Design, synthesis, and in silico-in vitro antimalarial evaluation of 1,2,3-triazole-linked dihydropyrimidinone quinoline hybrids

In response to the malaria parasite's resistance towards quinoline-based antimalarial drugs, we have employed quinoline-containing compounds in combination with dihydropyrimidinone (DHPM) analogues as resistance reversal agents (RAs) and investigated their antimalarial activities based on DHPM's resistance reversal abilities. The present study employed click chemistry to link DHPM and quinoline compounds which offered several synthetic advantages over the previously used amide coupling for the same hybrids. Among the synthesised compounds, 4 hybrids with the 7-chloroquinoline moiety showed antimalarial activity below 1 mu M while compounds with the mefloquine moiety showed lower antimalarial activity than chloroquine (CQ) and the 7-chloroquinoline hybrids. Among the tested hybrids for the IC50 determination, four compounds displayed good antimalarial activity with increased sensitivity against the CQ-resistant K1 strain between 421 and 567 nM and showed higher activity between 138 and 245 nM against the NF54 CQ-sensitive strain, while three compounds have IC50 values greater than 5 mu M. Additionally, in silico molecular docking and molecular dynamics studies were conducted to investigate the binding affinities of all the synthesised compounds as glutathione reductase protein competitive inhibitors. Further optimisation of the compound with the highest binding affinity generated 16 compounds with higher binding affinities than the flavine adenine dinucleotide (FAD) cofactor.

Automated summary

In response to the resistance of malaria parasite towards quinoline-based antimalarial drugs, a study has employed quinoline-containing compounds combined with dihydropyrimidinone (DHPM) analogues as resistance reversal agents (RAs) to investigate their antimalarial activities. By using click chemistry, the study linked DHPM and quinoline compounds which offered synthetic advantages over amide coupling. Among the synthesized compounds, 4 hybrids with the 7-chloroquinoline moiety showed potent antimalarial activity below 1 μM while mefloquine-containing compounds showed lower activity compared to chloroquine (CQ) and the 7-chloroquinoline hybrids.