Synthesis of marine-derived 3-alkylpyridinium alkaloids with potent antiprotozoal activity

ACS Med Chem Lett. 2011 Oct 5;2(12):901-6. doi: 10.1021/ml200160k.

Boris Rodenko ¹, Mohammed I Al-Salabi ², Ibrahim A Teka ², William Ho ², Nasser El-Sabbagh ², Juma A M Ali ², Hasan M S Ibrahim ², Martin J Wanner ³, Gerrit-Jan Koomen ³, Harry P de Koning ²

Affiliations

1 Van't Hoff Institute for Molecular Sciences, University of Amsterdam , The Netherlands ; College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
2 College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
3 Van't Hoff Institute for Molecular Sciences, University of Amsterdam , The Netherlands.

PMID: 24900279 DOI: 10.1021/ml200160k

Abstract

Given the pressing need for new antiprotozoal drugs without cross-resistance with current (failing) chemotherapy, we have explored 3-tridecylpyridinium Alkaloids (3TPAs), derivatives of viscosamine, as antiparasitic agents. We have developed a simple synthetic route toward viscosamine and related cyclic and linear monomers and oligomers. Evaluation for cytotoxicity on the protozoan parasites Trypanosoma brucei, Leishmania spp., and Plasmodium falciparum revealed several 3TPAs with antiprotozoal activity in the nanomolar range. Their promising selectivity index in vitro prompted us to study the dynamics of cytotoxicity on trypanosomes in more detail. Parasites were killed relatively slowly at therapeutically safe concentrations, in a process that did not target the cell cycle. Clearance of T. brucei cultures was observed at drug concentrations of 1-10 μM.

Keywords

Alkylpyridinium alkaloids; antileishmanial activity; antiplasmodial activity; antitrypanosomal activity; cytotoxicity; synthesis.

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