Oxazolidinones

3.3.1 History

Oxazolidinones are a new structural class of synthetic antibacterial drugs. Reports of structurally novel anti-infectives by DuPont (Fig. 15; 15a,b) in the mid-1980s [187] drew the interest of researchers at the former Pharmacia and Upjohn Inc. (now Pfizer) [188-190]. Two lead compounds, eperezolid (Fig. 15; 15c) and line-zolid (LZD, Fig. 15; 15d) [191], proved to be exceedingly effective wide-spectrum drugs, although LZD was better tolerated in clinical trials. Further development of the oxazolidinone scaffold has yielded PNU-100480 (15e) [191], a linezolid analog currently in phase II clinical trials [192,193], as well as DA-7218 (Fig. 15; 15g) and its metabolite DA-7157 (Fig. 15; 15h), which are in preclinical development (Dong-A Pharmaceuticals, Ltd.) [194]. Ranbaxy Laboratories Limited (acquired in 2008 by Daiichi Sankyo Company) has also made contributions in the form of RBx-7644 (15i) and its more potent analog RBx-8700 (15j) [195], which are in preclinical development. Additionally, AstraZeneca has developed two oxazolidi-nones, AZD2563 (15k) [196] (discontinued at preclinical stage) and AZD5847 (structure not yet available) which is starting phase II clinical trials [197, 198].

3.3.2 Structure-Activity Relationship

Because the oxazolidinones were not developed specifically to treat TB, their SARs have been developed mostly against a number of Gram-positive and Gram-negative bacteria, and little is known about TB-specific SAR. DuPont was the first to publish

15c X = NCOCH2OH; U-100592 (Eperezolid) 15f Y = NHAc; DA-7867 15d X = O; U-100755 (Linezolid, LZD) 15g Y = OPO3Na2; DA-7218

15a X = S; DUP-105 15c X = NCOCH2OH; U-100592 (Eper 15b X = C; DUP-721 15d X = O; U-100755 (Linezolid, LZD) 15e X = S; PNU-100480

15c X = NCOCH2OH; U-100592 (Eperezolid) 15f Y = NHAc; DA-7867 15d X = O; U-100755 (Linezolid, LZD) 15g Y = OPO3Na2; DA-7218

15a X = S; DUP-105 15c X = NCOCH2OH; U-100592 (Eper 15b X = C; DUP-721 15d X = O; U-100755 (Linezolid, LZD) 15e X = S; PNU-100480

NHAc

15i X = O; RBx-7644 (Ranbezolid) 15j X = S; RBx-8700

AZD-2563 15k

NHAc

15i X = O; RBx-7644 (Ranbezolid) 15j X = S; RBx-8700

AZD-2563 15k

Fig. 15 Oxazolidinones

Electron-donating N well tolerated and can improve safety profile

X = Electron-withdrawing substituent best for activity

Xv-T

N' xo S-configuration ^ required meta-F dramatically improves activity

R should contain basic nitrogen - morpholine, meta-F dramatically piperazine, pyridine, elc^ïp^^

/ V-NHAc N-Aryl group i required j

N-Acetylaminomethy l group required

S-configuration required

-NHAc

N-Aryl group required

N-Acetylaminomethy l group required

1st Generation SAR

2nd Generation SAR

3rd Generation SAR

Fig. 16 Evolution of SAR in oxazolidinone class of antibacterials

Table 4 MIC of various oxazolidinone candidates against TB

Drug candidate MIC against MIC against RIF or INH-

H37Rv (mM) resistant clinical isolates (mM) [Ref.] [Ref.]

MIC against RIF and INH-resistant clinical isolates (mM) [Ref.]

Linezolid (15d)

DA-7867 (15f) DA-7157 (15h) DA-7218 (15g) RBx-87GG (15j)

their conclusions about the structural motifs required for antibacterial activity (Fig. 16) [199-201]. These relationships were further refined during the development of eperezolid and LZD [202]. Finally, the development of the RBx and DA compounds has expanded the limits of the functional groups that display antitubercular activity [203].

Activities of the oxazolidinones against TB are shown in Table 4. LZD (Fig 15; 15d) has an MIC against first-line susceptible TB strains of 1.55 mM [204]. For the DA class of compounds, which contain a triazole as the basic side chain, DA-7867 (Fig 15; 15f) proved to be poorly water soluble; hence, a water-soluble prodrug DA-7128 (Fig 15; 15g, which is metabolized to DA-7157, Fig 15; 15h) was developed. Interestingly, against MTb, prodrug DA-7128 performed similar to its (usually more active) metabolite against MTb, giving an MIC of 0.25 mM [207].

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