Synthesis of Quinic Acid-Derived Sialylmimetics and Their Effects on T. cruzi and Trans-Sialidase

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects 6–7 million people worldwide, mainly in South and Central America. A key enzyme in the disease's progression is Trypanosoma cruzi trans-sialidase (TcTS), which facilitates parasite invasion by transferring sialic acid residues from host glycoconjugates to the parasite's surface mucins. Given the potential of sialic acid-based inhibitors to block TcTS activity, we designed and synthesized novel sialylmimetics using quinic and shikimic acids. These precursors were chosen for their structural similarity to sialic acid and high enantiomeric purity. Furthermore, the potent antitrypanosomal activity previously observed for derivatives containing the 4-(4-nitrophenyl)-1H-1,2,3-triazole unit led us to hypothesize that a hybrid could achieve strong TcTS inhibition while retaining anti-parasitic activity. A lead compound, bearing the 5R-4-(4-nitrophenyl)-1H-1,2,3-triazole, emerged as the most effective TcTS inhibitor (IC₅₀ 226 ± 13 µm), while its 5S counterpart was less active. Additional analogs with modified side chains were synthesized, leading to the dimerized triazole compound, which demonstrated strong anti-T. cruzi activity (IC₅₀ 10.60 ± 2.12 µm) and a high selective index. These findings highlight the potential of sialylmimetic hybrids as promising candidates for new antitrypanosomal drugs, addressing the urgent need for improved treatments against Chagas disease.