New potent 5-nitrofuryl derivatives as inhibitors of Trypanosoma cruzi growth. 3D-QSAR (CoMFA) studies.
Growth inhibitory activity in vitro of sixteen new 5-nitrofuryl derivatives against the protozoan parasite Trypanosoma cruzi, the causative agent of American trypanosomiasis, was studied. The designed compounds combine in the same molecule the recognized 5-nitrofuryl group, an oxidative stress promoter, and lateral chains that could interact with biomolecules such as trypanothione reductase. Some of the derivatives were found to be very active against the epimastigote form of the parasite, being near to 3.0-fold more active than the reference compound, nifurtimox. Moreover, three-dimensional requirements for activity were clearly observed using a 3D-QSAR study based on a comparative molecular field analysis (CoMFA). The best CoMFA model, r(2) = 0.970 and q(2) = 0.725, points to the importance of a specific hydrogen-bonding pattern around the carbonyl or thiocarbonyl moieties, as well as the requirement for hydrophobic lateral chains. Theoretical pharmacokinetics (Lipinski's rule, PSA) supports further in vivo studies.
Departamento de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
Gabriela
G
Aguirre
Mariana
M
Boiani
Eliana
E
Cabrera
Hugo
H
Cerecetto
Rossanna
R
Di Maio
Mercedes
M
González
Ana
A
Denicola
Carlos Mauricio R
CM
Sant'anna
Eliezer J
EJ
Barreiro
D000818:Animals; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D009581:Nitrofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013055:Spectrophotometry, Infrared; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development*
D007202:Indicators and Reagents; D009581:Nitrofurans; D014344:Trypanocidal Agents