Design and synthesis of novel antimalarial agents based on a polyaromatic scaffold

The increasing resistance of the malaria parasite P. falciparum to currently available drugs demands a continuous effort to develop new classes of drugs being affordable, rapidly acting, orally bioavailable, with low potential to develop resistance and structurally based on novel pharmacophores. Clotrimazole (CLT), a potent anti-mycotic drug, shows promising antimalarial activity in vitro against chloroquine (CQ)-resistant strains of P. falciparum. The imidazole moiety of CLT is believed to behave as an axial ligand which form heme-CLT complex thereby disturbing the hemoglobin catabolism in the malarial parasite. The relatively low toxicity of CLT and its proven clinical safety prompted us to use its scaffold to develop novel compounds based on CLT structure. Based on the polyaromatic scaffold of CLT we generated a large number of analogues for SAR studies (EP06005306.3 and EP06005307.1). 3-D interaction models of CLT and analogues in complex with free heme, C.albicans 14αlanosterol-demethylase, human cytochrome P450s have been developed and used as design tools to drive the chemical functionalization of the new derivatives in order to optimize their efficacy, selectivity, and resistance profile. The new antimalarial agents, typified by NF990, are characterized by high potency against CQ-R strains, selectivity for free haem and increased penetration into the parasite food vacuole. Furthermore, NF990 proved to be poorly active against a panel of Candida spp and Aureoginosa fungi, showing low cytotoxicity. NF990 inhibits beta-haematin formation in the BHIA (β-Haematin Inhibitory Activity) assay proving interference with haem detoxification, similarly to CQ. However, the concentration of NF990 and analogues required to inhibit beta-haematin formation is not directly correlated to its antimalarial activity. Generation of free radicals may be involved in the mechanism of action of NF990 and analogues, similarly to artemisinin.