QUINOLAC

We have developed a synthesis of two series of fluoroalkylated gamma-lactams derived from 4-aminoquinoline as part of a research theme dedicated to synthesis and discovery of new drug candidates for malaria treatment. These molecules could be obtained in several steps resulting in the identification of several molecules with moderate to good activity with three "hits" with in vitro activity against P. falciparum clones of variable sensitivity (IC50 near 100-400 nM). These data indicate that our molecules have similar or improved activity compared to chloroquine (CQ) and also this activity is not impaired by the chloroquine resistance phenotype (indexes of resistance of the three "hits" close to 1.0). Our goals within this ANR proposal are a) to improve the in vitro activity of our "hits" to reach IC50 in the range of 10-30 nM from chemical structure optimizations and to demonstrate that these molecules have a good activity profile (active in vivo with a acceptable dose and no cytotoxicity), b) to develop alternative syntheses of the three first hits with shorter steps or at least at a reasonable cost, and c) to propose new gamma-lactams with new chemical approaches that are not covered by our first patent. While the current molecules do incorporate a fluorinated unit, our current chemical and biological knowledge cannot yet established what are the critical substitutions (to detect any activity) with a validated pharmacophore; one of the major objective will try to respond to this important question with a thorough structure-activity relationship (SAR) using different and efficient chemical approaches.