Synthesis and antiviral evaluation of alkoxyalkyl esters of acyclic purine and pyrimidine nucleoside phosphonates against HIV-1 in vitro

Antiviral Research
Nadejda ValiaevaKarl Y Hostetler

Abstract

Alkoxyalkyl esters of cidofovir, an acyclic nucleoside phosphonate, have been shown to have antiviral activities several orders of magnitude greater than unmodified cidofovir against cytomegalovirus, herpes simplex virus, vaccinia, cowpox, ectromelia and adenoviruses in vitro. Hexadecyloxypropyl-cidofovir is orally bioavailable and active in lethal animal models of vaccinia, cowpox, ectromelia and cytomegalovirus. To see if this strategy is also applicable to other acyclic nucleoside phosphonates, we have converted several phosophonomethoxyethyl purines and pyrimidines to their hexadecyloxypropyl, octadecyloxyethyl and oleyloxyethyl esters and compared their activity against HIV-1 with the activity of the respective unmodified acyclic nucleoside phosphonates. The hexadecyloxypropyl esters of phosphonomethoxyethyl-adenine, phosphonomethoxyethyl-2,6-diaminopurine and phosphonomethoxyethyl-N(6)-cyclopropyl-diaminopurine were 3-5 orders of magnitude more active against HIV-1 in vitro than the parent nucleotides. The EC(50) values for these compounds were in the 10-20 pM range with selective indexes of 1,250 to >4,000. The acyclic pyrimidine phosphonates were generally inactive against HIV-1 in vitro. Phosphonomethoxyethyl-cytosine ...Continue Reading

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Citations

Nov 30, 2006·Antimicrobial Agents and Chemotherapy·Hyunah ChooKarl Y Hostetler
Sep 4, 2009·Future Virology·Scott ParkerR Mark Buller
Nov 26, 2010·Virus Research·Mark N Prichard, Earl R Kern
Aug 22, 2014·Chemical Reviews·Ugo PradereRaymond F Schinazi
Jul 31, 2013·Medicinal Research Reviews·Ondřej Baszczyňski, Zlatko Janeba
Apr 18, 2019·Beilstein Journal of Organic Chemistry·David J JonesTimothy P O'Sullivan
Apr 23, 2008·Current Protocols in Nucleic Acid Chemistry·James R Beadle

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