A scaffold hopping exercise undertaken to expand the structural diversity of the fenarimol series of anti-Trypanosoma cruzi (T. cruzi) compounds led to preparation of simple 1-[phenyl(pyridin-3-yl)methyl]piperazinyl analogues of fenarimol which were investigated for their ability to inhibit T. cruzi in vitro in a whole organism assay. A range of compounds bearing amide, sulfonamide, carbamate/carbonate and aryl moieties exhibited low nM activities and two analogues were further studied for in vivo efficacy in a mouse model of T. cruzi infection. One compound, the citrate salt of 37, was efficacious in a mouse model of acute T. cruzi infection after once daily oral dosing at 20, 50 and 100 mg/kg for 5 days.
Keenan, M.; Alexander, P.W.; Diao, H.; Best, W.M.; Khong, A.; Kerfoot, M.; Thompson, R.A.; White, K.L.; Shackleford, D.M.; Ryan, E.; Gregg, A.D.; Charman, S.A.; von Geldern, T.W.; Scandale, I.; Chatelain, E. Design, structure&#8211;activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi. Bioorganic and Medicinal Chemistry (2013) 21 (7) 1756-1763. [DOI: 10.1016/j.bmc.2013.01.050]