Discovery of 1,3,4,5-tetrasubstituted pyrazoles as anti-trypanosomatid agents: Identification of alterations in flagellar structure of L. amazonensis

Trypanosoma cruzi and Leishmania species are causative agents of Chagas disease and Leishmaniasis, respectively, known as Neglected Tropical Diseases. Up to now, the treatments are inadequate and based on old drugs. Thus, we report herein the discovery of 1,3,4,5-tetrasubstituted pyrazole derivatives that presented potent and selective inhibition against promastigote forms of L. amazonensis, and epimastigote forms of T. cruzi. The structure-activity relationship led to the identification of three compounds (2m, 2n and 2p) with an in vitro IC50 of 7.4 mu M (selective index - SI >= 133.0), 3.8 mu M (SI in the range of 148.4 to 200.8), and 7.3 mu M (SI in the range of 87.2 to 122.4) against L. amazonensis, respectively. Also, those compounds exhibited in vitro IC50 of 9.7 mu M (SI >= 101.5), 4.5 mu M (SI in the range of 125.3 to 169.6) and 17.1 mu M (SI in the range of 37.2 to 52.2) against T. cruzi, respectively. A preliminary study about the reaction mechanism in promastigotes showed that 2n caused an increase of the production of ROS and of lipid storage bodies. Furthermore, 2n induced abnormalities in the flagellum that may have an impact on the parasite motility.

Automated summary

A novel tetrasubstituted pyrazole derivative was discovered to exhibit potent and selective inhibition against both L. amazonensis and T. cruzi, offering a new approach for the treatment of Chagas disease and Leishmaniasis.