Synthesis and Anti-Trypanosomal Activity of Various 8-Aza-7-deaza-5‘-noraristeromycin Derivatives

A recent observation that (+)-7-deaza-5‘-noraristeromycin (1), as an l-like analogue of aristeromycin, possessed meaningful anti-trypanosomal properties has prompted a search of other 7-deazapurines with similar or improved anti-trypanosomal responses. In that direction a series of pyrazolo[3,4-d]pyrimidines (that is, 8-aza-7-deaza-5‘-noraristeromycin derivatives, 2−11) related to 1 have been prepared. These derivatives were evaluated against bloodstream forms of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense grown in vitro. Of these compounds, the parent l-like derivative 2 was less potent (IC50 40−70 μM) than 1 (IC50 0.165−5.3 μM) whereas the d-like analogue 3 was inactive, which is the same trend observed previously with 7-deaza-5‘-noraristeromycin. Interestingly, some moderate activity (IC50 12.2−16.8 μM) was seen in the d-like 4‘-methyl derivative 7 while its l-like partner was inactive.