Nonpeptidic Templates

Some examples of non-actinonin-based, non-peptidic PDF inhibitors have been described, which are structurally quite different from the inhibitors detailed in the above sections. Most were identified through high-throughput screening efforts.

Thyropropic acid analogues

In 2000, Pfizer published a report of thyropropic acid derivatives as novel, non-peptidic inhibitors of E. coli PDF [99]. Screening of the historical Parke-Davis compound collection resulted in the identification of these novel carboxylic acid PDF inhibitors, as well as peptidic hydroxamic acids similar to actinonin. Thyropropic acid analogues such as (18) inhibit E. coli PDF in the 1-20 mM range, but generally lack antibacterial activity. SAR studies indicated that the carboxylic acid is required for anti-PDF activity, as ester and amide analogues are less potent by two orders of magnitude. Presumably, the carboxylic acid group binds to the enzyme's metal centre. GlaxoSmithKline has published a patent application covering the hydroxamic acid (19) and N-formyl-N-hydroxylamine (20) analogues of a thy-ropropic acid core as PDF inhibitors [100, 101].

CH2COOH

0 0

Post a comment