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The side-chains of quinoline antimalarial agents are the major concern of focus to build novel and efficaciaous bioactive and clinical antimalarials. Bioative antimalarial analogs may play a critical role in pH trapping in the food vacuole of RBC’s with the help of fragmented amino acid, thus lead to β-hematin inhibition. Here, the authors tried to summarize a useful, comprehensive compilation of side-chain modified ACQs along with their synthesis, biophysical and therapeutic applications etc. of potent antiplasmodial agents and therefore, opening the door towards the potential clinical status.

Abstract: Apicomplexian parasite of the genus Plasmodium is the causative agent of malaria, one of the most devastating, furious and common infectious disease throughout the world. According to the latest World malaria report, there were 229 million cases of malaria in 2019 majorly consist of children under 5 years of age. Some of known analogues viz. quinine, quinoline-containing compounds have been used for last century in the clinical treatment of malaria. Past few decades witnessed the emergence of multi-drug resistance (MDR) strains of Plasmodium species to existing antimalarials pressing the need for new drug candidates. Thus, in those decades bioorganometallic approach to malaria therapy has been introduced which led to the discovery of noval metalcontaining aminoquinolines analogues viz. ferroquine (FQ or 1), Ruthenoquine (RQ or 2) and other related potent metalanalogues. It observed that some metal containing analogues (Fe-, Rh-, Ru-, Re-, Au-, Zn-, Cr-, Pd-, Sn-, Cd-, Ir-, Co-, Cu-, and Mn-aminoquines) were more potent; however, some were equally potent as Chloroquine (CQ) and 1. This is probably due to the intertion of metals in the CQ via various approaches, which might be a very attractive strategy to develop a SAR of novel metal containing antimalarials. Thus, this review aim to summarize the SAR of metal containing aminoquines towards the discovery of potent antimalarial hybrids to provide an insight for rational designs of more effective and less toxic metal containing amonoquines.