Structure–Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5‐Bromo‐1<i>H</i>‐indole‐3‐acetohydroxamic Acid

Abstract SAR by NMR : A series of indole compounds derived from 5‐bromo‐1 H ‐indole‐3‐acetohydroxamic acid were synthesized. Their inhibitory activities were evaluated against purified peptide deformylases (PDFs), and their antibacterial activities against B. subtilis, E. coli (wild type and tolC ), and a variety of pathogens were also determined. The potency of the best inhibitors was related to the NMR footprints of the respective acids with 15 N‐labeled E. coli Ni‐PDF. magnified image The lead compound 5‐bromoindolyl‐3‐acetohydroxamic acid ( 10 ) was recently identified as a potent inhibitor of bacterial peptide deformylases (PDFs). The synthesis and associated activities of new variants were investigated at position 5 to optimize the fit at the S1′ subsite and at position 1 to improve both potency and antibacterial activity. A morphomimetic series, termed “reverse‐indole” was synthesized. The indole derivatives remain selective in vitro inhibitors of PDF2 over PDF1. Bromide is the best group at position 5 and cannot be replaced by bulkier substituents. In this series, an N‐benzyl group at position 1 in 19 e improves the potency relative to 10 . In the case of PDF1, and unlike PDF2, potency is increased as the alkyl chain becomes longer and more ramified. These data support the results of NMR footprinting experiments that were performed with 15 N‐labeled Ni‐PDF and the corresponding 3‐acetic acid derivatives. Most of the compounds have antibacterial activities toward B. subtilis , but are inefficient toward E. coli owing to active removal by the major efflux pumps. Among the reverse‐indole derivatives, 23 c , which is the exact mirror image of 19 e , shows strong potency in vitro against PDF2, but little against PDF1, although this compound displays significant antibacterial activity toward an efflux‐minus mutant of E. coli . All the compounds were assessed with major pathogenic bacteria, but most of them are inefficient antibacterial agents. The reverse‐indole compounds 23 a and 23 c have potency against S. pneumoniae that is similar to that of actinonin.