A novel 4-aminoquinoline derivative exhibiting curative activity against drug resistant malaria has been identified for preclinical development as a blood schizontocidal agent. The lead molecule, selected after detailed SAR studies, has good solid state properties and has promising activity against in vitro and in vivo experimental malaria models. The in vitro ADME parameters have indicated favourable drug-like profile with no off–target ion channel activities.
Aminoquinolines such as chloroquine had been the most important animalarials for more than four decades in view of their efficacy against all species of human malaria and their safety profile. Emergence of resistance to this class of compounds during 1980’s created a genuine health crisis in the developing world. Studies on elucidation of mechanism of resistance and general trend emerging from the SAR-studies revealed that chloroquine resistance does not involve any change to the target of this class of drugs but involves compound specific efflux mechanism. Based on this premise a number of research groups have developed short chain analogues of 4-aminoquinoline, which are active against CQ-resistant strains of P. falciparum. However, these derivatives undergo biotransformation (de-alklylation) significantly affecting lipid solubility of the drug. In view of this background information, we introduced modification in the side chain that would prevent de-alkylation leading to improved activity. This prompted us to explore the amino acid conjugates with a view to achieve improved antimalarial activity and to the best of our knowledge such amino acid conjugates have not been hitherto reported in the literature in the case of 4-aminoquinolines. The seminal finding of our study is that a new series of compounds having significant activity against CQ resistant parasites has been identified.