title: Solid phase synthesis and antiprotozoal evaluation of di- and trisubstituted 5'-carboxamidoadenosine analogues.
abstract: The rapid increase of resistance to drugs commonly used in the treatment of tropical diseases such as malaria and African sleeping sickness calls for the prompt development of new safe and efficacious drugs. The pathogenic protozoan parasites lack the capability of synthesising purines de novo and they take up preformed purines from their host through various transmembrane transporters. Adenosine derivatives constitute a class of potential therapeutics due to their selective internalisation by these transporters. Automated solid-phase synthesis can speed up the process of lead finding and we pursued the solid-phase synthesis of di- and trisubstituted 5'-carboxamidoadenosine derivatives by using a safety-catch approach. While efforts with Kenner's sulfonamide linker remained fruitless, successful application of the hydrazide safety-catch linker allowed the construction of two representative combinatorial libraries. Their antiprotozoal evaluation identified two compounds with promising activity: N(6)-benzyl-5'-N-phenylcarboxamidoadenosine with an IC(50) value of 0.91 microM against Trypanosoma brucei rhodesiense and N(6)-diphenylethyl-5'-phenylcarboxamidoadenosine with an IC(50) value of 1.8 microM against chloroquine resistant Plasmodium falciparum.
authors.affiliation: Van't Hoff Institute for Molecular Sciences, Universiteit van Amsterdam, The Netherlands.
authors.forename: Boris
authors.initials: B
authors.lastname: Rodenko
authors.forename: Remko J
authors.initials: RJ
authors.lastname: Detz
authors.forename: Victorine A
authors.initials: VA
authors.lastname: Pinas
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wanner
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Koomen
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000981:Antiprotozoal Agents; D006834:Hydrazines; D013449:Sulfonamides; D019830:Adenosine-5'-(N-ethylcarboxamide); D002738:Chloroquine