Synthesis, anti-HBV activity and renal cell toxicity evaluation of mixed phosphonate prodrugs of adefovir.
A series of phosphonate ester prodrugs of adefovir incorporating l-amino (thio)acid and non-steroidal anti-inflammatory drug (NSAID) moieties were synthesized and their anti-HBV activity and renal cell toxicity were evaluated in HepG2 2.2.15 and HK-2 cells respectively. Bioactivity evaluation results revealed that this kind of adefovir prodrug have lower renal cell toxicity than adefovir dipivoxil. Compounds 8a and 8b, incorporating the NSAID ketoprofen and the l-amino acid (Val or Ile) structural fragments, exhibited more potent anti-HBV activity than adefovir dipivoxil with IC(50) = 0.51 and 0.73 μM, SI = 1697.64 and 881.92 respectively. In vitro stability studies showed that the synthesized prodrugs have higher chemical and plasma stability than the positive control adefovir dipivoxil.
School of Pharmacy, Guiyang Medical College, Guiyang, Guizhou, PR China.
Xiao-Zhong
XZ
Fu
Yu
Y
Ou
Jian-Ying
JY
Pei
Ying
Y
Liu
Jing
J
Li
Wen
W
Zhou
Yan-Yu
YY
Lan
Ai-Min
AM
Wang
Yong-Lin
YL
Wang
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000188:drug therapy; D006515:Hepatitis B virus / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; C053001:adefovir; D000225:Adenine