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.