One-Pot Synthesis of Novel Tetrasubstituted α-Aminophosphonates Derived from α-Methylphosphoserine and <i>In Vivo</i> Evaluation as Anti-Inflammatory Agents

A series of new tetrasubstituted α-aminophosphonate derivatives with a methylphosphoserine fragment were described. These compounds were synthesized by a three-component (3-CR) "Kabachnik-Fields reaction." The novel α-aminophosphonates were screened for <i>in vivo</i> anti-inflammatory activity through topical and oral administration routes. All compounds decreased TPA-induced ear edema in a dose-dependent fashion. In this test, compounds <b>2</b>, <b>5,</b> and <b>7</b> showed the same efficacy (≈ 90%) and higher potency than indomethacin and decreased the inflammatory marker neutrophil-to-lymphocyte ratio (NLR). Moreover, oral pretreatment and post-treatment with compounds <b>2</b>-<b>7</b> reduced CFA-induced paw edema, as did indomethacin or (<i>S</i>)-naproxen. Based on the promising <i>in vivo</i> anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles <i>in silico</i>. The analysis also revealed that the novel tetrasubstituted α-aminophosphonates did not break Lipinski's rule of five and had drug-likeness and favorable ADME properties for oral and transdermal administration.