Identification of a Novel Oxazolidinone (U-100480) with Potent Antimycobacterial Activity

Abstract

During the course of our investigations in the oxazolidinone antibacterial agent area, we have identified a subclass with especially potent in vitro activity against mycobacteria. The salient structural feature of these oxazolidinone analogues, 6 (U-100480), 7 (U-101603), and 8 (U-101244), is their appended thiomorpholine moiety. The rational design, synthesis, and evaluation of the in vitro antimycobacterial activity of these analogues is described. Potent activity against a screening strain of Mycobacterium tuberculosis was demonstrated by 6 and 7 (minimum inhibitory concentrations or MIC's < or = 0.125 micrograms/mL). Oxazolidinones 6 and 8 exhibit MIC90 values of 0.50 micrograms/mL or less against a panel of organisms consisting of five drug-sensitive and five multidrug-resistant strains of M. tuberculosis, with 6 being the most active congener. Potent in vitro activity against other mycobacterial species was also demonstrated by 6. For example, 6 exhibited excellent in vitro activity against multiple clinical isolates of Mycobacterium avium complex (MIC's = 0.5-4 micrograms/mL). Orally administered 6 displays in vivo efficacy against M. tuberculosis and M. avium similar to that of clinical comparators isoniazid and azithromycin, respectively. Consideration of these factors, along with a favorable pharmaco-kinetic and chronic toxicity profile in rats, suggests that 6 (U-100480) is a promising antimycobacterial agent.

New Small-Molecule Synthetic Antimycobacterials

“…Several analogues were found to possess MICs Ͻ0.125 g/ml. This potent activity in vitro was complemented by good antitubercular activity against multiple strains of M. tuberculosis (9). Most significantly, activity comparable to that of isoniazid was observed in a mouse model of M. tuberculosis infection.…”

Novel Treatments for Drug-Resistant Tuberculosis

“…35,37 sutezolid Sutezolid is a novel oxazolidinone undergoing premarketing evaluation, which -similar to linezolid, itself a first-generation oxazolidinone -exerts bactericidal activity by inhibiting bacterial protein synthesis. 38 Sutezolid has antimycobacterial activity, and in a murine model, it was found to be more potent than linezolid against M. tuberculosis. 39 In in vitro studies, sutezolid has demonstrated better antimycobacterial activity than linezolid against isolates of MDR-TB and XDR-TB.…”

Tuberculosis: Still a Way to go ahead for a Lead- A Review

“…The prime encounter mode of the chemical entity is through the protein synthesis inhibition of the bacilli. Another potent compound of this class, also have come on the timeline with the research investigation effort, is AZD5847 which is highly effective in intracellular bacilli as well as extracellular cells to that of linezolid without showing antagonism effect to the anti-TB regimen dugs which indicates to the development of the moiety, which has specific protein synthesis hindrance activity as the prior mechanism for anti-TB effect [49][50][51][52][53][54][55][56][57].…”