Hortensia Rodríguez

CuAAC: An Efficient Click Chemistry Reaction on Solid Phase

Click chemistry is an approach that uses efficient and reliable reactions, such as Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), to bind two molecular building blocks. CuAAC has broad applications in medicinal chemistry and other fields of chemistry. This review describes the general features and applications of CuAAC in solid-phase synthesis (CuAAC-SP), highlighting the suitability of this kind of reaction for peptides, nucleotides, small molecules, supramolecular structures, and polymers, among others. This versatile reaction is expected to become pivotal for meeting future challenges in solid-phase chemistry.

Solvent-free synthesis of 4-aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones under microwave irradiation

Abstract 4-Aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones have been prepared in one-pot condensation from Meldrums acid, methyl acetoacetate and the appropriate benzaldehyde in the presence of ammonium acetate using microwave irradiation without solvent. This rapid method produced pure products in high yields (81–91%) due essentially to a specific non-thermal microwave effect (17–28%) by conventional heating under the same conditions.

Development of a novel virtual screening cascade protocol to identify potential trypanothione reductase inhibitors.

The implementation of a novel sequential computational approach that can be used effectively for virtual screening and identification of prospective ligands that bind to trypanothione reductase (TryR) is reported. The multistep strategy combines a ligand-based virtual screening for building an enriched library of small molecules with a docking protocol (AutoDock, X-Score) for screening against the TryR target. Compounds were ranked by an exhaustive conformational consensus scoring approach that employs a rank-by-rank strategy by combining both scoring functions. Analysis of the predicted ligand−protein interactions highlights the role of bulky quaternary amine moieties for binding affinity. The scaffold hopping (SHOP) process derived from this computational approach allowed the identification of several chemotypes, not previously reported as antiprotozoal agents, which includes dibenzothiepine, dibenzooxathiepine, dibenzodithiepine, and polycyclic cationic structures like thiaazatetracyclo-nonadeca-hexaen-3-ium. Assays measuring the inhibiting effect of these compounds on T. cruzi and T. brucei TryR confirm their potential for further rational optimization.

Ultrasound-assisted one-pot, four component synthesis of 4-aryl 3,4-dihydropyridone derivatives.

The condensation of Meldrums acid, aromatic aldehydes, alkyl acetoacetates and ammonium acetate in glacial acetic acid under ultrasound irradiation at room temperature results in the formation of 3,4-dihydropyridone derivatives (4a-p) in 85-96% yields. Compared with conventional methods, the main advantages of the present procedure are milder conditions, shorter reaction times and higher yields.

In Vitro and in Vivo Assays of 3,5-Disubstituted-Tetrahydro-2H-1,3,5-Thiadiazin-2-Thione Derivatives against Trypanosoma cruzi

Cytotoxicity assays of 24 new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives were performed. The 17 compounds with higher anti-epimastigote activity and lower cytotoxicity were, thereafter, screened against amastigote of Trypanosoma cruzi. Out of these 17 derivatives S-2d was selected to be assayed in vivo, because of its remarkable trypanocidal properties. To determine toxicity against J774 macrophages, a method based on quantification of cell damage, after 24 h, was used. Cell respiration, an indicator of cell viability, was assessed by the reduction of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to formazan. Anti-amastigote activity was estimated after 48 h by microscopic counts of May Grünwald-Giemsa-stained monolayers. Nifurtimox and benznidazole were used as reference drugs. For the in vivo experiences, mice were infected with 10(4) blood trypomastigotes and then treated during 15 days with S-2d or nifurtimox by oral route. All of the compounds were highly toxic at 100 micro g/ml for macrophages and a few of them maintained this cytotoxicity even at 10 microg/ml. Of the derivatives assayed against amastigotes 3k and S-2d showed an interesting activity, that was held even at 1microg/ml. It is demonstrated that the high anti-epimastigote activity previously reported is mainly due to the non-specific toxicity of these compounds. In vivo assays assessed a reduction of parasitemia after administration of S-2d to infected mice.

A convenient microwave-enhanced solid-phase synthesis of short chain N-methyl-rich peptides

Structural modification of the peptide backbone via N‐methylation is a powerful tool to modulate the pharmacokinetic profile and biological activity of peptides. Here we describe a rapid and highly efficient microwave(MW)‐assisted Fmoc/tBu solid‐phase method to prepare short chain N‐methyl‐rich peptides, using Rink amide p‐methylbenzhydrylamine (MBHA) resin as solid‐phase support. This method produces peptides in high yield and purity, and reduces the time required for Fmoc‐N‐methyl amino acid coupling. Copyright

Solid-phase synthesis of 4-aryl substituted 5-carboxy-6-methyl-3,4-dihydropyridones

Substituted 3,4-dihydro-2-pyridones have been efficiently prepared by solid-phase synthesis using Wang resin from the immobilised β-ketoester and further Hantzsch-type heterocyclisation.

Solid phase synthesis of 3-(5′-carboxypentyl)-5-substituted tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives

Abstract The solid phase synthesis of 3-(5′-carboxypentyl)-5-substituted tetrahydro-2 H -1,3,5-thiadiazin-2-thione derivatives 5 is described. 6-Amino- n -hexanoic acid was attached via its C-terminal to hydroxymethyl polystyrene using a ‘SASRIN’ linker. The bound amino acid was converted to the corresponding dithiocarbamate 3 followed by cyclization in the presence of formaldehyde and the corresponding free amino acids to afford 3-(5′-carboxypentyl)-5-substituted tetrahydro-2 H -1,3,5-thiadiazin-2-thiones 4 . The final products were cleaved from the resin and obtained in moderate yields.

Imidazole-1-sulfonyl Azide-Based Diazo-Transfer Reaction for the Preparation of Azido Solid Supports for Solid-Phase Synthesis

An efficient, standard, mild, and copper-free imidazole-1-sulfonyl azide hydrochloride-based diazo-transfer method was implemented in a set of four resins that cover a broad range of hydrophobicity. The imidazole-1-sulfonyl azide hydrochloride is easily prepared/commercially available, stable upon storage at 4 °C, and proved to be a suitable alternative to triflyl azide for diazo-transfer reactions in amine functionalized resins. We have successfully applied the azido resins for the conjugation of a TFA-labile Wang-type linker using Click Chemistry.

Efficient sonochemical synthesis of alkyl 4-aryl-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate derivatives.

A facile, efficient and environment-friendly protocol for the synthesis of 6-chloro-5-formyl-1,4-dihydropyridine derivatives has been developed by the convenient ultrasound-mediated reaction of 2(1H)pyridone derivatives with the Vilsmeier-Haack reagent. This method provides several advantages over current reaction methodologies including a simpler work-up procedure, shorter reaction times and higher yields.