Synthesis and SAR of 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines as novel antileishmanial agents

Abstract

(See P157 in Book of Abstracts above). Leishmaniasis is a disease which infects approximately 12 million people globally, and kills 20 to 50 thousand people annually. The disease presents in both ‘cutaneous’ and ‘visceral’ forms with the cutaneous form manifesting as disfiguring skin ulcerations, and the visceral form as a fever, low red blood cell count, enlarged spleen and liver. The disease is caused by infection with any one of over twenty protozoal parasites, of the genus Leishmania, which are transmitted from person to person occurs through a sand fly insect vector. The novel 7-substituted oxazine class exemplified by 3 and 4 were initially explored as part of an anti-tuberculosis drug development program involving the ACSRC and TB-Alliance. Later phenotypic screening of the oxazines by DNDi led to the discovery of their potent activity against Leishmania donovani. In an effort to improve solubility and safety while maintaining high VL activity over 140 phenyl, and linker group derivatives were synthesised. The most promising leads 36938 and 36940 which were synthesised in enantiopure form are being further evaluated as backup clinical candidates to DNDi’s antileishmaniasis preclinical lead VL-2098.