Acyclic nucleoside phosphonates (ANPs) represent an important class of antiviral nucleotide analogues in which a phosphonate group is linked to the alkyl side chain of various purine and pyrimidine nucleobases. One of the ANPs common disadvantages is the negative charge of the phosphonate moiety, which causes their poor bioavailability due to the low cellular uptake. Therefore, to solve this problem, several prodrugs approaches have been investigated. The first most successful prodrugs were Adefovir dipivoxil and Tenofovir disoproxil fumarate, approved for the treatment of hepatitis B and HIV infections, respectively. Very recently, the ProTide technology has been successfully applied to ANPs with Tenofovir alafenamide fumarate (TAF) first approved in 2015 for the treatment of HIV, and later in 2016 for HBV infections.
In search for more potent acyclic nucleoside phosphate and phosphonate with a better safety profile, we are currently studying the impact of the ProTide motif on the antiviral activity of new purine and pyrimidine ANPs derivatives and their prodrugs. The medicinal chemistry aspect of this project involves the development of novel and highly efficient synthetic procedures and the exploration of the SAR of the prodrugs.