Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as Pf CDPK1 kinase inhibitors

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development of target-oriented molecules with novel modes of action. Given the importance of a plant-like Calcium-Dependent Protein Kinase 1 ( CDPK1) as a stand-alone multistage signalling regulator of . , we designed and synthesized 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs - and directed towards CDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a 'click' reaction. The selected CQTrICh-analogs: and inhibited the growth of chloroquine-sensitive 3D7 strain and -resistant RKL-9 isolate of , with IC values of & ( ), and & ( ), respectively, and showed no apparent hemolytic activity and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: and are effective against the mature stages of the parasite. and were found to stably interact with the catalytically active ATP-binding pocket of CDPK1 via energetically favourable H-bonds. The interaction was confirmed by microscale thermophoresis and kinase assays, which demonstrated that the active hybrids interact with CDPK1 and inhibit its kinase activity which is presumably responsible for the parasite growth inhibition. Interestingly, and showed no inhibitory effect on the human kinases, indicating their selectivity for the parasite kinase. We report the antiplasmodial potential of novel kinase-targeting bio-conjugates, a step towards developing pan-kinase inhibitors which is a prerequisite for multistage anti-malarial protection.