Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: electrochemical studies on the effects of the quinoidal moiety.
In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8μM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6μM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent.
Instituto de Ciências Exatas, Departamento de Química, UFMG, 31270-901 Belo Horizonte, MG, Brazil.
Emilay B T
EB
Diogo
Gleiston G
GG
Dias
Bernardo L
BL
Rodrigues
Tiago T
TT
Guimarães
Wagner O
WO
Valença
Celso A
CA
Camara
Ronaldo N
RN
de Oliveira
Mauro G
MG
da Silva
Vitor F
VF
Ferreira
Yen Galdino
YG
de Paiva
Marilia O F
MO
Goulart
Rubem F S
RF
Menna-Barreto
Solange L
SL
de Castro
Eufrânio N
EN
da Silva Júnior
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D055664:Electrochemical Techniques; D004566:Electrodes; D051379:Mice; D008968:Molecular Conformation; D032383:Myocytes, Cardiac / Q000166:cytology; D009285:Naphthoquinones / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects
D009285:Naphthoquinones; D014230:Triazoles; D014344:Trypanocidal Agents
Chagas disease; Click chemistry; Electrochemical parameters; Lapachol; Quinone; Trypomastigote; β-Lapachone