Theoretical study of the influence of spatial atomic arrangement in trypanocidal sesquiterpene lactones with high selectivity index

SÜLSEN V, FABIAN L, FRANK F, CAZORLA SI, FINKIELSZTEIN L, MARTINO V, MUSCHIETTI L, CATALÁN C, MOGLIONI A

Simposio; The 5th Brazilian Symposium on Medicinal Chemistry; 2010

Chagas’s disease is one of the most important health problems throughout South America. It is caused by the intracellular protozoan Trypanosoma cruzi, which infects about 9–12 million people in Central and South America.Despite the progress made in the study of T. cruzi biochemistry and physiology in which several crucial enzymes, for parasite survival, have been identified as potential targets of new drugs, the chemotherapy to control this parasitic infection remains underdeveloped. The pharmacology is based on old and quite unspecific drugs associated with long term treatments that rise to severe side effects. In the search for new effective agents for the treatment of Chagas disease we have previously reported the in vitro and in vivo trypanocidal activity of sesquiterpene lactones (STLs) isolated from Argentine medicinal plants.Herein, we present the advances of a preliminary study of geometry optimization of a set of 12 STLs, with the aim to establish their structure. Trypanosoma cruzi, which infects about 9–12 million people in Central and South America.Despite the progress made in the study of T. cruzi biochemistry and physiology in which several crucial enzymes, for parasite survival, have been identified as potential targets of new drugs, the chemotherapy to control this parasitic infection remains underdeveloped. The pharmacology is based on old and quite unspecific drugs associated with long term treatments that rise to severe side effects. In the search for new effective agents for the treatment of Chagas disease we have previously reported the in vitro and in vivo trypanocidal activity of sesquiterpene lactones (STLs) isolated from Argentine medicinal plants.Herein, we present the advances of a preliminary study of geometry optimization of a set of 12 STLs, with the aim to establish their structure. It is a well known fact that most agents that can beused for the treatment of Chagas disease compromise their clinical usefulness because of their high toxicity. Thus, the high selectivity index (SI) found for many of the evaluated compounds encouraged us to establish a SAR study, as a means of lead structure optimization. The trypanocidal activity was measured on T.  COS-7 cells by the trypan blue dye exclusion method. A theoretical study allowed us to establish a relationship between the trypanocidal observed activity and the atomic spatial arrangement of the evaluated STLs. The geometry and electrostatic potentials of these compounds have shown the high dependence of the activity closely related to steric parameters. The theoretical study was performed using Gaussian 03 and Hyperchem 8.0 software. The theoretical study developed on these natural compounds, allowed us to conclude that: - The presence of the lactone function appears to be essential for the activity observed but not the C=C conjugated to the carbonyl group of the lactone. - The configuration of the a-C with respect to the carbonyl of the lactone group also appears to be important in the observed potency. - The size and location of the substituents on cyclic system also appears to be determinant in the observed activity.a-C with respect to the carbonyl of the lactone group also appears to be important in the observed potency. - The size and location of the substituents on cyclic system also appears to be determinant in the observed activity.