Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure–Activity Relationship, Metabolism, and Biology Triaging

Screening
of a library of small polar molecules against Mycobacterium
tuberculosis (Mtb)
led to the identification of a potent benzoheterocyclic oxime carbamate
hit series. This series was subjected to medicinal chemistry progression
underpinned by structure–activity relationship studies toward
identifying a compound for proof-of-concept studies and defining a
lead optimization strategy. Carbamate and free oxime frontrunner compounds
with good stability in liver microsomes and no hERG channel inhibition
liability were identified and evaluated in vivo for
pharmacokinetic properties. Mtb-mediated permeation
and metabolism studies revealed that the carbamates were acting as
prodrugs. Toward mechanism of action elucidation, selected compounds
were tested in biology triage assays to assess their activity against
known promiscuous targets. Taken together, these data suggest a novel
yet unknown mode of action for these antitubercular hits.