Synthesis and Biological Evaluation of N-Formyl Hydroxylamine Derivatives as Potent Peptide Deformylase Inhibitors

Abstract

Antibacterial resistance to hospital-acquired Grampositive bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE), has been increasing at an alarming rate. Therefore there is an urgent need to identify novel antibacterial drugs with new modes of action. Peptide deformylase (PDF), which catalyzes the removal of the N-terminal formyl group from newly synthesized polypeptides and is essential in a variety of pathogenic bacteria but is not required for cytoplasmic protein synthesis in eukaryotes, is an attractive target for the discovery of novel antibiotics. Many PDF inhibitors have been reported in recent years, some of which showed excellent antibacterial activity in vitro and in animal models. Amongst these inhibitors, NVPPDF-713 (2, Vicuron and Novartis) and BB-83698 (3, Vernalis) are currently in phase I clinical trials for the treatment of respiratory tract infections (Fig. 1). Based on the mechanism of deformylation of peptides and the pharmacophore requirements for PDF inhibitor, a new series of arylamidopiperidine derivatives at the P3' position was designed and synthesized. We chose tert-leucine as the P2' residue because other PDF inhibitors containing this P2' residue have shown excellent antibacterial activity and bioavailability. We report here the synthesis and preliminary in vitro evaluation of a new series of PDF inhibitors having an arylamidopiperidine at P3' position. The general route for the synthesis of the arylamidopiperidine derivatives is outlined in Scheme 1. The 1-Boc-4aminopiperidine 6 was prepared in two steps from commercially available N-Boc-piperidin-4-one 5 by reductive amination with benzyl amine followed by hydrogenolysis of the benzyl group. Acylation of the 4-amino group was readily accomplished by treating 6 with p-substituted benzoyl chloride to yield intermediate 7. The piperidine hydrochloride 7 was subsequently coupled by standard peptide coupling conditions using N-Boc-L-tert-leucine to give amide 8. Removal of the N-Boc group with HCl (g)/EtOAc gave amine hydrochloride 9. The N-formyl hydroxylamine analogues were synthesized as shown in Scheme 2. The required chiral intermediate 11 containing the P1' residue was prepared by using Evan’s asymmetric alkylation methodology described previously literature. Reaction of (S)-4-benzyl-2-oxazolidinone with acid 10 in the presence of n-BuLi provided the corresponding oxazolidinone amide. Trichlorotitanium enolate of oxazolidinone amide in CH2Cl2 was obtained by treatment of the amide successively with 1.1 equiv each of TiCl4 and Et3N. Subsequent treatment of this enolate with 2.0 equiv of benzyl chloromethyl ether provided 11 selectively in 90% yield. Removal of the auxiliary group of 11 by hydrolysis under