Synthesis And Antibacterial Activity Of (2S)-1-[(2R)-2-[(N-hydroxy-formylamino)methyl-1-oxohexyl]Pyrrolidine-2-carboxamides And Their Analogues

Multidrug-resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) have become a serious problem in clinic. Peptide deformylase (PDF) is considered as a novel target for antibacterial drugs and its inhibitors will be a new class of drugs for drug-risistant bacteria.To date, the known PDF inhibitors are mainly peptidomimetic compounds. The metal binding group (MBG) in the inhibitor such as N-hydroxy-formylamino or hydroxamate and the P1 group such as n-butyl or cyclopentylmethyl are necessary pharmacophore. The P2 and the P3 in the inhibitor can provide additional binding energy. Introducing aromatic group at P3-position sometimes leads to an improvement of whole-cell activities. In this paper, LBM-415 was taken as the lead compound and some hydrophobic phenyl groups were introduced at P3-position. It is well known that one of the most important features of the fluoroquinolone antibacterials is the presence of an azacycle at position 7 in the quinolone scanffold, with the effect of improving antibacterial activity and/or pharmacokinetic properties. With this in mind, the azacycles were linked to the phenyl of the P3-position. So (2S)-N-(substituted phenyl)-1-[(2R)-2-[(N-hydroxy-formylamino)methyl]-1-oxohexyl]pyrrolidine-2- carboxamides (A) were designed. Four (2S)-N-[4-(N-oxo-azacyclo-substituted) phenyl]-1-[(2R)-2-[(N-hydroxy-formylamino)methyl]-1-oxohexyl]pyrrolidine-2- carboxamides (B) were prepared by oxidation of some compounds A. The metal ion in PDF adopts a pentacoordinate geometry, bound by the two oxygen atoms of the (N-hydroxy-formylamino)methyl of LBM-415 along with Cys90, His132 and His136 of PDF. It was assumed that the 1,3-dihydroxypropyl may also provide the bidentate ligand to the metal ion by forming six-membered-ring complex. So 21 (2S)-N-aryl-1- [2-(1,3-dihydroxy-2-propyl)-1-oxohexyl]pyrrolidine-2-carboxamides (C) were designed. All of the fifty-one target compounds including A, B and C were unknown and their structures were confirmed by 1HNMR and MS. Some physical and chemical constants such as melting point and [ ]D were also reported. The configuration of compounds C was determined by X-ray crystallographic analysis.Reaction of (2S)-1-benzyloxycarbonyl-pyrrolidine-2-carboxylic acid with various anilines provided (2S)-N-(substituted phenyl)-1-benzyloxycarbonyl-pyrrolidine-2- carboxamides (Ⅲ), which were deprotected to form (2S)-N-(substituted phenyl)- pyrrolidine-2-carboxamides(Ⅰ). Condensation of compoundsⅠwith (2R)-2- [[(N-benzyloxy)formamido]methyl]hexanoic acid (24) gave (2S)-N-(substituted phenyl)-1-[(2R)-2-[(N-benzyloxy)formamido] methyl]-1-oxohexyl]pyrrolidine-2- carboxamides(Ⅱ), followed by debenzylation by catalystic hydrogenation to afford the target compounds A. Oxidation of compound A16, A17, A19 and A20 with m-chloroperbenzoic acid (mCPBA) provided the target compound B1, B2, B3 and B4.Butylation of 4-benzyloxy-3-(benzyloxymethyl)butanoic acid gave racemic 2-(1,3- dibenzyloxy-2-propyl)hexanoic acid(47). Resolution of compound 47 with (R)- - methyl-benzylamine provided (2S)-(+)-2-(1,3-dibenzyloxy-2-propyl)hexanoic acid(50), on the other hand (2R)-(-)-2-(1,3-dibenzyloxy-2-propyl)hexanoic acid(51) was gotten by neutralization the remaining liquid followed by resolution with (S)- -methyl-benzylamine. Condensation of compoundsⅠwith compound 50 or 51 provided (2S)-N-aryl-1-[(2S)-2-(1,3-dibenzyloxy-2-propyl)-1-oxohexyl] pyrrolidine- 2-carboxamides (52) or (2S)-N-aryl-1-[(2R)-2-(1,3-dibenzyloxy-2-propyl)-1-oxo- hexyl]pyrrolidine-2-carboxamides(53). Debenzylation of compounds 52 gave the target compounds C1-C10 and the diasteroisomers C11-C20 were obtained from compounds 53 by the same method. Oxidation of C1 provided C21.All the target compounds were tested in vitro against six Gram-positive and fourteen Gram-negative bacteria by two-fold dilution method. The compounds A showed antibacterial activity equivalent or superior to that of LBM-415 against Gram-positive strains. The compounds B have less potent than compounds A. The compounds C didn’t give significant effect. Studies in vitro against recent clinical isolates Gram-positive bacteria showed that compounds A12, A13 and A21 had superior activity to that of Linezolid. In the in vivo antibacterial studies against MASR-infected mice, the sodium salts of compound A12 and A13 demonstrated more potent than the free acid A12 and A13, but less potent than LBM-415 or Linezolid.