Synthesis and structure-activity relationships of antibacterial phosphonopeptides incorporating (1-aminoethyl)phosphonic acid and (aminomethyl)phosphonic acid

Abstract

Phosphonodipeptides and phosphonooligopeptides based on L- and D-(1-aminoethyl)phosphonic acids L-Ala(P) and D-Ala(P) and (aminomethyl)phosphonic acid Gly(P) at the acid terminus have been synthesized and investigated as antibacterial agents, which owe their activity to the inhibition of bacterial cell-wall biosynthesis. A method for large-scale synthesis of the potent antibacterial agent L-Ala-L-Ala(P) (1, Alafosfalin) is described. Structure-activity relationships in the dipeptide series have been studied by systematic variation of structure 1. L stereochemistry is generally required for both components. Changes in the L-Ala(P) moiety mostly lead to loss of antibacterial activity, but the phosphonate analogues of L-phenylalanine, L-Phe(P), and L-serine, L-Ser(P), give rise to weakly active L-Ala-L-Phe(P) and L-Ala-L-Ser(P). Replacement of L-Ala in 1 by common and rare amino acids can give rise to more potent in vitro antibacterials such as L-Nva-L-Ala(P) (45). Synthetic variation of these more potent dipeptides leads to decreased activity. Phosphonooligopeptides such as (L-Ala)2-L-Ala(P) have a broader in vitro antibacterial spectrum than their phosphonodipeptide precursor, but this is not expressed in vivo, presumably due to rapid metabolism to 1. Stabilized compounds such as Sar-L-Nva-L-Nva-L-Ala(P) (46) have been developed that are more potent in vivo and have a broader in vivo antibacterial spectrum than the parent phosphonodipeptide.

Microwave Assisted One-pot Synthesis of Novel α-Aminophosphonates and heir Biological Activity

“…13 The aminophosphonic and aminophosphinic acids are of considerable interest due to their applications as agrochemicals such as plant growth regulators, pesticides and herbicides.…”

“…Further, heterocyclic phosphonates and ω-aminophosphonates are an important class of compounds, with several potential applications in medicine as anticancer agents, 3 potent enzyme inhibitors, 4 antiviral agents, 5 peptide mimetics, 6 haptens of catalytic antibodies, antibiotics, and pharmacological agents. 7 Their diverse applications include inhibition of synthase, 8 HIV protease, 9 renin, 10 and PTPases.…”

Methods for the synthesis of α-heterocyclic/heteroaryl-α-aminophosphonic acids and their esters

“…These features explain the large range of biological activities displayed by the members of this important class of compounds and the applications. [2][3][4][5] They have been found in areas ranging from medicine to agriculture, for example, as antibiotics, 6 enzyme inhibitors, 7 anticancer agents 8 and herbicides. 9,10 These biological properties mostly are associated with the tetrahedral structure of the phosphonyl group acting as a "transition-state" analogue.…”

Conformation of Sterically Hindered 4-Methyl-2-oxo-2-trityl-1,3,2-dioxaphosphorinane in the Solid State and the Solution

“…Among these the posphonate moiety is an important pharmacophore in the pharmaceutical chemistry [1][2][3][4][5][6] and can be used as a building block for antibiotics [7][8][9][10], herbicides [11,12], insecticides [13], fungicides [14] and anti-viral agents [15]. Additionally, the phosphonic acids and their derivatives may be considered as long life analogues of transition states for tetrahedral intermediates in amide/ester hydrolysis [16].…”