Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal.

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents.

An analogous library of 2-substituted quinoline compounds was synthesized with the aim to identify a potential drug candidate to treat visceral leishmaniasis. These molecules were tested for their in vitro and in vivo biological activity against Leishmania donovani. Metabolic stability of these compounds was also improved through the introduction of halogen substituents. Compound (26g), found to be the most active; exhibited an IC50 value of 0.2 µM and >180 fold selectivity. The hydrochloride salt of (26g) showed 84.26 ± 4.44 percent inhibition at 50 mg/kg × 5 days (twice daily, oral route) dose in L. donovani/hamster model. The efficacy was well correlated with the PK data observed which indicating that the compound is well distributed.

High throughput physical organic chemistry: analytical constructs for monomer reactivity profiling.

A polymer-supported analytical construct was used to quantify the reactivity of a range of monomers in the Ugi four-component condensation using positive electrospray ionization mass spectrometry (MS) as a quantitative analytical tool. The construct incorporated a bromo group to act as a peak splitter and a quaternary ammonium to act as a MS sensitizer and ionization leveler, thereby allowing direct quantitation of the cleaved adducts by MS. The relative reactivities of 10 carboxylic acids were quantified by the relative levels of product generated as determined by MS and 10 isonitriles, and 10 aldehydes were investigated in the same way. The effect of concentration variations on monomers reactivity and product profiles were rapidly determined using this approach, and the method opens up the way for studying, in a single pot, multiple reactions with a broad range of monomers under identical and self-consistent reaction conditions.