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

Abstract

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.

Rapid and General Protocol towards Catalyst‐Free Friedel–Crafts C‐Alkylation of Indoles in Water Assisted by Microwave Irradiation

“…The NMR spectra of the products 3aa, [8] 3ba, [8] 3ca, [9] 3da, [10] 3fa, [11] 3ha, [12] 3ja [11] and 3ka [13] are in accordance with those in the literature. concentration were screened, and it was found that only a 1.2:1.0 ratio of indole/benzyl bromide was required for an efficient conversion, thereby preventing the use of a large excess of reagents without any concentration influence.…”

New Antibiotic Molecules: Bypassing the Membrane Barrier of Gram Negative Bacteria Increases the Activity of Peptide Deformylase Inhibitors

“…Actinonin was used as reference molecule to characterize the antibacterial activities of the newly produced PDF-Is for which an in vitro activity has been previously reported [19]. In Table 1 were presented the results obtained on isogenic strains in the absence or in the presence of various sub-inhibitory concentrations of the cyclic peptide antibiotic polymyxin B (Pol B) or its derivative the polymyxin nonapeptide (PMBN) known to increase membrane permeability [25], [26].…”

“…Most of them such as actinonin, the main characterized inhibitor, are pseudopeptidic molecule [17]. Recently we described a new series of heterocyclic compounds, with an indol scaffold, that inhibit efficiently bacterial PDF in the nM range [18], [19]. Two main mechanisms mediating resistance to peptide deformylase inhibitors in bacteria have been previously described.…”

“…We decided to investigate the involvement of the membrane barrier (the “in and the out” transport) in the activity of some indolic PDF-Is structurally unrelated to actinonin group (Figure 1) and recently produced [18], [19] in various strains and clinical MDR isolates.…”

Direct, enantioselective synthesis of pyrroloindolines and indolines from simple indole derivatives

“…Procedure for Vilsmeier-Haack reaction followed by LiAlH 4 reduction was adapted from Petit et al 16 In a flame-dried flask under nitrogen, POCl 3 (0.42 mL, 4.6 mmol) was added at 0 °C to 4-methyl-1 H -indole (0.5 g, 3.8 mmol) in DMF (7.6 mL). The reaction was stirred at room temperature overnight.…”