Xavier J. Salom-Roig

Dual Molecules as New Antimalarials

A new antimalarial pharmacological approach based on inhibition of the plasmodial phospholipid metabolism has been developed. The drugs mimic choline structure and inhibit de novo phosphatidylcholine biosynthesis. Three generations of compounds were rationally designed. Bisquaternary ammonium salts showed powerful antimalarial activity, with IC(50) in the nanomolar range. To remedy their low per os absorption, bioisosteric analogues (bis-amidines) were designed and exhibited similar powerful activities. Finally, the third generation compounds are bis-thiazolium salts and their non-ionic precursors: prodrugs, which in vivo can lead to thiazolium drugs after enzymatic transformation. The compounds are equally effective against multiresistant Plasmodium falciparum malaria. These molecules exert a very rapid cytotoxic effect against malarial parasites in the very low nanomolar range and are active in vivo against P. vinckei-infected mice, with ED(50) lower than 0.2 mg/kg. They are able to cure highly infected mice and, retain full activity after a single injection. They also retain full activity against P. falciparum and P. cynomolgi in primate models with no recrudescence and at lower doses. Compounds are accumulated in P.falciparum-infected erythrocyte, which ensures their potency and specificity. Recently, we discovered that compounds also interact with malarial pigment enhancing the antimalarial effect. It is quite likely that they are dual molecules, exerting their antimalarial activity via two simultaneous toxic effects on the intracellular intraerythrocytic parasites. The current leader compounds are accessible in few steps from commercial products. These crystalline molecules present a remarkable biological activity and low toxicity which is promising for the development of a new antimalarial drug.

Faster and cleaner dynamic kinetic resolution via mechanochemistry

Application of the ball-milling techniques to dynamic kinetic resolution accelerates reactions while avoiding the use of toxic organic solvents and reactants commonly required in these processes. In this way, dynamic kinetic resolutions can be both faster and “cleaner” in the sense that mechanochemistry enables the reduction of their environmental impact.

Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials.

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.

Lewis Acid Induced Switch of Torquoselectivity in the Nazarov Cyclization of Activated Dienones Bearing a Chiral Sulfoxide.

A Nazarov cyclization of activated dienones bearing a dihydropyran as an electron-donating group (EDG) and a chiral sulfoxide group as an electron-withdrawing group (EWG) and chiral inductor is described. The direction of the torquoselectivity depends highly on the nature of the Lewis acid promoter. This diastereodivergent strategy furnishes both trans stereoisomers from a common precursor. The potential of the Nazarov cyclization products was highlighted by further synthetic elaboration.

New Insights into the Synthesis and Biological Activity of the Pamamycin Macrodiolides.

After a brief account of the biological properties of pamamycins, this review highlights the latest developments on the total synthesis and the biosynthesis of these macrodiolides.

First Total Synthesis of Pamamycin-621D

Pamamycin-621D, a member of a large family of macrodiolides with antimycobacterial properties, has been synthesized and fully characterized for the first time. A convergent and flexible strategy based on a key aldol coupling delivered this less abundant pamamycin congener. Furthermore, the synthesis of a new unsaturated precursor using cross-metathesis was developed in order to suppress regioselectivity issues in the aldol coupling step.