Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors

• DOI: 10.1016/j.heliyon.2024.e25077
• Publication Date: 2024-01-23T17:24:27Z
• Authors: Iram Irfan; Amad Uddin; Ravi Jain; Aashima Gupta; Sonal Gupta; John V. Napoleon; Afzal Hussain; Mohamed F. Alajmi; Mukesh C. Joshi; Phool Hasan; Purnendu Kumar; Mohammad Abid; Shailja Singh
• Keywords: Side chain

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development target-oriented molecules with novel modes action. Given importance plant-like Calcium-Dependent Protein Kinase 1 (PfCDPK1) as stand-alone multistage signalling regulator P. falciparum, we designed and synthesized 7-chloroquinoline-indole-chalcones tethered triazole (CQTrICh-analogs 7 (a–s) 9) directed towards PfCDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde 4-azido-7-chloroquinoline, respectively via 'click' reaction. selected CQTrICh-analogs: 7l 7r inhibited growth chloroquine-sensitive 3D7 strain -resistant RKL-9 isolate Plasmodium IC50 values 2.4 μM & 1.8 (7l), 3.5 2.7 (7r), respectively, showed no apparent hemolytic activity cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that active hybrids: are effective against mature stages parasite. were found stably interact catalytically ATP-binding pocket PfCDPK1 energetically favourable H-bonds. interaction confirmed vitro microscale thermophoresis kinase assays, which demonstrated hybrids inhibit its is presumably responsible parasite inhibition. Interestingly, inhibitory effect on human kinases, indicating their selectivity kinase. We report antiplasmodial potential kinase-targeting bio-conjugates, step developing pan-kinase inhibitors prerequisite anti-malarial protection.