Novel heterocyclic nitrofurfural hydrazones. In vivo antirypanosomal activity.
Hydrazine derivatives of several pyrazolo[1,5-alpha]pyrimidines (A), pyrazolo[1,5-alpha]-1,3,5-triazines (B), s-triazolo[1,5-alpha]pyrimidines (C), and imidazo[1,2-alpha]pyrimidines (D) were synthesized and condensed with 5-nitrofurfural in order to obtain the corresponding nitrofurfural hydrazones of each heterocycle (1d-14d). Each compound was screened for in vitro activity against Trypanosoma cruzi. The compounds were then tested in vivo against experimental infections of T. cruzi in laboratory (C3H/He strain) mice. An interesting structure-activity relationship was uncovered, revealing that 5-methyl-7-(5-nitrofurfurylidenehydrazino)pyrazolo[1,5-alpha]pyrimidine (2d) greatly increased the mean survival time (IMST) of mice with terminal infections. Subtle alterations in the structure of 2d, such as the substitution of a 5-hydrogen for the 5-methyl group (1d) or the substitution of the 3-hydrogen by the water-soluble 3-sulfonic acid (3d) or 3-sodium sulfonate (4d), resulted in a drastic loss of in vivo and in vitro activity.
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D006835:Hydrazones / Q000138:chemical synthesis / Q000627:therapeutic use; D007093:Imidazoles / Q000138:chemical synthesis / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009581:Nitrofurans / Q000138:chemical synthesis* / Q000627:therapeutic use; D011720:Pyrazoles / Q000138:chemical synthesis / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000627:therapeutic use
D006835:Hydrazones; D007093:Imidazoles; D009581:Nitrofurans; D011720:Pyrazoles; D011743:Pyrimidines; D014230:Triazoles; D014344:Trypanocidal Agents