cannot be subject for major structural changes, endorsing its unique potential. Structural factors that may affect the pharmacological activity will be discussed, but more of the above listed plant genera should be investigated to establish a more complete SAR. Maesabalide sapogenin Acknowledgements: WHO-TDR (Geneva, Switserland), DGOS (Brussels, Belgium), Tibotec (Mechelen, Belgium) References : 1. Maes, L., et al. (2004), Antimicrob. Agents & Chemotherap. 48: 130–136 . 2. Maes, L., et al. (2004), Antimicrob. Agents & Chemotherap. 48: 2056–2060 . 3. Germonprez, N., et al. (2005), J. Med. Chem, 48: 32–37 .