Antimalarial activity of S-farnesylthiosalicylic acid analogues in Plasmodium falciparum transfected with ultra bright NanoLuc

MAURO MARQUES ACEVEDO; GUILLERMO R. LABADIE; IGNASI BOFILL VERDAGUER; RODRIGO A. SUSSMAN CELSCHINI; ALEJANDRO M. KATZIN; EXEQUIEL O. J. PORTA; EMILIA KIMURA AKEMI SHIRAISHI

Caxambu

Congreso; Congresso Brasileiro de Parasitologia; 2017

Sociedade Brasileira de Parasitologia

Due to the increasing malaria parasite resistance to antimalarial compounds, new approaches to drug design are needed. Our group studies the biosynthesis of several secondary isoprenoid compounds in Plasmodium falciparum (1). Previously, our group selected some terpenes, the antineoplasic modified terpene, S-farnesylthiosalicylic (FTS, compound 14º figure 4), to be tested on cultures of the intraerythrocytic stages of P. falciparum (2). The concentration that produces a 50% of inhibition (IC50) value of FTS was found to be in micromole scale. FTS and most terpenes tested inhibited the biosynthesis of ubiquinone and dolichol in the schizont stages when 3H farnesyl pyrophosphate was used as precursor probably because of its chemical analogism. At the same time, treatment of schizont stages with the S-farnesylthiosalicylic acid decrease in intensity the band corresponding a p21ras protein (3). This is the same chemotherapeutic mechanism which is supposed to be acting in mammal cells. According to bioinformatic and chemoinformatic approaches, in the present study we synthetized and tested 39 FTS analogues for its antimalarial activity in vitro and we will study its toxic effect on cancer cells (figure 1). For this purpose we used exogenous luciferase based methodology. We used a Plasmodium falciparum expressing the NanoLuc (Nluc) assays, which previously showed at least 100 times brighter than the commonly used firefly luciferase, a low cost and a better sensibility (3).