Sintesi di nuovi composti ad attività antimalarica con particolare riferimento ai derivati della 4-amminochinolina

To develop new classes of antimalarial agents, the possibility of replacing the phenolic ring of amodiaquine, tebuquine, and isoquine with other aromatic nuclei was investigated. Within a first set of pyrrole analogues, several compounds displayed high activity against both D10 (CQ-S) and W-2 (CQ-R) strains of P. falciparum. The isoquine structure was also modified by replacing the diethylamino group with more metabolically stable bicyclic moieties and by replacing the aromatic hydroxyl function with a chlorine atom. Among these compounds, two quinolizidinylmethylamino derivatives displayed high activity against both CQ-S and CQ-R strains. Recently prof. Sparatore’s research group synthesized new 4-aminoquinoline derivatives endowed with a remarkable antimalarial activity and demonstrated that the presence of a bulky, strongly basic and lipophilic bicyclic moiety (such as the quinolizidine or the pyrrolizidine ring), is an interesting structural feature to overcome resistance. Among these kind of compounds, 7-chloro-4-{N-[(octahydro-2H-quinolizin-1-yl)methyl]amino}quinoline (-)-AM1 appeared very interesting as a potential antimalarial drug and is being thoroughly examined. As (–)-AM1 was obtained by a semi-synthetic route starting from l-lupinine (extracted from Lupinus luteus seeds) and as the available supply of l-lupinine is insufficient for market purposes, we explored the alternative possibility to develop the much cheaper and easier to be synthesized racemic AM1. In order to verify if the two enantiomers of AM1 display the same biological activity and toxicity, allowing the development of the racemic mixture instead of the single enantiomer, the total synthesis of racemic AM1 as well as of (+)-AM1 was set up and here we describe.