Rational Design, Synthesis and Biological Evaluation of Heterocyclic Quinolones Targeting the respiratory chain of Mycobacterium tuberculosis.

A High-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). 11,000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11,000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ~100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further ~90 hits across three quinolone sub-templates. Quinolones containing the amine based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, MTC420 displays acceptable anti-tuberculosis activity (Mtb IC50 =525 nM, Mtb Wayne IC50 = 76 nM and MDR Mtb patient isolates IC50 = 140 nM) and favourable pharmacokinetic and toxicological profiles