NOVEL ARYLPYRROLYLAMINOQUINOLINES AS POTENT ANTIMALARIAL AGENTS

In order to develop new classes of antimalarial agents, we recently explored the possibility of replacing the phenolic ring of amodiaquine and tebuquine with other kinds of aromatic rings such as a pyrrole nucleus, still linked to the quinoline moiety through the usual NH. We showed that this new class of compounds is associated with a good antimalarial activity also against chloroquine-resistant (CQ-R) strains of P. falciparum.1 Starting from this evidence, a set of new 7-chloro-4-[N-[2-methyl-[5-(4-R-phenyl)pyrrol-1-yl]amino]quinoline (1a,b-4a,b) and 7-chloro-4-[N-[3-(5-(4-chlorophenyl)-2-methylpyrrol-1-yl]propyl]amino]quinoline (5a,b), bearing a diethylaminomethyl or a pyrrolidinomethyl moiety as basic head, was synthesized, in order to explore the best electronic and lipophilic requirements for the antimalarial activity of this class of compounds. In particular, the role of the substituent in the para position of the phenyl ring, as well as the role of the distance between the pyrrolic nitrogen and the 4-aminoquinoline was investigated. Moreover, the inhibition of beta-haematin formation by some representative compounds indicate that their mechanism of action is similar to CQ. All compounds exhibited high activity against D-10 (CQ-S) strain of P. falciparum, which was comparable to that of CQ, while a clear correlation between the lipophilicity of the different molecules and their activity on W-2 (CQ-R) strain of P. falciparum has been evidenced. The ANTIMAL –EU18834 support is acknowledged. (1) Casagrande, M. et al. A. Bioorg. Med. Chem. 2008, 16, 6813.