Design and synthesis of novel cytochrome bc1 inhibitors for the treatment of toxoplasmosis

Toxoplasmosis is a highly prolific and neglected disease, and current
treatments fail to adequately address the challenges it presents. As such
development of new more efficacious treatments, tailored to the complex
nature of the infection, is required. The causative parasite Toxoplasma gondii
is a resilient and resourceful organism, adept at invasion, avoidance and
survival within its host. The cytochrome bc1 complex has been proven to be a
validated target for the treatment of a number of apicomplexan parasitic
diseases, including both malaria and toxoplasmosis. Recent work has also
identified overexpression of this complex within a strain expressing the difficult
to treat bradyzoite phenotype, which supported by findings that treatment with
known bc1 inhibitor atovaquone shows reduction in cyst burden, suggests this
may be a particularly promising target for an effective systemic parasite
treatment.
Within discusses the design, synthesis and analysis of a number of
cytochrome bc1 inhibitors across several novel scaffolds. Designs focused on
improving deficiencies identified in previous inhibitors. Successful synthesis
of a number of these designs and biological evaluation identified several submicromolar examples. After preliminary ADMET evaluation of the synthesised
scaffolds the tetrahydroquinolone scaffold was selected for further
development. Optimisation of the synthesis to the tetrahydroquinolones
(THQ’s) resulted in access to a library of analogues. From these analogues
compound 169 was selected for further analysis, characterisation and
ultimately progressed to early stage in vivo assays, in which it demonstrated
exceptional potency and efficacy.