Synthesis and In vitro Leishmanicidal Activities of Six Quercetin Derivatives

Today, leishmaniasis is a widespread, infectious parasitic disease caused by Leishmania spp. Natural-derived compounds are likely to provide a valuable source of new pharmaceuticals, and among them, quercetin derivatives may have antileishmanial effects. The antileishmanial activity of 3,5,7,3',4'-pentahydroxyflavonol (quercetin) derivatives is partly attributed to the position and pKa of phenolic or catechol hydroxyl groups. Therefore, to optimize their leishmanicidal effect, the structural features of quercetin and its derivatives were improved by acylation or alkylation of hydroxyl groups and changing their pKa and consequently their activities.

In this study, during a regioselective method, quercetin derivatives were synthesized. The structures of synthesized compounds were confirmed by mass, IR, ¹H-, and ¹³C-NMR spectral data. The antileishmanial activities of compounds 1-6 were compared with glucantime as the standard drug against promastigotes of Leishmania major using standard cell-based leishmanicidal assay.

In this study, during a regioselective method, two 7-O-quercetin derivatives (5 and 6), and three quercetin acetate derivatives (2, 3, and 4) were synthesized. In detail, the IC₅₀ values found against L. major were (1) 2.5 ± 0.92; (2) 2.85 ± 0.99; (3) 15.5 ± 1.95; (4) 13.5 ± 3.5; (5) 2.6 ± 0.57; and (6) 1.3 ± 0.35 μM while IC₅₀ value of glucantime as the standard drug was 88.5 ± 9.47 μM.

The present study showed an effective antileishmanial activity of quercetin semisynthetic compounds (1-6) against in vitro promastigotes of L. major. Among them, quercetin analogs with more lipophilic and iron-chelating activity showed more antiparasite activity.