Design, synthesis and activity against Trypanosoma cruzi of azaheterocyclic analogs of megazol.
This study describes the design, synthesis and trypanocidal evaluation of new azaheterocyclic derivatives (4-8). These compounds were designed as megazol (1) analogs based on bioisosterism tools and were synthesized to investigate the possible pharmacophoric contribution of the 1,2,4-triazole nucleus, the position of the heterocyclic nucleus and presence of the nitro group, to the activity against the bloodstream trypomastigote forms of Trypanosoma cruzi. The most potent compound was 6, a nitro derivative obtained by substitution of a thiadiazole by a triazole ring and by moving the nitro group from C-5 position, as in 1, to the C-4 position. Finally, we have used semi-empirical theoretical calculations to discuss the correlation of some stereo electronic properties with biological activity in an attempt to understand the possible mechanism of action of the designed series of compounds.
Carvalho
A S
AS
Departamento de Síntese Orgânica, Farmanguinhos, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Rio de Janeiro, RJ, Brazil.
Menna-Barreto
R F S
RF
Romeiro
N C
NC
de Castro
S L
SL
Boechat
N
N
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D001372:Aza Compounds; D006571:Heterocyclic Compounds; D013830:Thiadiazoles; C013378:megazol