Synthesis and Biological Activity of Novel Cephalosporins Containing a (Z)-Vinyl Dimethylphosphonate Group.

Abstract

A series of cephalosporins containing a novel 7-[2-(Z)-(2-amino-thiazol-4-yl)-3-(dimethoxyphosphoryl)-acryloylamino] group were prepared and their antibacterial activity measured against a range of pathogens. In general the compoundsdisplayed a broad spectrum of activity against both Grampositive and Gramnegative organisms, except Pseudomonasaeruginosa. Activity against the latter could be achieved by introducing a catechol moiety at the 3 position of the cephalosporin. The methyl phosphonates in general were stable to a wide range of /Mactamases, including the TEM enzymes and the Enterobacter cloacae P99 chromosomal enzyme. In addition, they showed the advantage of being highly water soluble.The emerging resistance to so-called third generation cephalosporins is largely due to the expression of the new, extended spectrum TEMderived /Mactamases. This is a dynamic problem and newagents are needed to moderate this threat. As part of our programmetowards the development of novel broad spectrum cephalosporins with improved /Mactamasestability we embarked on the synthesis of a series of analogues derived from third generation aminothiazolyl oxime cephalosporins in which the oxime moiety 1 was replaced with a (Z)-substituted olefin 2. At the commencement of this work it was well established in the literature that olefinic replacements for the oxime could lead to useful antibacterial activity. The Meiji group had described the synthesis of carboxyvinyl analogues 2a which displayed good Gram-negative activity,1} the orally active ceftibuten 2b was known to display excellent Gram-negative activity and /Mactamase stability2) and (Z)-vinyl sulphones 2c had been prepared by the Bayer group.3~4)To extend the range of olefin substituents we have prepared a series of (Z)-vinyl dimethylphosphonates 2dand herein report their synthesis and biological properties. Results ChemistryOlefination of the glyoxalate 3a5) with the bis-phosphonate 4 afforded the vinylphosphonate ethyl ester 5, as a 1 : 1 mixture of(E) and (Z) isomers which were Illustration 1.Illustration 2.

Species selectivity of new siderophore-drug conjugates that use specific iron uptake for entry into bacteria

“…Several workers showed that it was possible to use outer membrane iron-regulated proteins to transport drugs into gram-negative bacteria. Some investigators have shown that semisynthetic ␤-lactams having a terminal catechol moiety have increased activity relative to other deriv-atives against various microbes, including P. aeruginosa strains (14,33,44,53). Curtis et al (8) showed that activity of a dihydroxybenzoyl derivative of a cephalosporin was dependent on a TonB-mediated transport through the bacterial outer membrane.…”

Ruthenium-Catalyzed [2+2+2] Bis-Homo-Diels–Alder Cycloadditions of 1,5-Cyclooctadiene with Alkynyl Phosphonates

“…Vinyl phosphonates have been found to be important biomolecules in metabolic processes, as anticancer and antiviral drugs, and as antibacterial and antifungal compounds. [13][14][15][16][17][18] The vinyl phosphonate group can be further modified by established procedures. The alkene can undergo cyclopropanation, 19 ozonolysis, 20 or Diels-Alder cycloadditions 21 while the phosphonate can be converted to a variety of other phosphorus groups including phosphines.…”

“…Several polar protic, polar aprotic, and nonpolar solvents were investigated. Using NMP, 1,4-dioxane, THF, or DCE as a solvent (Table 1, entries 2, 8,10,14) or running the reaction neat (entry 1) produced the desired cycloadduct in a 48-85% yield but only using cat. B.…”

Copper-Catalyzed C−P Bond Construction via Direct Coupling of Secondary Phosphines and Phosphites with Aryl and Vinyl Halides

“…In this communication, we wish to report a general protocol for copper- catalyzed synthesis of tertiary phosphines and phosphonates from aryl or vinyl halides and secondary phosphines or phosphites. Both classes of products are of great importance in organic synthesis: tertiary phosphines are widely used as ligands for transition-metal-catalyzed reactions, and alkenylphosphonates are common precursors for preparation of biologically active molecules, flame retardants, and polymer additives…”