New antitubercular pretomanid analogues as potent payloads in polymeric micelles: Leveraging zebrafish assays to accelerate lead optimisation

Third-generation derivatives of the tuberculosis drug pretomanid featuring acetylene-bridged aryl-heteroaryl or heterotriaryl side chains were designed as novel agents for nanoparticle-based delivery, seeking better efficacy and safety. While all nitro compounds retained excellent activity against Mycobacterium tuberculosis , several examples in the latter class excelled as having potency superior to the original lead ( 7 ) but equivalent to or reduced lipophilicity, implying enhanced lipophilic efficiency. Initial studies suggested a similar mode of action against the related fish pathogen, M. marinum ; therefore, fourteen candidates were further assessed as micellar formulations in M. marinum- infected zebrafish embryo assays. Overall, the best new analogue was 14 (the 6-amino-linked congener of 7 ), which was non-toxic and displayed efficacy comparable to 7 in both the blood and neural tube M. marinum infection models. Lead 14 also exhibited high microsomal stability, moderate cell permeability in an MDR1-MDCKII screen, and an enhanced pharmacokinetic profile in mice, with 93% oral bioavailability. • 25 novel compounds, 15 with MIC potencies in the range 1-20 nM vs M. tuberculosis • Nitrogen heterocycles increase lipophilic efficiency, MDR1-MDCKII cell permeability • Studies of original lead imply an equivalent mode of action in M. tb and M. marinum • Micellar formulations of 14 molecules are non-toxic, efficacious in zebrafish model • Amino-linked analogue of original lead has a better pharmacokinetic profile in mice