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). The 11000 compounds
were selected for the HTS based on the known phenothiazine Ndh inhibitors,
trifluoperazine and thioridazine. Combined HTS (11000 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 subtemplates. 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,
42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb
patient isolates IC50 = 140 nM) and favorable pharmacokinetic
and toxicological profiles.