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A facile synthetic route towards either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.

The transmembrane (TM) proteins are gateways for molecular transport across the cell membrane that are often selected as potential targets for drug design. The bilitranslocase (BTL) protein facilitates the uptake of various anions, such as bilirubin, from the blood into the liver cells. As previously established, there are four hydrophobic transmembrane segments (TM1&ndash, TM4), which constitute the structure of the transmembrane channel of the BTL protein. In our previous studies, the 3D high-resolution structure of the TM2 and TM3 transmembrane fragments of the BTL in sodium dodecyl sulfate (SDS) micellar media were solved using Nuclear Magnetic Resonance (NMR) spectroscopy and molecular dynamics simulations (MD). The high-resolution 3D structure of the fourth transmembrane region (TM4) of the BTL was evaluated using NMR spectroscopy in two different micellar media, anionic SDS and zwitterionic DPC (dodecylphosphocholine). The presented experimental data revealed the existence of an &alpha, helical conformation in the central part of the TM4 in both micellar media. In the case of SDS surfactant, the &alpha, helical conformation is observed for the Pro258&ndash, Asn269 region. The use of the zwitterionic DPC micelle leads to the formation of an amphipathic &alpha, helix, which is characterized by the extension of the central &alpha, helix in the TM4 fragment to Phe257&ndash, Thr271. The complex character of the dynamic processes in the TM4 peptide within both surfactants was analyzed based on the relaxation data acquired on 15 N and 31 P isotopes. Contrary to previously published and present observations in the SDS micelle, the zwitterionic DPC environment leads to intensive low-frequency molecular dynamic processes in the TM4 fragment.