Synthesis and in vitro antiprotozoal evaluation of novel Knoevenagel hydroxychloroquine derivatives

Abstract

Leishmaniasis and Chagas diseases affect millions of people, particularly in developing countries, with conventional treatments proving unsatisfactory due to increasing drug resistance and high toxicity. Therefore, there is an urgent need for new drugs to combat neglected tropical diseases (NTDs). In this study, we synthesized 15 new Knoevenagel adducts derived from hydroxychloroquine and evaluated their antiprotozoal activity against Leishmania infantum, L. amazonensis, and Trypanosoma cruzi. The new adducts exhibited low toxicity in epithelial LLC-MK2 cells and J774A.1 macrophages. The Knoevenagel adducts derived from meta- and para-chloro benzaldehyde demonstrated antiprotozoal activity against T. cruzi epimastigotes, though with a lower selective index (SI) compared to the standard drug benznidazole. However, the adducts derived from isovaleraldehyde and ortho-, meta-, and para-chloro benzaldehyde showed SI values ranging from 10.97 to 8.11 against L. amazonensis, similar to Amphotericin B (AmpB, SI = 9.37), with no statistically significant difference (p > 0.05). These same compounds inhibited L. infantum promastigotes, but with less activity compared to AmpB. These results suggest that Knoevenagel adducts derived from hydroxychloroquine may serve as selective antileishmanial agents.