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

Abstract

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 in vivo 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 2, 5, and 7 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 2–7 reduced CFA-induced paw edema, as did indomethacin or (S)-naproxen. Based on the promising in vivo anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles in silico. 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.