SAR of Nitroimidazooxazines

PA-824 shows bactericidal activity against drug susceptible (MIC range 0.04-0.8 mM) and resistant (MIC range 0.08-1.5 mM) MTb strains [142]. SAR studies show that the key features responsible for aerobic activity are the nitro group at the 4-position of the imidazole ring (Table 1, Entry 1), the conformationally rigid bicyclic system (Table 1, Entry 3) and the lipophilic tail at the 6-position of the oxazine ring (Table 1, Entries 4 and 5) [145-147]. Antitubercular activity was seen with a biaryl linker (para > meta > ortho), but these compounds exhibited poor solubility in most cases [146]. Heterobiaryl analogs improved solubility over biaryl linkers, and varying lengths of hydrophobic regions at the 6-position of the oxazine

Table 1 SAR of PA-824 [145-147]

Entry

Compound name

Structure

MIC against H37Rv (mM)

1

11d

>160

2

n^°chs

>125

^°CFS

6.25

4

11g

0.04

5

11h

°2N—i J, ,_.

0.05

ring were well tolerated [148] indicating the presence of a large hydrophobic pocket in the active site of Rv3547 (see below for further discussion of mode of action).

The oxygen at 2-position of the nitroimidazole ring could be substituted with nitrogen or sulfur with equipotent aerobic activity, but acylation of the nitrogen, oxidation of sulfur, or replacement of oxygen by a methylene lead to decreased activity (Table 2) [148]. The S-enantiomer is more than 100-fold more active than the R-enantiomer. Replacement of the benzylic ether at the 6-position with an amine marginally increased activity and improved water solubility [148]. Overall SARs for PA-824 are summarized in Fig. 13.

Was this article helpful?

0 0

Post a comment