Microwave-assisted synthesis of C-8 aryl and heteroaryl inosines and determination of their inhibitory activities against Plasmodium falciparum purine nucleoside phosphorylase

• Novel 8-aryl and pyridyl inosines have been synthesized by a direct arylation reaction mediated by Pd/Cu complexes.
• Extensive Quadrasil MP treatment has allowed removal of metal contaminants.
• Several aryl inosines selectively inhibited Plasmodium falciparum PNP but not human or prokaryotic PNPs.

8-Arylinosines have been scarcely studied for therapeutic purposes, probably due to difficulties in their synthesis. The recently described direct arylation reaction at position 8 of purine nucleosides has been employed to synthesize a series of 8-aryl and 8-pyridylinosines. These compounds have been studied for hydrolytic stability and subjected to biological evaluation. Three compounds have shown a pronounced specific inhibition of Plasmodium falciparum-encoded purine nucleoside phosphorylase, an important target for antimalarial chemotherapy.

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