A series of adefovir mono-L-amino acid esters, mono non-steroidal anti-inflammatory drugs   carboxylic ester prodrugs with more potent anti-HBV activity and lower nephrotoxicity were designed and   synthesized.  Adefovir bis (L-amino acid) ester was used as lead compound, according to pathological and pharmacological findings that non-steroidal anti-inflammatory drugs can effectively inhibit the organic anion transporter 1 (hOAT1)-mediated adefovir phosphonic acid pairs of anion transport across tubular basement  membrane thereby reducing the nephrotoxicity of adefovir.  Flatten design principle was used to introducing non-steroidal anti-inflammatory drugs structural fragments to design and synthesize target adefovir mixture ester prodrugs.  HepG2 2.2.15 cell line was used as in vitro anti-HBV activity evaluation model.  Five compounds exhibited antiviral activity, and compound 18 showed the most potent anti-HBV activity and relatively high   selective index (EC₅₀ 3.92 μmol·L⁻¹, SI 9.97).  HK-2 cell line was used as in vitro model to evaluate nephrotoxicity.  Results suggested the target compounds have lower cytotoxicity than the positive control.  Moreover, by analyzing the primary structure and activity relationship of these compounds, it could suggest that mono-L-amino acid ester, mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.