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 μM against Trypanosoma brucei rhodesiense and N 6-diphenylethyl-5′-phenylcarboxamidoadenosine with an IC 50 value of 1.8 μM against chloroquine resistant Plasmodium falciparum.