Evaluation of 1-indanone thiazolylhydrazone derivatives as probable squalene epoxidase inhibitors of Trypanosoma cruzi

VANESA PUENTE, GUIDO J NOGUERA, ALCIRA BATLLE, LILIANA M FINKIELSZTEIN AND ELISA LOMBARDO

Mar del Plata

Congreso; X Congreso Argentino de Protozoología y Enfermedades Parasitarias; 2014

Sociedad Argentina de Protozoología

Sterol biosynthesis inhibitors are promising entities for the treatment of trypanosomal diseases. Squalene epoxidase (SE) is a key enzyme of ergosterol biosynthetic pathway and an attractive potential target for antichagasic drugs. We have developed a serie (17 compounds) of 1-indanone thiazolylhydrazone derivatives (TZHs) with relevant activity against the proliferative stages of Trypanosoma cruzi. Previous results suggest that inhibition of ergosterol biosynthesis could be a possible target for the action of these TZHs. In this work, our aim was verify that the anti T.cruzi activity of this drugs is due to the inhibition of squalene epoxidase. Using the ShaEP software, the molecular overlap among TZHs and the terbinafine (specific inhibitor of squalene epoxidase) was assayed. This program evaluates the structural similarity based on the shape and electrostatic potential of overlapping molecules. Simultaneously, the effect of THZs on squalene epoxidase activity was evaluated, using a cell-free supernatant (derived from parasites sonicated and then centrifuged at 10000 g for 15 min) as enzyme source. After incubation the extracted lipids were dissolved in chloroform and analyzed by TLC. A higher percentage of enzyme inhibition was observed for a greater structural similarity index from computer analysis. So, for TZH 8 and 9, which showed the highest percentages of inhibition (38.88 ± 1.12 and 40.17 ± 6.50 respectively), the computational analysis yielded values of about 80.3 to 75.9 % similarity in shape and 73.7 to 65.7% similarity in electrostatic potential, respectively. In conclusion, the biological and computational results showed that TZHs could be able to inhibit squalene epoxidase activity. These results prompt us to continue with the structural modifcation of these compounds to obtain better inhibitors of this enzyme.