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IntroductionBecause of deficiency in innovative advance in the anti-bacterial drug development, the increasing incidence andprevalence of bacterial resistance to clinically useful anti-biotics is one of the most serious global health threats of thelast two decades.1-4 Oxazolidinones are a new class of anti-bacterial agents used to overcome the innovation deficiency.29444
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Linezolid (Figure 1) is the first oxazolidinone antibioticsapproved in 2000 for the treatment of Gram-positive bacterialinfections in humans.5 It exhibits consistent activity againstmulti-resistant gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistantEnterococci (VRE) and penicillin-resistant Streptococcuspneumouniae.6,7 Furthermore, oxazolidinone class antibioticsshow good activity against multidrug resistance Mycobacteriumtuberculosis infections which is one of the most threateningand wide spreading infectious disease.8-10Linezolid is known to inhibit bacterial protein synthesis bybinding to 50S ribosomal subunit at the translation step andprevent the formation of 70S complex, and the bindingmode was confirmed by X-ray crystallography.11Linezolid is widely used in clinical care as a syntheticunnatural antibiotics and is now prescribed as a last resortantibiotics for the treatment of multi-resistant pathogens likevancomycin, however, clinical emergences of linezolid re-sistant bacteria including Staphylococci and Enterococcihave been reported.12-14 The most common mechanism oflinezolid resistance is point mutations in the 23S rRNApeptidyl transferase region,15-18 and recently a new resistancemechanism mediated by cfr gene encoding methyltransfer-ase has been reported.19,20 Thus, there is a significant needfor the development of new oxazolidinone series with animproved potency and spectrum of antibacterial activity.Four types of chemical modifications of linezolid andoxazolidinone-type antibiotics have been reported,21-24including modifications on each of the A, B and C-rings aswell as the C-5 side chain of the A-ring substructure.22,25Among them, recently, torezolid25 and radezolid27 as shownin Figure 1 are under clinical development.Oxazolidinones containing a lactam substituent represent-ed not only antibacterial agents28,29 but also antithrombotic agents. Rivaroxaban, a lactam substituted oxazolidinonemarketed as Xarelto, is orally active and highly potentcoagulation factor Xa inhibitors and has been approved inUnited States recently for the prophylaxis of venousthromboembolism (VTE).30Herein we report the synthesis and biological evaluationof a series of oxazolidinone-type antibiotics in which the C-ring has been modified by substituted pyrrolidinone ring asshown in Figure 2. Both acetamide and triazole are used as aC-5 side chain. The resulting compounds were then screenedagainst Gram-positive, Gram-negative bacteria, and alsoMycobacterium tuberculosis (Mtb)
H37Rv.Experimental SectionGeneral. 1H and 13C-NMR spectra were recorded onBruker DPX 300 MHz spectrophotometer using CDCl3,CD3OD, DMSO-d6 as NMR solvent. TMS was used as aninternal standard and chemical shift data are reported in partsper million (ppm) and s, d, t, and m are designated as singlet,doublet, triplet and multiplet respectively. Coupling con-stants (J) were reported in hertz (Hz). Mass spectra wererecorded on Waters Acquity UPLC/Synapt G2 QTOF MSmass spectrometer. The reaction progress was monitored bythin layer chromatography (TLC). (S)-N-(4-(5-(Acetamidomethyl)-2-oxo-oxazolidin-3-yl)-2-fluorophenyl)-4-chlorobutanamide (2a). Sodium carbo-nate (87 mg, 0.89 mmol) was added to the solution of aniline1a (20 mg, 0.74 mmol) in acetone at room temperature. 4-Chlorobutyryl chloride (0.10 mL, 0.89 mmol) was added tothe mixture slowly. Reaction mixture was stirred at the sametemperature for 5 h and concentrated. Water (5 mL) wasadded and the mixture was extracted with CH2Cl2 (10 mL ×2). The combined organic layers were dried over MgSO4 andconcentrated under reduced pressure. The residue was puri-fied by flash chromatography on silica gel (hexane/EtOAc,10:1) to yield amide 2a (24 mg, 86%):