Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth

With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need
for new oral drugs with novel mechanisms of action. A number of scaffolds
with potent anti-tubercular in vitro activity have
been identified from phenotypic screening that appear to target MmpL3.
However, the scaffolds are typically lipophilic, which facilitates
partitioning into hydrophobic membranes, and several contain basic
amine groups. Highly lipophilic basic amines are typically cytotoxic
against mammalian cell lines and have associated off-target risks,
such as inhibition of human ether-à-go-go related gene (hERG)
and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy
in a murine model of acute tuberculosis (TB) infection. However, this
highly lipophilic monobasic amine was cytotoxic and inhibited the
hERG ion channel. Herein, the related spirocycles (1–2) are described, which were identified following phenotypic screening
of the Eli Lilly corporate library against M. tuberculosis. The novel N-alkylated pyrazole portion offered improved physicochemical
properties, and optimization led to identification of a zwitterion
series, exemplified by lead 29, with decreased HepG2
cytotoxicity as well as limited hERG ion channel inhibition. Strains
with mutations in MmpL3 were resistant to 29, and under
replicating conditions, 29 demonstrated bactericidal
activity against M. tuberculosis. Unfortunately,
compound 29 had no efficacy in an acute model of TB infection;
this was most likely due to the in vivo exposure
remaining above the minimal inhibitory concentration for only a limited
time.