An Extensive Review of Recent Progress In Kinase-targeting Antimalarial Drug Discovery.

Abstract

Malaria remains a major global health challenge, with the rise of drug-resistant Plasmodium falciparum strains necessitating the development of novel therapeutic strategies. Kinases, which regulate essential processes throughout the parasite life cycle, including invasion, egress, development, proliferation, gametogenesis, and transmission, have emerged as promising drug targets, leading to significant advances in kinase inhibitor development over the past five years. This review examines recent advances in kinase-targeted antimalarial drug discovery, with particular emphasis on inhibitor scaffolds, SARs, target selectivity, biological efficacy across multiple parasite life stages, and mechanisms of kinase inhibition. A literature search of PubMed and Google Scholar was conducted to identify studies published between 2019 and 2024. Studies reporting computational, biochemical, cellular, or in vivo evaluations of inhibitors targeting P. falciparum kinases were examined. Particular attention is given to inhibitors of calcium-dependent protein kinases, AGC kinases, including PKA, PKB, and PKG, CMGC kinases, phosphoinositide lipid kinases, NIMA-related kinases, aurora-related kinases, and orphan kinases. The integration of high-throughput screening, molecular docking, virtual screening, machine-learning approaches, and structure-guided optimization has accelerated the identification of lead compounds. Several inhibitors demonstrated nanomolar enzymatic or cellular potency, multistage antiplasmodial activity, and encouraging selectivity over human kinases. Nevertheless, challenges involving target validation, kinase selectivity, pharmacokinetic properties, toxicity, resistance liability, and translation from computational or biochemical activity to in vivo efficacy remain. Continued research integrating biological validation, selectivity profiling, and pharmacokinetic optimization is crucial for translating promising kinase inhibitors into innovative, effective, and durable antimalarial treatments capable of reducing the global burden of malaria.