Perumal Senthil K, Pratt R F
Department of Chemistry, Wesleyan University, Middletown, Connecticut 06459, USA.
J Org Chem. 2006 Jun 23;71(13):4778-85. doi: 10.1021/jo060364v.
A series of amidoketophosph(on)ates of general structure PhCH2OCONHCH(R)COCHR'(CH2)n(O)P(O2-)(O)R'' (R = H, CH3; R' = H, CH3; n = 0, 1; R'' = H, CH3, Et, Ph) have been prepared as a potential source of beta-lactamase inhibitors. The phosphonates (n = 0) were obtained by means of the Arbuzov reaction while most of the phosphates were achieved from reaction of phosph(or/on)ic acids with the appropriate diazoketone PhCH2OCONHCH(R)COCR'N2. The electrophilicity of the carbonyl group in the resulting phosph(on)ates was assessed by the degree of hydration in aqueous solution, determined from NMR spectra. These compounds inhibited typical class C and class D beta-lactamases, particularly the latter group, but showed no activity against class A enzymes. To enhance the carbonyl electrophilicity, an alpha-difluorinated analogue (R = H, CHR' = CF2, n = 0, R'' = Et) was also prepared, but no enhanced inhibitory activity was observed. All evidence suggested that these compounds inhibited in the carbonyl form rather than by formation of tetrahedral adducts at the beta-lactamase active site. They show promise as leads to specific class D beta-lactamase inhibitors.
一系列通式为PhCH2OCONHCH(R)COCHR'(CH2)n(O)P(O2-)(O)R''（R = H，CH3；R' = H，CH3；n = 0，1；R'' = H，CH3，Et，Ph）的脒基酮膦（氧）酸酯已被制备出来，作为β-内酰胺酶抑制剂的潜在来源。膦酸酯（n = 0）通过阿尔布佐夫反应获得，而大多数磷酸酯是由膦（氧）酸与适当的重氮酮PhCH2OCONHCH(R)COCR'N2反应制得。通过核磁共振光谱测定水溶液中的水合程度来评估所得膦（氧）酸酯中羰基的亲电性。这些化合物抑制典型的C类和D类β-内酰胺酶，尤其是后者，但对A类酶没有活性。为了增强羰基亲电性，还制备了一种α-二氟取代类似物（R = H，CHR' = CF2，n = 0，R'' = Et），但未观察到增强的抑制活性。所有证据表明，这些化合物以羰基形式抑制，而不是通过在β-内酰胺酶活性位点形成四面体加合物来抑制。它们有望成为特定D类β-内酰胺酶抑制剂的先导化合物。
