title: Synthesis of marine-derived 3-alkylpyridinium alkaloids with potent antiprotozoal activity.
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.
authors.affiliation: 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.
authors.forename: Boris
authors.initials: B
authors.lastname: Rodenko
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: Al-Salabi
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Teka
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Ho
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
authors.forename: Nasser
authors.initials: N
authors.lastname: El-Sabbagh
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
authors.forename: Juma A M
authors.initials: JA
authors.lastname: Ali
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
authors.forename: Hasan M S
authors.initials: HM
authors.lastname: Ibrahim
authors.affiliation: Van't Hoff Institute for Molecular Sciences, University of Amsterdam , The Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wanner
authors.affiliation: Van't Hoff Institute for Molecular Sciences, University of Amsterdam , The Netherlands.
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Koomen
authors.affiliation: College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow , United Kingdom.
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
keywords: Alkylpyridinium alkaloids; antileishmanial activity; antiplasmodial activity; antitrypanosomal activity; cytotoxicity; synthesis