Late-Stage Diversification of Rewired Purine C-Nucleosides Reveals Potent Antitrypanosomatid Agents with In Vivo Efficacy
Ewout Van de Velde, Anouk Van Hauwermeiren, Izet Karalic, Natascha Van Pelt, An Matheeussen, Pim-Bart Feijens, Sarah Hendrickx, Denise da Gama Jaén Batista, Ludmila Ferreira de Almeida Fiuza, Cecilia Faria do Carmo, Roberson Donola Girão, Yevva Cranshoff, Siegrid De Baere, Siska Croubels, Maria de Nazaré Correia Soeiro, Guy Caljon, Serge Van CalenberghAbstract
Human African trypanosomiasis, Chagas disease, and leishmaniasis are neglected, debilitating diseases caused by protozoa of the Trypanosomatidae family. In search of new effective therapies, subtle modifications of purine nucleosides have previously afforded agents that demonstrate promising activity against these protozoa, also in vivo. Here, a library of imidazo[2,1-f][1,2,4]triazine ribosides with varying substituents at C6 (trivial purine numbering) was synthesized through late-stage diversification of a common propyl thioether precursor and screened against a panel of the aforementioned Trypanosomatidae. While numerous analogues displayed selective antitrypanosomatid activity, an N6,N6-butylmethylamine analogue 58 proved exquisitely potent against L. infantum, T. cruzi, and T. bruceispp. This analogue was progressed to an acute Chagas and a bioluminescent visceral leishmaniasis mouse model with encouraging results.