Authors
J A Gordon1; C W Fishwick1; 1 University of Leeds Discussion
Toxoplasmosis is a highly prevalent apicomplexan parasite, estimated to infect around a third of the world’s population, with an exceptionally broad range of outcomes ranging from apparently asymptomatic to causing potentially fatal toxoplasmic encephalitis. Current treatments are unsuitable for a number of reasons; including side effects leading to intolerance as well as crucially being unable to entirely eliminate the parasite from the host. This can then lead to the potential of recrudescence only preventable by long term prophylactic treatment. The cytochrome bc1 complex as a vital component of the electron transport chain has been validated as promising target for protozoan infections, including evidence of upregulation in the dormant bradyzoite life stage. A number of series are being developed against this target, in particular a number of quinolone/pyridine based series. These series however have suffered from a number of flaws, most notably solubility. In this work we attempt to address a number of these intrinsic flaws while building upon the promising activity these series have obtained. By exploring simple rationally directed scaffold jumps we have reached a series of tetrahydroquinolones (THQ’S) with improved solubility while demonstrating good cellular activity and impressive in vivo efficacy. 
