Construction of NH-Unprotected Spiropyrrolidines and Spiroisoindolines by [4+1] Cyclizations of γ-Azidoboronic Acids with Cyclic N-Sulfonylhydrazones.

The reactions of N-sulfonylhydrazones derived from cyclic ketones with γ-azidopropylboronic acid and 2-(azidomethyl)phenylboronic acid give rise to spirocyclic pyrrolidines and spiroisoindolines, respectively. The reactions proceed without the need of any transition-metal catalyst through a domino process that comprises the formation of a Csp3 -C and a Csp3 -N bond of the former hydrazonic carbon. The scope of the reaction has been explored by the preparation of over 50 examples of NH-unprotected spirocyclic derivatives. Importantly, this methodology could be applied for the preparation of alkaloid steroids from steroid N-tosylhydrazones.

Synthesis of Pyrrolidines by a Csp3 -Csp3 /Csp3 -N Transition-Metal-Free Domino Reaction of Boronic Acids with γ-Azido-N-Tosylhydrazones.

The reaction between γ-azido-N-tosylhydrazones and boronic acids leads to the obtention of 2,2-disubstituted pyrrolidines in a domino process that includes 1) diazoalkane formation, 2) intermolecular carboborylation of the diazocompound, and 3) intramolecular carborylation of the azide, and comprises the formation of a Csp3 -Csp3 and a Csp3 -N bonds on the same carbon atom. The reaction proceeds without the need of any transition-metal catalyst under microwave activation and features wide scope in both reaction partners. It can be applied to both alkyl and arylboronic acids with equal efficiency. With N-tosylhydrazones derived from 2-(2-azidoethyl)-cyclopentanone and cyclohexanone the reactions are highly diastereoselective leading to the cis-fused bicyclic systems as unique diastereoisomers. The scope of the process is illustrated by over sixty examples, including scaffolds present in natural alkaloids, and the mechanistic proposal is suppported by DFT-based computations.

Cascade and multicomponent synthesis of structurally diverse 2-(pyrazol-3-yl)pyridines and polysubstituted pyrazoles.

The cascade reaction between N-tosylhydrazones and 2-alkynylpyridines leads to 2-(pyrazol-3-yl)pyridines, important structural motifs in ligands for transition metals and bioactive molecules. When the reaction is conducted with 2,6-diethynylpyridine, the important 2,6-bis(pyrazolyl)pyridines are obtained, featuring the arrangement of tridentate and also pentadentate ligands. A novel three-component version of the reaction has been designed, which involves the use of α-bromo-N-tosylhydrazones, alkynylpyridines and NH-azoles. The generality of the multicomponent reaction is further illustrated by the preparation of different polysubstituted pyrazoles by employing an array of terminal alkynes. In these multicomponent reactions, complex molecules featuring three different heterocycles are assembled in a single step from commercial materials, enabling the fast generation of molecular diversity.

Structurally Diverse π-Extended Conjugated Polycarbo- and Heterocycles through Pd-Catalyzed Autotandem Cascades.

The Pd-catalyzed reaction between 2,2'-dibromobiphenyls and related systems with tosylhydrazones gives rise to new π-extended conjugated polycarbo- and heterocycles through an autotandem process involving a cross-coupling reaction followed by an intramolecular Heck cyclization. The reaction shows wide scope regarding both coupling partners. Cyclic and acyclic tosylhydrazones can participate in the process. Additionally, a variety of aromatic and heteroaromatic dibromoderivatives have been employed, leading to an array of diverse scaffolds featuring a fluorene or acridine central nucleus, and containing binaphthyl, thiophene, benzothiophene and indole moieties. The application to appropriate tetrabrominated systems led to greater structural complexity through two consecutive autotandem cascades. The photophysical properties of selected compounds were studied through their absorption and emission spectra. Fluorescence molecules featuring very high quantum yields were identified, showing the potential of this methodology in the development of molecules with interesting optoelectronic properties.

Stability of Non-Ionic Surfactant Vesicles Loaded with Rifamycin S.

These days, the eradication of bacterial infections is more difficult due to the mechanism of resistance that bacteria have developed towards traditional antibiotics. One of the medical strategies used against bacteria is the therapy with drug delivery systems. Non-ionic vesicles are nanomaterials with good characteristics for encapsulating drugs, due to their bioavailability and biodegradability, which allow the drugs to reach the specific target and reduce their side effects. In this work, the antibiotic Rifamycin S was encapsulated. The rifamycin antibiotics family has been widely used against Mycobacterium tuberculosis, but recent studies have also shown that rifamycin S and rifampicin derivatives have bactericidal activity against Staphylococcus epidermidis and Staphylococcus aureus. In this work, a strain of S. aureus was selected to study the antimicrobial activity through Minimum Inhibitory Concentration (MIC) assay. Three formulations of niosomes were prepared using the thin film hydration method by varying the composition of the aqueous phase, which included MilliQ water, glycerol solution, or PEG400 solution. Niosomes with a rifamycin S concentration of 0.13 µg/g were satisfactorily prepared. Nanovesicles with larger size and higher encapsulation efficiency (EE) were obtained when using glycerol and PEG400 in the aqueous media. Our results showed that niosomes consisting of an aqueous glycerol solution have higher stability and EE across a diversity of temperatures and pHs, and a lower MIC of rifamycin S against S. aureus.

Strong in vitro activities of two new rifabutin analogs against multidrug-resistant Mycobacterium tuberculosis.

Two new rifabutin analogs, RFA-1 and RFA-2, show high in vitro antimycobacterial activities against Mycobacterium tuberculosis. MIC values of RFA-1 and RFA-2 were ≤0.02 µg/ml against rifamycin-susceptible strains and 0.5 µg/ml against a wide selection of multidrug-resistant strains, compared to ≥50 µg/ml for rifampin and 10 µg/ml for rifabutin. Molecular dynamic studies indicate that the compounds may exert tighter binding to mutants of RNA polymerase that have adapted to the rifamycins.

Spiropiperidyl rifabutins: expanded in vitro testing against ESKAPE pathogens and select bacterial biofilms.

The expanded microbiological evaluation of a series of rifastures, novel spiropiperidyl rifamycin derivatives, against clinically relevant ESKAPE bacteria has identified several analogs with promising in vitro bioactivities against antibiotic-resistant strains of Enterococcus faecium and Staphylococcus aureus. Thirteen of the rifastures displayed minimum inhibitory concentrations (MICs) below 1 µg/ml against the methicillin- and vancomycin-resistant forms of S. aureus and E. faecium (MRSA, VRSA, VRE). Aryl-substituted rifastures 1, 11, and 12 offered the greatest bioactivity, with MICs reaching ≤0.063 µg ml-1 for these human pathogens. Further analysis indicates that diphenyl rifasture 1 had greater antibiofilm activity against S. aureus and lower cytotoxicity in mammalian HEK cells than rifabutin.

Synthesis of 1,1-Disubstituted Indenes and Dihydronaphthalenes through C-C/C-C Bond-Forming Pd-Catalyzed Autotandem Reactions.

A novel synthesis of 1,1-disubstituted 1H-indenes is described involving the Pd-catalyzed cascade reaction between o-bromophenyl-ß-bromostyrenes and N-tosylhydrazones in a process comprising the consecutive formation of two Csp3-C bonds on the same carbon atom: the cross-coupling of the N-tosylhydrazone with the alkenyl bromide and the intramolecular Heck reaction on the newly formed double bond. A similar approach has been applied to the preparation of 1,1-disubstituted naphthalenes.

Synthesis of 1,3-diaryl-3-trifluoromethylcyclopropenes by transition-metal-free reaction of 2,2,2-trifluoroacetophenone tosylhydrazones with alkynes: the effect of the trifluoromethyl group.

1,3-Diaryl-3-trifluoromethylcyclopropenes and 2-aryl- or 2-alkyl-1,3-diaryl-3-trifluoromethylcyclopropenes are prepared in a very simple way by reaction between 1,1,1-trifluoroacetophenone tosylhydrazones and terminal or internal alkynes, respectively, in a base promoted process that does not require the presence of any metal catalyst. The essential role of the trifluoromethyl group, which enables the formation of the cyclopropenes instead of the expected pyrazoles, has been computationally investigated, suggesting the participation of a free carbene.

Pd-catalyzed autotandem C-C/C-C bond-forming reactions with tosylhydrazones: synthesis of spirocycles with extended π-conjugation.

A new Pd-catalyzed autotandem process is presented by the reaction of tosylhydrazones of cyclic ketones and 2,2'-dibromobiphenyls and related systems. The process involves cross-coupling with tosylhydrazone followed by an intramolecular Heck reaction and gives rise to spirocyclic structures. Noteworthy, two C-CAr bonds are formed on the hydrazonic carbon during the process. Depending on the starting dibromide, an array of spirofluorenes, spirodibenzofluorenes, spiroacridines, and spiroanthracenes have been prepared. Thus, this methodology may be applied for the preparation of interesting structures useful in the development of optoelectronic materials.

New rifabutin analogs: synthesis and biological activity against Mycobacterium tuberculosis.

The synthesis, structure, and biological evaluation of a series of novel rifamycin derivatives, Rifastures (RFA) with potent anti-tuberculosis activity are presented. Some of these derivatives showed higher in vitro activity than rifabutin and rifampicin against not only Mycobacterium tuberculosis strains but also against MAC and Mycobacterium kansasii.

NMR spectroscopic analysis of new spiro-piperidylrifamycins.

New spiro-piperidylrifamycin derivatives are presented. These compounds were synthesized from the reaction of 3-amino-4-iminorifamycin S and enantiomerically pure 4-piperidones, which generate diasteroisomeric rifabutin analogues with a new stereocentre at the spiranic carbon. The (1)H and (13)C NMR spectra of these new compounds, and also the configuration of the new stereogenic centres, were assigned using 2D NMR spectroscopic techniques. A preliminary study of the (1)H and (13)C NMR spectra of the starting compounds rifamycin S, 3-amino-4-iminorifamycin S and the related rifabutin was also carried out and as a result, their previously published (13)C NMR data were corrected.