Acyclic nucleoside phosphonates containing the amide bond

ABSTRACT: To study the influence of a linker rigidity and donor–acceptor properties, the P–CH(2)–O–CHR– fragment in acyclic nucleoside phosphonates (e.g., acyclovir, tenofovir) was replaced by the P–CH(2)–HN–C(O)– residue. The respective phosphonates were synthesized in good yields by coupling the straight chain of ω-aminophosphonates and nucleobase-derived acetic acids with EDC. Based on the (1)H and (13)C NMR data, the unrestricted rotation within the methylene and 1,2-ethylidene linkers in phosphonates from series a and b was confirmed. For phosphonates containing 1,3-propylidene (series c) fragments, antiperiplanar disposition of the bulky O,O-diethylphosphonate and substituted amidomethyl groups was established. The synthesized ANPs P–X–HNC(O)–CH(2)B (X = CH(2), CH(2)CH(2), CH(2)CH(2)CH(2), CH(2)OCH(2)CH(2)) appeared inactive in antiviral assays against a wide variety of DNA and RNA viruses at concentrations up to 100 μM while marginal antiproliferative activity (L1210 cells, IC(50) = 89 ± 16 μM and HeLa cells, IC(50) = 194 ± 19 μM) was noticed for the analog derived from (5-fluorouracyl-1-yl)acetic acid and O,O-diethyl (2-aminoethoxy)methylphosphonate. GRAPHICAL ABSTRACT: [Image: see text]