Nonlinear tetraoxane antimalarials, and the design and synthesis of peroxide and non-peroxide containing anti-tuberculosis drugs

Malaria and tuberculosis (TB) are diseases which have both plagued humanity for thousands of years and remain a significant cause of global death to this day. In 2019 there were a predicted 229 million cases of malaria worldwide causing 409,000 deaths. In the same period there were 10 million cases of active TB and a corresponding 1.4 million deaths. Though treatment for malaria and TB can be effective and curative, treatment failure rates owing to resistance to front-line antimalarial and anti-TB drugs threatens to undermine currently available therapies – therefore the development of novel drugs is essential to the continuing treatment and eradication of these diseases. This work describes three projects focussing on the development of novel peroxide and non-peroxide containing drugs for the treatment of malaria and TB. Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biologicallyrelevant media represents a barrier to clinical development. We present methodology for the synthesis of nonlinear analogues � away from C3 of the coredihydrocarbostyril ring. We hypothesised that incorporation of an electrophilic warhead at this position would enable covalent attachment of the dihydrocarbostryril scaffold to generate covalent inhibitors. These inhibitors could be used in head-to-head studies with non-covalent counterparts to investigate resistance acquisition of covalent versus non-covalent inhibitors. A range of ring-closed and ring-opened covalent analogues were designed and synthesised, guided by molecular docking studies. All synthesised ring-opened analogues were found to be inactive in vitro against Mtb while dihydrocarbostryril containing control compounds 5.10a,b were found to maintain activity. This suggests that the interactions of the dihydrocarbostyril ring system are important to the potency of this class of inhibitors. Ring-closed analogues may better preserve this interaction and are the subject of synthesis by another group member at the time of writing.