Development of novel organometallic-based antiparasitic drug candidates
Over the recent years, organometallic compounds have shown enormous potential in medicinal chemistry and chemical biology.1-4 An interesting concept in these fields has been the replacement of an organic part (e.g. phenyl ring) of an existing drug by an organometallic complex (e.g. ferrocene). This idea has been pioneered by the group of Gérard Jaouen at Chimie ParisTech by manipulating the organic anticancer drug Tamoxifen to produce the so-called Ferrocifens (Figure 1).2 The most successful example utilising this concept is undoubtedly the antimalarial drug candidate Ferroquine (Figure 1).3 Ferroquine is a ferrocenyl analogue of the antimalarial drug Chloroquine which is currently undergoing phase IIb clinical trial. For both Ferrocifen and Ferroquine, the addition of a metal complex has allowed metal-specific modes of action to be uncovered, which has enabled resistance to be overcome and/or the bioactivity of the organic drug to be enhanced.
Figure 1. Structures of Tamoxifen, Ferrocifen, Chloroquine and Ferroquine.
In this research project, we are currently using a similar concept to fight schistosomiasis. Schistosomiasis is the second most prevalent parasitic disease in the world after malaria. At the moment, schistosomiasis is treated with the organic drug Praziquantel (PZQ, Figure 2). However, PZQ has several drawbacks (i.e. low metabolic stability, inactivity against juvenile worms, etc.). But more worryingly, a decrease in activity has been observed in certain regions of the globe suggesting that PZQ could become (much less) effective in the future.5-7 Over the recent years, in collaborations with Prof. Jennifer Keiser from the Swiss Tropical and Public Health Institute in Basel, we have screened several organometallic compounds as novel antischistosomal drug candidates.8-11 Of high interest, two chromium tricarbonyl complexes were found to have a sub-nanomolar activity against S. mansoni worms (Figure 2).
Figure 2. Structures of Praziquantel (PZQ) and of two chromium tricarbonyl complexes of PZQ.
- Gasser, G.; Metzler-Nolte, N. Curr. Opin. Chem. Biol. 2012, 16, 84.
- Hillard, E. A.; Vessières, A.; Jaouen, G. In Medicinal Organometallic Chemistry; Jaouen, G., Metzler-Nolte, N., Eds.; Springer-Verlag: Heidelberg, 2010; Vol. 32, p 81.
- Biot, C.; Dive, D. In Medicinal Organometallic Chemistry; Jaouen, G., Metzler-Nolte, N., Eds.; Springer-Verlag: Heidelberg, 2010; Vol. 32, p 155.
- Gasser , G. Chimia 2015, accepted.
- Ismail, M.; Botros, S.; Metwally, A.; William, S.; Farghally, A.; Tao, L. F.; Day, T. A.; Bennett, J. L. Am. J. Trop. Med. Hyg. 1999, 60, 932.
- Melman, S. D.; Steinauer, M. L.; Cunningham, C.; Kubatko, L. S.; Mwangi, I. N.; Wynn, N. B.; Mutuku, M. W.; Karanja, D. M. S.; Colley, D. G.; Black, C. L.; Secor, W. E.; Mkoji, G. M.; Loker, E. S. PLoS Negl. Trop. Dis. 2009, 3, e504.
- Greenberg, R. M. Parasitology 2013, 140, 1534.
- Hess, J.; Keiser, J.; Gasser , G. Future. Med. Chem. 2015, 8, 821.
- Patra, M.; Ingram, K.; Leonidova, A.; Pierroz, V.; Ferrari, S.; Robertson, M.; Todd, M. H.; Keiser, J.; Gasser, G. J. Med. Chem. 2013, 56, 9192.
- Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Gasser, R. B.; Keiser, J.; Gasser, G. Chem. Eur. J. 2013, 19, 2232.
- Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Keiser, J.; Gasser, G. J. Med. Chem. 2012, 55, 8790.