Structure-activity relationships of some arylglycine analogues and catechol isosteres of BRL 36650, a 6 alpha-formamido penicillin.

Earlier reports from these laboratories outlined the preparationx) and biological properties2>3) of 6a-formamido penicillins. The catecholic acylureido derivative BRL 36650 (1) was the most potent, especially against Pseudomonas aeruginosa strains. Wenowreport on analogues of 1 which either retain a catechol or dihydroxyphenyl unit or contain various catechol isosteres. The general concept of isosteric modification in drug design has been reviewed40. Catechol isosteres are meant to prevent enzymic methylation, in particular by catechol 0-methyl transferase into less active monomethyl ethers as reported for other /Mactams5). Frequently the /?ara-hydroxy group has been retained and the meta-hydroxyreplaced with a group bearing a relatively acidic proton6'7) such as -carboxy (4a), methanesulfonamido (4b), or