Modelaje molecular

Bioorganic & Medicinal Chemistry 15 (2007) 1117–1126

Molecular modeling of some 1H-benzimidazole derivatives with biological activity against Entamoeba histolytica: A comparative molecular field analysis studyq
´ ´ ´ Fabian Lopez-Vallejo,a Jose Luis Medina-Franco,b Alicia Hernandez-Campos,a a c c ´ ´ ´ Sergio Rodrıguez-Morales, Lilian Yepez, Roberto Cedillo and Rafael Castilloa,*
´Departamento de Farmacia, Facultad de Quımica, UNAM, CU, D.F. 04510, Mexico b BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA c ´ ´ ´ Unidad de Investigacion Medica en Enfermedades Infecciosas y Parasitarias, IMSS. Mexico, DF 06720, Mexico
Received 15 July 2006; revised 23 September 2006; accepted 11 October 2006 Available online 18 October 2006
a

Abstract—Comparative molecular fieldanalysis (CoMFA) was performed on a set of 1H-benzimidazole derivatives. Molecular modeling and 3D-QSAR were employed to determine the tautomeric form that would probably fit a target receptor in Entamoeba histolytica. CoMFA results suggest that the antiamoebic activity is favored with steric bulk at position 5 of the benzimidazole ring and low electron density on the group at position 2. To the best ofour knowledge this is the first 3D-QSAR study performed for benzimidazoles as antiamoebic agents. The CoMFA models derived will be very valuable to design new and more potent compounds against E. histolytica. Ó 2006 Elsevier Ltd. All rights reserved.

1. Introduction Parasitic infections such as amoebiosis and other protozooses are still major threats against public health, especially indeveloping countries. The infections caused by Entamoeba histolytica mainly affect the infant population with high morbidity and mortality indices due to severe diarrhea and dehydration.1 Although drug therapy exists for the control of these infections, such as the nitroheterocycles, they produce severe side effects and in some cases resistance by the parasites have also been reported.2 Consequently, thesearch for new therapeutic agents is of utmost importance. We have recently reported that some 1H-benzimidazole derivatives with hydrogen at position 1, non 2-carbamates, were very active in vitro against E. histolytica.3–6 Since there are no reports on the target receptor for these types of compounds and in order to obtain more informa-

tion regarding the structural requirements of benzimidazolederivatives to be active against E. histolytica, computational studies were carried out. Three-dimensional quantitative structure–activity relationship (3D-QSAR) methods, such as comparative molecular field analysis (CoMFA),7 have been applied in many cases for the design of new active molecules; especially, when the binding site and mechanism of action are known.8 Additionally, it is also usefulwhen the binding site is unknown.9 Although CoMFA studies have been conducted for benzimidazole derivatives,10–14 there are no computational analyses that study the activity against E. histolytica. In order to rationalize the structure–activity relationships of a set of 41 1H-benzimidazole derivatives (cf., Table 1), in this paper 3D-QSAR studies using CoMFA were carried out. A particularchallenge for the present CoMFA study is to deal with the tautomeric forms of compounds 3, 8, 13, 29, 32, 36, and 40; and the tautomeric forms of compounds 6, 7, 9, 10, 17, 21, and 23 shown in Figures 1 and 2, respectively. The challenge is to determine which tautomer is most likely to be the active one when the QSAR studies are carried out. Each

Keywords: Amoebiosis; CoMFA; QSAR validation; Tautomers.q ´ Taken in part from the Ph.D. dissertation of Fabian Lopez-Vallejo. * Corresponding author. Tel./fax: +52 5622 5329; e-mail: rafaelc@servidor.unam.mx 0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2006.10.019

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´ F. Lopez-Vallejo et al. / Bioorg. Med. Chem. 15 (2007) 1117–1126

Table 1. Benzimidazole derivatives used in the CoMFA...