Multicomponent synthesis of 2-amino-tetrahydro-4H-chromenes catalyzed by chitosan and evaluation of anti-Leishmania activity.

AIM: This study describes a sustainable synthetic methodology employing unmodified commercial chitosan as a recyclable catalyst for the synthesis of chromene derivatives and the evaluation of their in vitro activity against Leishmania infantum.

METHODS

2-Amino-tetrahydro-4H-chromene derivatives (4a-p) were synthesized through multicomponent reactions (MCRs) via a Knoevenagel-Michael mechanism using benzaldehydes, malononitrile, and dimedone (0.5 mmol each) in aqueous medium at 60°C, catalyzed by commercial chitosan.

RESULTS

The methodology exhibited good selectivity, short reaction times (5-60 min), and satisfactory chromene yields (69-89%). Chitosan demonstrated excellent reusability, being recovered and reused for up to four cycles without significant loss of catalytic efficiency. The compounds 4a-p were evaluated in vitro against Leishmania infantum, showing moderate activity across the series (IC50 = 35.64-240.51 µM). Compound 4p stood out as the most active (IC50 = 4.62 µM) and maintained relevant activity against amastigotes (EC50 = 7.57 µM). In addition, it showed no significant toxicity (HC50 and CC50 >100 µM).

CONCLUSION

Direct use of unmodified commercial chitosan provides a simple, efficient, and recyclable catalytic system for chromene synthesis. This sustainable approach yielded compounds with promising antileishmanial activity, highlighting compound 4p as a promising lead for further investigation.