Synthesis and antiprotozoal activity of β-carboline-(piperazinyl)-1,3,5-triazine hybrids

Neglected tropical diseases, such as leishmaniasis and Chagas disease cause over 50,000 deaths annually and affect millions worldwide. Current drugs are limited due to their toxicity, prolonged treatment, and drug resistance. The β-carboline scaffold has emerged as a privileged nucleus in the search for novel antiprotozoal derivatives. Our previous studies demonstrated the antileishmanial activity of β-carboline-1,3,5-triazine hybrids containing a N-aminoethyl group as linker connecting the nucleus, as well as the antiprotozoal activity of β-carboline-piperazinyl derivatives. Based on these findings, and in literature reports on the potential of piperazine heterocycle, in this work we synthesized novel β-carboline-(piperazinyl)-1,3,5-triazine hybrids (4a-g), and evaluated their activity, and of its precursors (1a-g), against Leishmania amazonensis and Trypanosoma cruzi. The β-carboline-3-carboxylic acids 1a-e were weakly active for L. amazonensis promastigotes, with IC₅₀ values in the range of 55.9 to 159.7 μM. For amastigotes, the compounds exhibited moderate activity, with IC₅₀ values in the range of 18.2 to 62.6 μM. The hybrids 4a, 4c and 4d showed potent activity for L. amazonensis promastigotes, with IC₅₀ values in the range of 8.3 to 9.5 μM, and displayed higher activity and selectivity index (SI in the range of 5.40 to 17.3) than the reference drug miltefosine (IC_50pro = 22.71 μM, SI = 2.4). A moderated activity was observed towards L. amazonensis amastigotes (IC₅₀ in the range of 15.1 to 34.9 μM). The β-carboline carboxylic acids (1a-g) and β-carboline-(piperazinyl)-1,3,5-triazines (4a-g) showed no significant activity against T. cruzi epimastigotes.