Structure-Activity Relationships of Thieno[2,3-b]pyridine derivatives as potential anti-Giardia drugs
Loureiro, N.I.V.1,2; Rodrigues2, C.R.; Bernardino, A.M.R.3, Pinheiro3, L.C.S.; Lanfredi-Rangel3, A.; Sabatini-Lopes3, J.; Borges3, J.C.; Carvalho3, J.M.; Romeiro3, G.A.;Ferreira3, V.F.; Frugulhetti4, I.C. P. P.; Vannier-Santos5, M.A; Castro1, H.C.
1LABioMol, Departamento de Biologia Celular e Molecular, IB-UFF, RJ; 2ModMolQSAR, Faculdade de Farmácia, UFRJ, RJ; 3Departamento de Química Orgânica, IQ-UFF, RJ; 4Departamento de Biologia Celular e Molecular, IB-UFF, RJ; 5Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, BA.
Giardia lamblia is the causative agent of a water-borne enteric disease in developed and third world countries. Giardiasis symptoms include severe diarrhea, malabsorption and weight loss. Metronidazole is the current drug for treatment. Albendazole and mebendazole, that act by specifically inhibiting tubulin polymerization and hence microtubule assembly, are also available. However the high incidence of side effects and the increasing resistance to these traditional drugs has pointed out the need for searching newer and more effective antigiardial agents. In order to identify thienopyridine system as a promising group, in this work we described the Structure-Activity Relationships (SAR) of a new series of compounds analogous of ethyl 4-(phenylamino)thieno[2,3-b]pyridine-5-carboxylate. The substituents added in meta (2-7) or para (2a-7a) position of phenyl moiety (H, -CH3, -OCH3, -NO2, -F, -Cl, -Br) present different electronic and volume properties. We biologically tested these compounds and determined several theoretical parameters (HOMO and LUMO energy, higher HOMO coefficient orbital and density, electrostatic potential map and dipole moment) by using SPARTAN´04 (wavefunction Inc. Irvine, CA, 2000) to determine structural and stereo-electronic features that could be important to the giardicidal profile. Using the molecular modeling approach, structures were minimized and the equilibrium geometry was obtained in vacuum using semiempirical AM1 module. They were submitted to a single-point ab initio calculation with a 3-21G basis set. In this work, the MEPs isoenergy contours were generated in the range from –25.0 to +30.0 kcal/mol. Our results pointed the p-methoxy derivative (3a) with a significant giardicidal activity against the G. lamblia (at 50mM GA=88%) comparable to metronidazol (at 50mM GA=100%) and presenting some different electronic properties from the others. This derivative showed the highest HOMO and LUMO energy, higher HOMO coefficient orbital and density, localized in the phenyl ring, suggesting that these electronic features are important for displaying a significant anti-Giardia activity. Briefly this study pointed out the thieno[2,3-b]pyridine as a potential group for designing of new antiparasites and 3a as a leading compound. Supported by: UFF, CNPq and FAPERJ.
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