José M. Bueno

Synthesis and Structure-Activity Relationships of 4-Pyridones as Potential Antimalarials

A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC50 for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED50 against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc1 complex.

An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS

In 2010, GlaxoSmithKline published the structures of 13533 chemical starting points for antimalarial lead identification. By using an agglomerative structural clustering technique followed by computational filters such as antimalarial activity, physicochemical properties, and dissimilarity to known antimalarial structures, we have identified 47 starting points for lead optimization. Their structures are provided. We invite potential collaborators to work with us to discover new clinical candidates.

Stereoselective synthesis of the antifungal GM222712

Abstract An efficient and convergent synthesis of the antifungal agent GM222712 is described. The approach involves the preparation of the modified sugar moiety followed by its stereoselective anomeric O -alkylation with sordaricin triflate 19 .

Formation of mono- and di- nuclear complexes of Zn2+ from a 26 membered tetraester crown of 3,5-disubstituted pyrazole able to act as neutral and dianionic ligand

Abstract A selective synthesis of bis(3,5-diketo-1H-pyrazole)-[26]crown- 12 ( 1 , L 1 ) has been performed. Its deprotonation pK a values, and those of the acyclic analogues ( 3 – 5 ) have been measured. The disodium dipyrazolate salt of 1 ( 2 , [L 2 ] 2- 2Na + ) has been isolated, and mono- and di- nuclear complexes of Zn 2+ obtained from 1 ([L 1 Zn] 2+ ) and 2 ([L 2 Zn 2 ] 2+ ) have been studied by 13 C NMR spectroscopy in DMSO-d 6 solution.

Potent antimalarial 4-pyridones with improved physico-chemical properties.

Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species.

Case Study of Small Molecules As Antimalarials: 2-Amino-1-phenylethanol (APE) Derivatives.

Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4-0.5 μM are able to show in vivo activity.

Synthesis of a stable dinuclear complex formed from a 26 membered proton-ionizable crown of 3,5-disusbstituted 1H-pyrazole and homoveratrylamine

The 26 membered proton ionizable crown of 3.5-disubstituted 1H-pyrazole 1 acts as a synthetic receptor able to interac with the amino group common to neurotransmitter substrates, such as catecholamines. The synthesis of a solid and stable dinuclear complex formed by proton ionizable crown 1 and homoveratrylamines is described. The FAB mass apectrum of complex, and the difference found in 13C-RMN spectra of crown 1 and its dinuclear complex 3 we commented. The isolation of this dinuclear complex confirm the hypothesis that of synthetic receptor 1 is able to recognise catecholamines and to interact with the amno group of such amines.