<i>N</i>‑Aryl-2-aminobenzimidazoles:
Novel, Efficacious, Antimalarial Lead Compounds
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Abstract
From
the phenotypic screening of the AstraZeneca corporate compound
collection, <i>N</i>-aryl-2-aminobenzimidazoles have emerged
as novel hits against the asexual blood stage of <i>Plasmodium
falciparum</i> (<i>Pf</i>). Medicinal chemistry optimization
of the potency against <i>Pf</i> and ADME properties resulted
in the identification of <b>12</b> as a lead molecule. Compound <b>12</b> was efficacious in the <i>P. berghei</i> (<i>Pb</i>) model of malaria. This compound displayed an excellent
pharmacokinetic profile with a long half-life (19 h) in rat blood.
This profile led to an extended survival of animals for over 30 days
following a dose of 50 mg/kg in the <i>Pb</i> malaria model.
Compound <b>12</b> retains its potency against a panel of <i>Pf</i> isolates with known mechanisms of resistance. The fast
killing observed in the <i>in vitro</i> parasite reduction
ratio (PRR) assay coupled with the extended survival highlights the
promise of this novel chemical class for the treatment of malaria