Structure Activity Relationship

In an effort to increase potency against MTb, a series of EM analogs was synthesized with modifications at the 2, 3, 6, 9, 11, and 12 positions of the 14-membered lactone ring, as well as at the 4' position of cladinose and the 2" position of

Fig. 29 Erythromycin (EM), 20a, and telithromycin, 20b

desosamine [292-294] (Fig. 30). Specific modifications on the lactone ring such as 6-substitution, 11, 12-carbamate, 11, 12-carbazate, and 9-oxime substitutions enhance potency [294]. Substitution of fluorine at position 2 in ketolides appears to improve both potency and selectivity (i.e., cytotoxicity vs activity against MTb) [293, 294]. The C(6) substituent is critical for activity of the ketolides [293], as it affords acid stability by preventing internal hemiketalization with the 3-keto group

[292]. In general, ketolides are less potent than the corresponding cladinose-con-taining compounds for all substituents on the 6-position [293]. Among 9-oxime-substituted ketolides and macrolides, there is a correlation between the lipophilicity of the substituent on the 9-position (defined as calculated logP) and the potency

[293], with some C(9) oximes showing submicromolar MIC against MTb [294].

The substituent at 11, 12 position appears to significantly affect potency.

A variety of aryl-substituted 11, 12-carbamate and carbazate macrolides and ketolides demonstrated low or submicromolar MICs [294]. Also, the aryl substituent may be involved in determining cytotoxicity [294]. The substituted 11, 12-carba-zate compounds demonstrated significant dose-dependent inhibition of MTb growth in mice, with a 10-20-fold reduction of colony forming units (CFUs) in lung tissue [294].

To further enhance lipophilicity, the 2' and 4"-positions on desosamine and cladinose rings, respectively, have been modified via esterification, which generally improved potency and sometimes decreased CYP3A4 inhibition (more commonly in the cladinose-containing macrolides; see Sect. 4.3.3 for discussion of CYP3A4 inhibition) [293], although the substituent on the 9-position is generally more important than modifications on 2' and 4'' positions [293].

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