Synthesis, Characterization, Antimalarial Activity and Molecular docking of 2-Oxo-1,2-dihydro-1'H-spiro[indoline-3,2'-quinazoline]-4'- carbohydrazones

Abstract

Successfully combating the growing resistance to current antimalarial drugs requires the identification and targeting of essential metabolic pathways in the malaria parasite. In this study, Isatin 1 was used to synthesize isamic ester 2 and its hydrazide 3, which subsequently led to the development of a series of carbohydrazones (4–14). The interaction of these carbohydrazones with Plasmodium falciparum transketolase (PfTk) was evaluated using molecular docking techniques. Among the tested compounds, carbohydrazones 4 and 9 successfully passed pharmacokinetic screening, emerging as lead candidates for antimalarial drug development. PfTk plays a crucial role in generating ribose sugars essential for nucleic acid synthesis. In vivo antimalarial chemo-suppression studies using a murine model, with chloroquine and artemether as standards, revealed that compound 9 (10 mg/kg) exhibited activity comparable to chloroquine at the same dosage. Notably, no mortality was observed in test animals 24 days post-administration, suggesting the compound's potential as a PfTk inhibitor. The alignment between in silico predictions and biological study outcomes further supports this conclusion. Throughout the experiment, 84% of the test animals survived, highlighting the compound’s efficacy and low toxicity even at a minimal dose.