Parsons W H, Patchett A A, Bull H G, Schoen W R, Taub D, Davidson J, Combs P L, Springer J P, Gadebusch H, Weissberger B
Exploratory Chemistry Department, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
J Med Chem. 1988 Sep;31(9):1772-8. doi: 10.1021/jm00117a017.
We report the synthesis of a series of phosphinic acid dipeptide analogues, NH2CH(R1)PO(OH)CH2CH(R2)CO2H, related to DAla-DAla. The best of these compounds are potent, essentially irreversible inhibitors of DAla-DAla ligase, and their preferred stereochemistry was shown by chiral synthesis of (1(S)-aminoethyl)(2(R)-carboxy-1-n-propyl)phosphinic acid, 12b, and by X-ray crystallography of its derivative benzyl 1(S)-[(benzyloxycarbonyl)-amino]ethyl phosphinate, 13, to correspond to the stereochemical configuration of DAla-DAla at both centers. A mechanism for the inhibition of DAla-DAla ligase by these compounds is proposed to involve an ATP-dependent formation of phosphorylated inhibitor within the enzyme's active site. The antibacterial activities of these compounds are modest although their spectra include both Gram-positive and Gram-negative susceptible organisms. The best antibacterial activity was shown by (1(S)-aminoethyl) [2-carboxy-2(R)-(methylthio)-1-ethyl]phosphinic acid, 3e, whose MIC's range from 4-128 micrograms/mL on nine of a panel of 11 bacterial organisms. Combination of one of the more active phosphinic acids 12b with the alanine racemase inhibitor fluoro-D-alanine enhances the antibacterial spectrum of the latter on several strains of bacteria and inhibits fluoro-D-alanine's self-reversal, which normally occurs at concentrations several fold higher than its MIC level. This inhibition of fluoro-D-alanine self-reversal is consistent with an involvement of DAla-DAla ligase inhibition in the antibacterial activity of these compounds.
我们报道了一系列与丙氨酰 - 丙氨酸（DAla - DAla）相关的次膦酸二肽类似物NH2CH(R1)PO(OH)CH2CH(R2)CO2H的合成。这些化合物中最优的是DAla - DAla连接酶的强效、基本不可逆的抑制剂，(1(S)-氨基乙基)(2(R)-羧基 - 1 - 正丙基)次膦酸（12b）的手性合成以及其衍生物苄基1(S)-[(苄氧羰基)-氨基]乙基-甲氧羰基 - 1 - 丙基)次膦酸酯（13）的X射线晶体学研究表明，它们的优势立体化学结构在两个中心都与DAla - DAla的立体化学构型一致。有人提出这些化合物抑制DAla - DAla连接酶的机制涉及酶活性位点内ATP依赖的磷酸化抑制剂的形成。尽管这些化合物的抗菌谱包括革兰氏阳性和革兰氏阴性敏感菌，但它们的抗菌活性一般。(1(S)-氨基乙基)[2 - 羧基 - 2(R)-(甲硫基)-1 - 乙基]次膦酸（3e）表现出最佳的抗菌活性，在11种细菌组成的一组测试菌中，有9种菌的最低抑菌浓度（MIC）范围为4 - 128微克/毫升。一种活性较高的次膦酸12b与丙氨酸消旋酶抑制剂氟代 - D - 丙氨酸联合使用，可增强后者对几种细菌菌株的抗菌谱，并抑制氟代 - D - 丙氨酸的自我逆转，这种自我逆转通常发生在浓度比其MIC水平高几倍时。氟代 - D - 丙氨酸自我逆转的这种抑制作用与DAla - DAla连接酶抑制参与这些化合物的抗菌活性是一致的。
