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This diploma thesis focuses on the synthesis of novel prodrugs of tenofovir, one of the main components of medications against human immunodeficiency virus (HIV) infection. The design of the compounds is based on the concept of ProTides and takes inspiration from the previous work of Filip Kalčic. In this work, the aromatic ester on the phosphonate moiety, typical for the ProTides, is replaced by an aliphatic ester. This aliphatic moiety is represented by a derivative of the amino acid L-serine. All of the target compounds were synthesized in a one-pot manner from three key components (L-serine, L-alanine, and tenofovir), except for one, the synthesis of which remains unsuccessful. The prepared compounds exhibit single-digit micromolar to low nanomolar potency against HIV-1. The most active compound (as a mixture of epimers) exhibited similar anti-HIV-1 activity to the reference ProTide prodrug, tenofovir alafenamide. Most importantly, none of the synthesized ProTides showed cytotoxicity. This was one of the key properties of the compounds from Kalčic's project that we wanted to improve. The results of this thesis represent a stepping stone to a new category of ProTide prodrugs of phosphonates. Key words: prodrugs, acyclic nucleoside phosphonates, ProTides, tenofovir, serine, TAF |
