Synthesis of triazole-linked chloroquinoline derivatives as novel antimalarial agents

[摘要] Aminoquinolines are important class of drugs that have been used for malaria chemotherapy forcenturies. However, long-term exposure to these drugs leads to extensive spread of drugresistance. As such, modified chloroquinoline derivatives are being studied as alternativeantimalarial agents with the possibility to overcome drug resistance associated with chloroquineanalogues.In this study, 15 aminoquinoline derivatives that are linked by a 1,4-disubstituted 1,2,3-triazolering to an ethyl and propyl carbon spacer with a distal amine motif were designed andsynthesized as novel antimalarial agents using the Cu(I)-promoted Huisgen reaction. Thecompounds have been synthesized from the 7-chloro-N-(prop-2-yn-1-yl)quinolin-4-amine alkyneprecursor and the azides of ethyl and propyl amino moieties using a 1,3-dipolar cycloadditioncouplingin the presence of CuI catalyst to obtain moderate to good yields (53 – 85%). Thesecompounds have been characterized by the combination of NMR, ESI+ HRMS and IRspectroscopic methods.The antiplasmodial activity of the compounds was investigated in vitro against P. falciparumstrain NF54 using chloroquine as a reference drug together with a standard antimalarial drugartesunate. Of the 15 novel chloroquinoline derivatives, 11 have demonstrated to possesspromising potency by way of the inhibition concentrations less than 250 nM with the lowestbeing 28 nM. The observed activities have been ascribed to the overall modifications such as theintroduction of a triazole linker and changing of carbon chain length as these were the variables.The compounds are accordingly under further biological investigations and only the chloroquinesensitive results are reported in this work.

[发布机构] Stellenbosch University