Chemical and biological optimization and synthesis of novel heterocyclic 4-amino quinoline-gamma-lactam structures as antimalarials. From «hit» to a potential «lead». – QUINOLAC

Different chemical syntheses will be studied in order to access to more diversity and also to reach in vitro activities around 10-20 nM. Important features of the study will be to identify a convergent chemical approach with a reasonable cost and also to disclose new series. In vitro activities will be determined using two P. falciparum strains (one chloroquino-sensitive and one chloroquino-resistant); cytotoxicity of best active compounds will be measured as well as the determination of the mechanism of action with an oral efficacy on a murine model (intraperitoneal injection, 5-20mg/kg./day).

A large number synthesized molecules using different chemical approaches have demosntrated remarkable in vitro activity without cytoxicity and chemical stability at physiological pH. We are in the process of establishing their mechanism of action and to demosntrate an oral efficacy after having solved some solubility issues. In the near future we will envisage preliminary pharmakocinetic profile of a model compound in order to anticipate potential in vivo issues. Alltogether these results will enhance the possibility of a technology transfer and a future collabration with MMV and a pharmaceutical company or start-up.

Contribute to the development of a promising drug candidate for the treatment of malaria and a better understanding of mechanism of actions associated with. It is also planned to tackle new therapeutic pathways that may emerge from the results and our experience. Some of the molecules will be screened against neglected tropical diseases such Leishmaniose and Trypanosome with partnerships from teams, member of the Consortium Antiparasitaire (CaP ; www.consortium_aparasitaire.u-psud.fr) with also HTS at the Station Biologique de Roscoff under confidential agreements.

Part of the results (covered by our first patent) have been presented at different institutions and at national and international symposiums: Universiteit Katholiek Leuven, Belgique, April 2012; first summer school of the Consortium anti-Parasitaire (CaP), 25-27 June 2012, Les Pensières, Annecy; JNOEJC 2012, Lille, June 2012 ; BOSS 2012, Leuven (Belgique), July 2012); second symposium of the Consortium Antiparasitaire (CaP), Toulouse, February 2012. A fist paper has been published in January 2013 in the Journal of Medicinal Chemistry. A first patent has been issued and a international PCT extension is under progress.

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.