Abstract
Phosphonates, often used as isosteric replacements for phosphates, can provide important interactions with an enzyme. Due to their high charge at physiological pH, however, permeation into cells can be a challenge. Protecting phosphonates as prodrugs has shown promise in drug delivery. Thus, a variety of structures and cleavage/activation mechanisms exist, enabling release of the active compound. This review describes the structural diversity of these pro-moieties, relevant cleavage mechanisms and recent advances in the design of phosphonate prodrugs.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . The expanding role of prodrugs in contemporary drug design and development. Nat. Rev. Drug Discov. 17(8), 559–587 (2018). •• Prodrugs exist for a variety of functional groups and this article explains in great detail the importance of prodrugs and their expanding role in drug development.
- 2. . Chemical aspects of selective toxicity. Nature, 182, 421–422 (1958).
- 3. . A new classification of prodrugs: regulatory perspectives. Pharmaceuticals 2, 77–81 (2009).
- 4. , Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination in Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. Brunton L, Hilal-Dandan RKnollman B (Eds). McGraw-Hill, NY, USA (2018).
- 5. Goldstein AAronow LKalman S (Eds). Chapter 13: Drug Development in Principles of Drug Action. John Wiley & Sons, NJ, USA (1974).
- 6. . Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20–33 (2016).
- 7. . Prodrugs of phosphates and phosphonates. J. Med. Chem. 51(8), 2328–2345 (2008).
- 8. . Phosphonates as analogues of natural phosphates. Chem. Rev. 77, 349–367 (1977).
- 9. . Prodrugs of phosphonates and phosphates: crossing the membrane barrier. Top. Curr. Chem., 360, 115–160 (2015). • Wiemer and Wiemer excellently review not only the history and recent advances within phosphonate and phosphate prodrugs, but also include a thorough description of factors to consider when choosing a pro-moiety and how the active compound would be released.
- 10. . Measurement of transmembrane potentials in phospholipid vesicles. Proc. Natl Acad. Sci. USA, 69(6), 1508–1513 (1972).
- 11. Wuts PGM (Ed.). Protection for the Phosphate Group in Greene's Protective Groups in Organic Synthesis. Wiley, NJ, USA (2014).
- 12. . Bisphosphonate prodrugs: synthesis and in vitro evaluation of alkyl and acyloxymethyl esters of etidronic acid as bioreversible prodrugs of etidronate. Eur. J. Pharm. Sci. 11(2), 173–180 (2000).
- 13. . Synthesis and in vivo evaluation of prodrugs of 9-2-(phosphonomethoxy)ethoxy adenine. J. Med. Chem. 38(8), 1372–1379 (1995).
- 14. N-phosphonomethyl dipeptides and their phosphonate prodrugs, a new-generation of neutral endopeptidase (NEP, EC-3.4.24.11) inhibitors. J. Med. Chem. 37(4), 498–511 (1994).
- 15. Bis (para-methoxy)benzyl phosphonate prodrugs with improved stability and enhanced cell penetration. Bioorg. Med. Chem. Lett. 17(12), 3412–3416 (2007).
- 16. . Antibiotic (-)-cis-(1,2-Epoxypropyl)phosphonates. DE1805682 Merck, Germany (1973).
- 17. . Prodrugs of biologically active phosphate esters. Bioorg. Med. Chem. Lett. 11(6), 885–898 (2003).
- 18. . Biologically reversible phosphate-protective groups. J. Pharm. Sci. 72(3), 324–325 (1983).
- 19. Synthesis of acyloxyanlkyl acylphosphonates as potential prodrugs of the antiviral, trisodium phosphonoformate (foscarnet sodium). Tet. Lett. 30(51), 7141–7144 (1989).
- 20. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. New Eng. J. Med. 348(9), 808–816 (2003).
- 21. Synthesis, oral bioavailability determination, and in-vitro evaluation of prodrugs of the antiviral agent 9-2-(phosphonomethoxy)ethyl adenine (PMEA). J. Med. Chem. 37(12), 1857–1864 (1994).
- 22. The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs. Bioorg. Med. Chem. Lett. 24(2), 649–653 (2014).
- 23. Prodrugs of reverse fosmidomycin analogues. J. Med. Chem. 58(4), 2025–2035 (2015).
- 24. . Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues. Bioorg. Med. Chem. Lett. 25(10), 2112–2116 (2015).
- 25. Targeting cancer cells with a bisphosphonate prodrug. Chemmedchem 11(24), 2656–2663 (2016).
- 26. . HMBPP analog prodrugs bypass energy-dependent uptake to promote efficient BTN3A1-mediated malignant cell lysis by V gamma 9 V delta 2 T lymphocyte effectors. J. Immunol. 197(2), 419–428 (2016).
- 27. Phosphinophosphonates and their tris-pivaloyloxymethyl prodrugs reveal a negatively cooperative butyrophilin activation mechanism. J. Med. Chem. 60(6), 2373–2382 (2017).
- 28. Anti-tumor activity and immunotherapeutic potential of a bisphosphonate prodrug. Sci. Rep. 7, (2017).
- 29. . Pivalate-generating prodrugs and carnitine homeostasis in man. Pharmacol. Rev. 54(4), 589–598 (2002).
- 30. The National Institute for Occupational Safety and Health Registry of Toxic Effects of Chemical Substances: pivalic acid. (2014). https://www.cdc.gov/niosh-rtecs/TO757E20.html
- 31. The National Institute for Occupational Safety and Health Registry of Toxic Effects of Chemical Substances: formaldehyde. https://www.cdc.gov/niosh-rtecs/LP882F48.html (2014)
- 32. . Your prodrug releases formaldehyde: should you be concerned? No! J. Pharm. Sci. 97(10), 4184–4193 (2008).
- 33. . Degradation kinetics of oxycarbonyloxymethyl prodrugs of phosphonates in solution. Pharm. Res. 18(2), 234–237 (2001).
- 34. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2015 update. Clin. Gastroenterol. Hepatol. 13(12), 2071–2087 (2015).
- 35. Nucleotide analogue prodrug tenofovir disoproxil enhances lymphoid cell loading following oral administration in monkeys. Mol. Pharm. 6(4), 1145–1151 (2009).
- 36. Risk of drug resistance among persons acquiring hiv within a randomized clinical trial of single- or dual-agent preexposure prophylaxis. J. Infect. Dis. 211(8), 1211–1218 (2015).
- 37. A Phase I randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring. AIDS 30(5), 743–751 (2016).
- 38. Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA). J. Med. Chem. 59(6), 2810–2819 (2016).
- 39. Rational design for cytosolic delivery of nucleoside monophosphate - SATE and DTE as enzyme-labile transient phosphate protecting groups. Bioorg. Med. Chem. Lett. 3(12), 2521–2526 (1993).
- 40. Synthesis, in vitro antiviral evaluation, and stability studies of bis(S-acyl-2-thioethyl) ester derivatives of 9- 2-(phosphonomethoxy)ethyl adenine (PMEA) as potential PMEA prodrugs with improved oral bioavailability. J. Med. Chem. 39(25), 4958–4965 (1996).
- 41. . S-Acylthioethyl prodrugs of phosphonoformate. Eur. J. Pharm. Sci. 5(4), 199–208 (1997).
- 42. . Design and synthesis of dually branched 5'-norcarbocyclic adenosine phosphonodiester analogue as a new anti-HIV prodrug. Nucleosides Nucleotides Nucleic Acids 29(10), 721–733 (2010).
- 43. Evaluation of the mutagenic and genotoxic activities of anti-hepatitis B analogs of beta-L-adenosine by the Ames test and the Comet assay. Antivir. Res. 50(2), 139–145 (2001).
- 44. . cycloSal-PMEA and cycloAmb-PMEA: potentially new phosphonate prodrugs based on the cycloSal-pronucleotide approach. J. Med. Chem. 48(25), 8079–8086 (2005).
- 45. . cycloSal-2′, 3′-dideoxy-2′,3′-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system. J. Med. Chem. 41(9), 1417–1427 (1998).
- 46. Activities of alkoxvalkyl esters of cidofovir (CDV), cyclic CDV, and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine against orthopoxviruses in cell monolayers and in organotypic cultures. Antimicrob. Agents Chemother. 50(7), 2525–2529 (2006).
- 47. 1-((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl cytosine, an intracellular prodrug for (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine with improved therapeutic index in vivo. Antimicrob. Agents Chemother. 38(10), 2387–2391 (1994).
- 48. Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity. Mol. Pharm. 5(4), 598–609 (2008).
- 49. . Serine side chain-linked peptidomimetic conjugates of cyclic HPMPC and HPMPA: synthesis and interaction with hPEPT1. Mol. Pharm. 7(6), 2349–2361 (2010).
- 50. Tyrosine-based 1-(S) 3-Hydroxy-2-(phosphonomethoxy)propyl cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity, and in vivo transport studies. J. Med. Chem. 54(16), 5680–5693 (2011).
- 51. . Inhibitory activity of alkoxyalkyl and alkyl esters of cidofovir and cyclic cidofovir against orthopoxvirus replication in vitro. Antimicrob. Agents Chemother. 48(5), 1869–1871 (2004).
- 52. Synthesis of Ester Prodrugs of 9-(S)- 3-Hydroxy-2-(phosphonomethoxy)propyl -2,6-diaminopurine (HPMPDAP) as anti-poxvirus agents. J. Med. Chem. 53(19), 6825–6837 (2010).
- 53. Design, synthesis, and characterization of a series of cytochrome P-450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver. J. Am. Chem. Soc. 126(16), 5154–5163 (2004).
- 54. Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B. J. Med. Chem. 51(3), 666–676 (2008).
- 55. . Pradefovir, a liver-targeted prodrug of adefovir against HBV infection. Curr. Opin. Investig. Drugs. 8(8), 682–690 (2007).
- 56. Safety, pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir, a novel liver-targeting, anti-hepatitis B virus drug, in healthy Chinese subjects. Hepatol. Int. 11(4), 390–400 (2017).
- 57. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc. Natl Acad. Sci. USA 104(39), 15490–15495 (2007).
- 58. Synthesis and biological evaluation of a series of liver-selective phosphonic acid thyroid hormone receptor agonists and their prodrugs. J. Med. Chem. 51(22), 7075–7093 (2008).
- 59. A prodrug approach towards the development of tricyclic-based FBPase inhibitors. Bioorg. Med. Chem. Lett. 20(9), 2938–2941 (2010).
- 60. . Alkoxyakl esters of (S)-9- 3-Hydroxy-2-(phosphonomethoxy)propyl adenine are potent inhibitors of the replication of wild-type and drug-resistant human immunodeficiency virus type 1 in vitro. Antimicrob. Agents Chemother. 50(8), 2857–2859 (2006).
- 61. In vitro evaluation of the anti-orf virus activity of alkoxyalkyl esters of CDV, cCDV and (S)-HPMPA. Antivir. Res. 75(1), 52–57 (2007).
- 62. Comparative activities of lipid esters of cidofovir and cyclic cidofovir against replication of herpesviruses in vitro. Antimicrob. Agents Chemother. 49(9), 3724–3733 (2005).
- 63. Evaluation of hexadecyloxypropyl-9-R- 2-(phosphonomethoxy)propyl adenine, CMX157, as a potential treatment for human immunodeficiency virus type 1 and hepatitis B virus infections. Antimicrob. Agents Chemother. 51(10), 3505–3509 (2007).
- 64. Development of hexadecyloxypropyl tenofovir (CMX157) for treatment of infection caused by wild-type and nucleoside/nucleotide-resistant HIV. Antimicrob. Agents Chemother. 54(7), 2901–2909 (2010).
- 65. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. New Eng. J. Med. 369(13), 1227–1236 (2013).
- 66. Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir. Antimicrob. Agents Chemother. 46(4), 991–995 (2002).
- 67. . Increased antiviral activity of 1-O-hexadecyloxypropyl- 2-C-14 cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism. Mol. Pharm. 63(3), 678–681 (2003).
- 68. . Efficacy of oral active ether lipid analogs of cidofovir in a lethal mousepox model. Virology 318(2), 474–481 (2004).
- 69. . Oral treatment of cowpox and vaccinia virus infections in mice with ether lipid esters of cidofovir. Antimicrob. Agents Chemother. 48(2), 404–412 (2004).
- 70. . Oral treatment of murine cytomegalovirus infections with ether lipid esters of cidofovir. Antimicrob. Agents Chemother. 48(9), 3516–3522 (2004).
- 71. Comparison of the antiviral activities of alkoxyalkyl and alkyl esters of cidofovir against human and murine cytomegalovirus replication in vitro. Antimicrob. Agents Chemother. 49(2), 656–662 (2005).
- 72. Alkoxyalkyl esters of cidofovir and cyclic cidofovir exhibit multiple-log enhancement of antiviral activity against cytomegalovirus and herpesvirus replication in vitro. Antimicrob. Agents Chemother. 46(8), 2381–2386 (2002).
- 73. . Synthesis and early development of hexadecyloxypropyl-cidofovir: an oral antipoxvirus nucleoside phosphonate. Viruses 2(10), 2213–2225 (2010).
- 74. . Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses. Expert Rev. Anti Infect. Ther. 12(10), 1171–1178 (2014).
- 75. Brincidofovir for asymptomatic adenovirus viremia in pediatric and adult allogeneic hematopoietic cell transplant recipients: a randomized placebo-controlled Phase II trial. Biol. Blood Marrow Transplant. 23(3), 512–521 (2017).
- 76. Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant. Blood 129(14), 2033–2037 (2017).
- 77. Chimerix. The AdAPT trial; adenovirus after allogeneic pediatric transplantation. (2017). https://clinicaltrials.gov/ct2/show/NCT03339401
- 78. . Reduction sensitive lipid conjugates of tenofovir: synthesis, stability, and antiviral activity. J. Med. Chem. 59(15), 7097–7110 (2016).
- 79. . Next-generation reduction sensitive lipid conjugates of tenofovir: antiviral activity and mechanism of release. J. Med. Chem. 59(22), 10244–10252 (2016).
- 80. . Novel phosphate derivatives of zidovudine as anti-HIV compounds. AIDS 4(4), 371–373 (1990).
- 81. . Tenofovir alafenamide: a novel prodrug of tenofovir for the treatment of human immunodeficiency virus. Antivir. Res. 125, 63–70 (2016).
- 82. . Reactive cyclic intermediates in the ProTide prodrugs activation: trapping the elusive pentavalent phosphorane. Org. Biomol. Chem. 17(2), 315–320 (2019).
- 83. MB06322 (CS-917): a potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in Type 2 diabetes. Proc. Natl Acad. Sci. USA 102(22), 7970–7975 (2005).
- 84. Discovery of phosphonic diamide prodrugs and their use for the oral delivery of a series of fructose 1,6-bisphosphatase inhibitors. J. Med. Chem. 51(14), 4331–4339 (2008).
- 85. . Fructose-1, 6-bisphosphatase inhibitors for reducing excessive endogenous glucose production in Type 2 diabetes. Handb. Exp. Pharmacol. 203, 279–301 (2011).
- 86. Bisamidate prodrugs of 2-substituted 9- 2-(phosphonomethoxy)ethyl adenine (PMEA, adefovir) as selective inhibitors of adenylate cyclase toxin from bordetella pertussis. Chemmedchem 10(8), 1351–1364 (2015).
- 87. Design and synthesis of fluorescent acyclic nucleoside phosphonates as potent inhibitors of bacterial adenylate cyclases. Chemmedchem 11(22), 2534–2546 (2016).
- 88. . Amidate prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine as inhibitors of adenylate cyclase toxin from Bordetella pertussis. Antimicrob. Agents Chemother. 58(2), 664–671 (2014).
- 89. First crystal structures of mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase: complexes with GMP and pyrophosphate and with acyclic nucleoside phosphonates whose prodrugs have antituberculosis activity. J. Med. Chem. 58(11), 4822–4838 (2015).
- 90. Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases. Bioorg. Med. Chem. 23(17), 5502–5510 (2015).
- 91. Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs. Bioorg. Med. Chem. 25, 4008–4030 (2017).
- 92. Synthesis and evaluation of asymmetric acyclic nucleoside bisphosphonates as inhibitors of plasmodium falciparum and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferase. J. Med. Chem. 60(17), 7539–7554 (2017).
- 93. . Synthesis and evaluation of novel amidate prodrugs of PMEA and PMPA. Bioorg. Med. Chem. Lett. 11(8), 1053–1056 (2001).
- 94. . Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells. Chemmedchem 4(11), 1779–1791 (2009).
- 95. Discovery of a beta-D-2′-Deoxy-2′-alpha-fluoro-2′-beta-C-methyluridine nucleotide prodrug (psi-7977) for the treatment of hepatitis c virus. J. Med. Chem. 53(19), 7202–7218 (2010).
- 96. Discovery of GS-9131: design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148. Bioorg. Med. Chem. 18(10), 3606–3617 (2010).
- 97. Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside. J. Med. Chem. 54(20), 7247–7258 (2011).
- 98. . Design, synthesis, and biological evaluation of C1-phosphonamidate analogues of 2-deoxy-D-ribose-l-phosphate. Tetrahedron 69(43), 9111–9119 (2013).
- 99. PMPA and PMEA prodrugs for the treatment of HIV infections and human papillomavirus (HPV) associated neoplasia and cancer. Eur. J. Med. Chem. 78, 259–268 (2014).
- 100. ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents. Bioorg. Med. Chem. 22(9), 2816–2824 (2014).
- 101. . Correction of a genetic deficiency in pantothenate kinase 1 using phosphopantothenate replacement therapy. Mol. Gen. Metab. 116(4), 281–288 (2015).
- 102. Amidate prodrugs of deoxythreosyl nucleoside phosphonates as dual inhibitors of HIV and HBV replication. J. Med. Chem. 59(20), 9513–9531 (2016).
- 103. . Kinase-independent phosphoramidate S1P(1) receptor agonist benzyl ether derivatives. Bioorg. Med. Chem. Lett. 27(6), 1371–1378 (2017).
- 104. Expanding the antiviral spectrum of 3-fluoro-2-(phosphonomethoxy)propyl acyclic nucleoside phosphonates: diamyl aspartate amidate prodrugs. J. Med. Chem. 60(14), 6220–6238 (2017).
- 105. Kinetin riboside and its ProTides activate the parkinson's disease associated PTEN-induced putative kinase 1 (PINK1) independent of mitochondrial depolarization. J. Med. Chem. 60(8), 3518–3524 (2017).
- 106. . Medicinal chemistry of nucleoside phosphonate prodrugs for antiviral therapy. Antivir. Chem. Chemother. 22(5), 181–203 (2012).
- 107. . Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem. Rev. 114(18), 9154–9218 (2014).
- 108. . Nucleoside phosphate and phosphonate prodrug clinical candidates. J. Med. Chem. 59(23), 10400–10410 (2016).
- 109. . The ProTides boom. Chemmedchem 11(11), 1114–1116 (2016).
- 110. . Advanced prodrug strategies in nucleoside and non-nucleoside antiviral agents: a review of the recent five years. Molecules, 22(10), (2017).
- 111. . The ProTide prodrug technology: from the concept to the clinic. J. Med. Chem. 61(6), 2211–2226 (2018). • Offers a fascinating look into the history of how ProTides came to be and how they have advanced since their inception.
- 112. . Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antivir. Chem. Chemother. 26, (2018). •• Not only does the paper offer a brief introduction into the realm of antiviral nucleosides, but synthetic strategies to employ the ProTide method are discussed thoroughly.
- 113. . The methylerythritol phosphate pathway: promising drug targets in the fight against tuberculosis. ACS Infect. Dis. 4(3), 278–290 (2018).
- 114. . The function of terpene natural products in the natural world. Nat. Chem. Biol. 3(7), 408–414 (2007).
- 115. Diaryl ester prodrugs of FR900098 with improved in vivo antimalarial activity. Bioorg. Med. Chem. Lett. 11(6), 833–835 (2001).
- 116. Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity. Bioorg. Med. Chem. Lett. 13(13), 2163–2166 (2003).
- 117. Alkoxycarbonyloxyethyl ester prodrugs of FR900098 with improved in vivo antimalarial activity. Archiv. Der. Pharmazie. 338(7), 305–314 (2005).
- 118. . Synthesis and antimalarial activity of chain substituted pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098. Bioorg. Med. Chem. 14(15), 5121–5135 (2006).
- 119. . alpha-phenylethyl substituted bis(pivaloyloxymethyl) ester analogues of fosmidomycin and FR900098. Aus. J. Chem. 60(3), 154–158 (2007).
- 120. . Growth inhibition of Mycobacterium smegmatis by prodrugs of deoxyxylulose phosphate reducto-isomerase inhibitors, promising anti-mycobacterial agents. Eur. J. Med. Chem. 51, 277–285 (2012).
- 121. Design of potential bisubstrate inhibitors against Mycobacterium tuberculosis (Mtb) 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr)-evidence of a novel binding mode. Medchemcomm 4(7), 1099–1104 (2013).
- 122. Structure-activity relationships of the MEPicides: N-acyl and O-linked analogs of fr900098 as inhibitors of Dxr from mycobacterium tuberculosis and yersinia pestis. ACS Infect. Dis. 2(12), 923–935 (2016).
- 123. MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis. Sci.Rep. 7, (2017).
- 124. MEPicides: alpha,beta-unsaturated fosmidomycin analogues as DXR inhibitors against malaria. J. Med. Chem. 61(19), 8847–8858 (2018).
- 125. Antibacterial and antitubercular activity of fosmidomycin, FR900098, and their lipophilic analogs. Bioorg. Med. Chem. Lett. 21(23), 6973–6976 (2011).
- 126. . Geranylgeranyl diphosphate synthase: an emerging therapeutic target. Clin. Pharmacol. Ther. 90(6), 804–812 (2011).
- 127. . Bisphosphonate prodrugs: synthesis and biological evaluation in HuH7 hepatocarcinoma cells. Eur. J. Med. Chem. 77, 56–64 (2014).
- 128. . Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate. Bioorg. Med. Chem. Lett. 14(19), 4979–4982 (2004).
- 129. Activity of nitrogen-containing and non-nitrogen-containing bisphosphonates on tumor cell lines. J. Med. Chem. 49(19), 5804–5814 (2006).
- 130. Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. Bioorg. Med. Chem. 16(7), 3652–3660 (2008).
- 131. . A new motif for inhibitors of geranylgeranyl diphosphate synthase. Bioorg. Med. Chem. 24(16), 3734–3741 (2016).
- 132. Expansion of human T cells for adoptive immunotherapy using a bisphosphonate prodrug. Cancer Sci. 109(3), 587–599 (2018).
- 133. U.S. Food and Drug Administration approves Gilead's single tablet regimen genvoya (elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide) for treatment of HIV-1 infection (2015). http://www.gilead.com/news/press-releases/2015/11/us-food-and-drug-administration-approves-gileads-single-tablet-regimen-genvoya-elvitegravir-cobicistat-emtricitabine-and-tenofovir-alafenamide-for-treatment-of-hiv1-infection
- 134. Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. J. Hepatol. 62(3), 533–540 (2015).
- 135. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, Phase III, non-inferiority trial. Lancet Gastroenterol. Hepatol. 1(3), 185–195 (2016).
- 136. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled Phase III trial. Lancet HIV 3(4), E158–E165 (2016).
- 137. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, Phase III, non-inferiority trials. Lancet 385(9987), 2606–2615 (2015).
- 138. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Lancet HIV 4(5), E195–E204 (2017).
- 139. Tenofovir alafenamide (TAF) does not deplete mitochondrial DNA in human T-cell lines at intracellular concentrations exceeding clinically relevant drug exposures. Antivir. Res., 140, 116–120 (2017).
- 140. . Pharmacokinetics in mice of the antiretrovirals agent 9-(2-phosphonylmethoxyethyl)adenine. Drug Metab. Dispos. 20(5), 747–752 (1992).
- 141. In vitro evaluation of 9-(2-phosphonylmethoxyethyl)adenine ester analogues, a series of anti-HBV structures with improved plasma stability and liver release. Arch. Pharmacal Res. 37(11), 1416–1425 (2014).
- 142. . Synthesis and antiviral evaluation of base-modified deoxythreosyl nucleoside phosphonates. Org. Biomolec. Chem. 15(26), 5513–5528 (2017).
- 143. Synthesis and evaluation of novel acyclic nucleoside phosphonates as inhibitors of plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases. Chemmedchem 10(10), 1707–1723 (2015).
- 144. Acyclic nucleoside phosphonates containing 9-deazahypoxanthine and a five-membered heterocycle as selective inhibitors of plasmodial 6-oxopurine phosphoribosyltransferases. Chemmedchem 12(14), 1133–1141 (2017).
- 145. Evaluation of novel acyclic nucleoside phosphonates against human and animal gammaherpesviruses revealed an altered metabolism of cyclic prodrugs upon epstein-barr virus reactivation in P3HR-1 cells. J. Virol. 87(22), 12422–12432 (2013).
- 146. USC-087 protects Syrian hamsters against lethal challenge with human species C adenoviruses. Antivir. Res. 153, 1–9 (2018).