7-Chloroquinolinotriazoles: Synthesis by the azide–alkyne cycloaddition click chemistry, antimalarial activity, cytotoxicity and SAR studies

• Synthesis of 7-chloroquinolinotriazoles via click reaction.
• All compounds were evaluated for in vitro antimalarial activity and cytotoxicity.
• Most of them were non-cytotoxic and five compounds disclosed antimalarial activity.
• SAR studies allowed to understanding the antimalarial activity profile.
• Promising hits for the development of antimalarial quinolinotriazoles.

Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 μM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 μM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained.

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