New Lidocaine-Based Pharmaceutical Cocrystals: Preparation, Characterization, and Influence of the Racemic vs. Enantiopure Coformer on the Physico-Chemical Properties.

This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal was evaluated by means of X-ray diffraction, infrared spectroscopy, Raman, thermal analysis, and solubility experiments. The results were exhaustively compared with the first menthol-based pharmaceutical cocrystal, i.e., lidocaine:l-menthol, discovered in our group 12 years ago. Furthermore, the stable lidocaine/dl-menthol phase diagram has been screened, thoroughly evaluated, and compared to the enantiopure phase diagram. Thus, it has been proven that the racemic vs. enantiopure coformer leads to increased solubility and improved dissolution of lidocaine due to the low stable form induced by menthol molecular disorder in the lidocaine:dl-menthol cocrystal. To date, the 1:1 lidocaine:dl-menthol cocrystal is the third menthol-based pharmaceutical cocrystal, after the 1:1 lidocaine:l-menthol and the 1:2 lopinavir:l-menthol cocrystals reported in 2010 and 2022, respectively. Overall, this study shows promising potential for designing new materials with both improved characteristics and functional properties in the fields of pharmaceutical sciences and crystal engineering.

Dual Photoredox Ni/Benzophenone Catalysis: A Study of the NiII Precatalyst Photoreduction Step.

The combination of NiIIX2 salts with a bipyridine-type ligand and aromatic carbonyl-based chromophores has emerged as a benchmark precatalytic system to efficiently conduct cross-couplings mediated by light. Mechanistic studies have led to two scenarios in which Ni0 is proposed as the catalytic species. Nonetheless, in none of these studies has a NiII to Ni0 photoreduction been evidenced. By exploiting UV-visible, nuclear magnetic resonance, resonance Raman, electron paramagnetic resonance, and dynamic light scattering spectroscopies and also transmission electron microscopy, we report that, when photolyzed by UVA in alcohols, the structurally defined [NiII2(µ-OH2)(dtbbpy)2(BPCO2)4] complex 1 integrating a benzophenone chromophore is reduced into a diamagnetic NiI dimer of the general formula [NiI2(dtbbpy)2(BPCO2)2]. In marked contrast, in THF, photolysis led to the fast formation of Ni0, which accumulates in the form of metallic ultrathin Ni nanosheets characterized by a mean size of ∼100 nm and a surface plasmon resonance at 505 nm. Finally, it is shown that 1 combined with UVA irradiation catalyzes cross-couplings, that is, C(sp3)-H arylation of THF and O-arylation of methanol. These results are discussed in light of the mechanisms proposed for these cross-couplings with a focus on the oxidation state of the catalytic species.

Intramolecular Michael Additions in Uridine Derivatives: Isolation of the Labile 5'O-C6 Cyclonucleoside.

Uridine derivatives undergo a diastereospecific intramolecular hetero Michael addition onto uracil C6 to give cyclo-adducts. In contrast to the potent amine and thiol nucleophiles at the 5' position of ribose, which readily give the N- and S-cyclonucleosides in good yields, the cyclization reaction from the "natural" 5'-hydroxyl is tedious and has so far been overlooked most probably because of the thermodynamic instability of the O-cyclo-adduct. Here, we show that the O-cyclonucleoside 1 can be isolated, although in low isolated yields, in acidic conditions following an original mechanism. Whether such cyclization reactions occur from biologically relevant pyrimidine-based nucleosides is an open question of interest. Given the structures of thymidine-based antiviral drugs, our results suggest a new hypothetical mode of action for these drugs.

Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels-Alder Pattern Common to Three Classes of Natural Products.

Identification of a common Diels-Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from ß,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered ß,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.

Chiral Memory in Silyl-Pyridinium and Quinolinium Cations.

Pyridine- and quinoline-stabilized silyl cations have been prepared, and their structure in condensed phases unambiguously assigned using 1H, 13C, 15N, 29Si, and 1H DOSY NMR as well as X-ray diffraction studies. Solid state structures thus show in both cases a stabilization of the cationic silicon center through an N-Si interaction and formation of a highly strained four-membered ring system. Chiral memory at the silicon atom in these heterocycle-stabilized silyl cations was also established, leading to various levels of selectivity depending on the nature of the heterocycle. Lowest energy conformations of the starting silanes obtained through DFT calculations, along with the isolation and characterization of the Si-centered chiral silyl cation intermediates, finally allowed to propose a plausible hypothesis as to the configurational stability of these silyl cations.

p-Anisaldehyde-Photosensitized Sulfonylcyanation of Chiral Cyclobutenes: Enantioselective Access to Cyclic and Acyclic Systems Bearing All-Carbon Quaternary Stereocenters.

The photosensitized p-anisaldehyde-mediated addition of sulfonylcyanides onto the π-system of cyclobutenes is shown to afford highly functionalized cyclobutanes in high yields and diastereocontrol. The homochiral cyclobutene precursors are accessible on multigram scale in two steps through an asymmetric [2 + 2] cycloaddition/vinyl thioether reduction sequence. The enantiopure cyclobutylnitriles can be elaborated further through SmI2-mediated ring opening or converted into new enantiopure cyclobutenes through base-mediated sulfone elimination.

Bio-inspired Total Synthesis of Twelve Securinega Alkaloids: Structural Reassignments of (+)-Virosine†B and (-)-Episecurinol†A.

The so-called Securinega alkaloids constitute a class of tetracyclic biologically active specialised metabolites isolated principally from subtropical plants belonging to the Phyllanthaceae family. Following a strategy based on alternative hypotheses for their biosynthesis, an easy and time-efficient divergent synthesis enabled access to twelve of those alkaloids featuring (neo)(nor)securinane skeletons. Moreover, this work permitted to reassign the absolute configurations of (+)-virosine B and (-)-episecurinol A.

Synthesis of [7]Helicene Enantiomers and Exploratory Study of Their Conversion into Helically Chiral Iodoarenes and Iodanes.

The facile and convenient preparation of both enantiomers of a [7]helicene scaffold from inexpensive (l)-(+)-tartaric acid and 4-methylstyrene is described. These helical structures were transformed into bis-iodinated ether derivatives in order to explore their potential as precursors of novel chiral organoiodane reagents or as iodoarene pre-catalysts. Promising results were obtained in hydroxylative phenol dearomatization/[4+2] cycloaddition cascade and dearomative spirolactonization reactions with encouraging enantiomeric excesses.

An Approach towards the Synthesis of the Spiroimine Fragment of 13-Desmethylspirolide†C and Gymnodimine†A.

A general access to the spiroimine skeleton of gymnodimine and spirolides is described, relying on the construction of the cyclohexene fragment using an enantiocontrolled Diels-Alder reaction, the installation of the all-carbon quaternary stereocenter through a stereocontrolled alkylation or aldolisation and the elaboration of the lateral chains at C7 and C22 using Wittig-Horner olefinations. The spiroimine core of gymnodimine is made available through a 16-step linear sequence in a 21 % overall yield.

Discovery of a subnanomolar and selective spirocyclic agonist of the glucocorticoid receptor.

Pure diastereomeric spirocyclic analogs of fluorocortivazol were conveniently prepared by a short and efficient synthetic sequence recently developed in our laboratory. The structures and conformations of several key products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. Biological evaluation led to the identification of a highly potent hGR agonist with excellent anti-inflammatory effects in the subnanomolar range. All tested compounds from this series were also selective versus the progesterone receptor.

Synthesis and Multibromination of Nanosized Helical Aromatic Amide Foldamers via Segment-Doubling Condensation.

The synthesis of very long helical aromatic amide foldamers was thought to be limited by steric hindrance associated with stable folded conformations. This difficulty may be overcome by using pure reagents, relatively high concentrations, and long reaction times. Bromine substituents and careful identification and elimination of anhydride byproducts both greatly improve chromatographic purification, giving access to pure products amenable to a segment-doubling synthesis of sequences composed of up to 96 monomers. An efficient one-pot multibromination of helical oligomers is also reported.

Effective ascorbate-free and photolatent click reactions in water using a photoreducible copper(II)-ethylenediamine precatalyst.

The search for copper catalysts able to perform effectively click reactions in water in the absence of sodium ascorbate is an active area of current research with strong potential for applications in bioconjugation. The water-soluble and photoreducible copper(II)-EDA (EDA = ethylenediamine) complex 1, which has two 4-benzoylbenzoates acting as both counterion and photosensitizer, has been synthesized and characterized by different techniques including single crystal X-ray diffraction. Highly efficient photoreduction was demonstrated when solutions of 1 in hydrogen atom donating solvents, such as THF or MeOH, were exposed to UVA radiation (350-400 nm) provided by a low pressure mercury lamp (type TLC = thin-layer chromatography, 365 nm), or by a 23 W fluorescent bulb, or by ambient/sunlight. In water, a much poorer hydrogen atom donating solvent, the photoreduction of 1 proved inefficient. Interestingly, EPR studies revealed that complex 1 could nonetheless be effectively photoreduced in water when alkynes were present in solution. The catalytic activity of 1 for click reactions involving a range of water-soluble alkynes and azides, in particular saccharides, was tested under various illumination conditions. Complex 1 was found to exhibit a photolatent character, the photogenerated copper(I) being very reactive. On irradiating aqueous reaction mixtures containing 1 mol % of 1 at 365 nm (TLC lamp) for 1 h, click reactions were shown to proceed to full conversion.

Ligandless Palladium-Catalyzed Regioselective Direct C-H Arylation of Imidazo[1,2-a]imidazole Derivatives.

Herein a novel access to functionalizable 6-substituted imidazo[1,2-a]imidazole scaffolds is described. The reactivity of this heterobicyclic unit toward direct C-H arylation was studied, and conditions allowing regioselective arylation at position 3 were successfully developed. The practicability of this method is manifested by the ligandless conditions and low catalyst loading. The strategy is functional group tolerant and provides rapid access to a large variety of 3,6-di(hetero)arylated imidazo[1,2-a]imidazole derivatives. A second arylation at position 2 was then carried out, and a library of diversified 2,3,6-tri(hetero)arylated imidazo[1,2-a]imidazoles was generated in good yields. A one-pot, two-step procedure was finally developed.

Isosteric substitutions of urea to thiourea and selenourea in aliphatic oligourea foldamers: site-specific perturbation of the helix geometry.

Nearly isosteric oxo to thioxo substitution was employed to interrogate the structure of foldamers with a urea backbone and explore the relationship between helical folding and hydrogen-bonding interactions. A series of oligomers with urea bonds substituted by thiourea bonds at discrete or all positions in the sequence have been prepared and their folding propensity was studied by using a combination of spectroscopic methods and X-ray diffraction. The outcome of oxo to thioxo replacements on the helical folding was found to depend on whether central or terminal ureas were modified. The canonical helix geometry was not affected upon insertion of thioureas close to the negative end of the helix dipole, whereas thioureas close to the positive pole were found to increase the terminal flexibility and cause helix fraying. Perturbation was amplified when a selenourea was incorporated instead, leading to a structure that is only partly folded.

New imidazo[1,2-b]pyrazoles as anticancer agents: synthesis, biological evaluation and structure activity relationship analysis.

Synthesis and functionalization strategies of the imidazo[1,2-b]pyrazole core were developed giving a rapid access to three series of novel imidazo[1,2-b]pyrazole type derivatives: C-2/C-6/C-7 trisubstituted, C-2/C-3/C-6 tri(hetero)arylated and C-2/C-3/C-6/C-7 tetrasubstituted imidazo[1,2-b]pyrazoles. 39 of the synthetized products were evaluated for in vitro anticancer activity using the MTT colorimetric assay against 5 human and 1 murine cancer cell lines. Promising in vitro growth inhibitory activities were exhibited by some of the target compounds. Of the 39 evaluated products, 4 displayed an IC50 ≤ 10 µM in the 6 cell lines analyzed (compounds 4d, 4g, 9a, 11a). A structure activity relationship analysis is also reported in this paper.

Design of α7 nicotinic acetylcholine receptor ligands in quinuclidine, tropane and quinazoline series. Chemistry, molecular modeling, radiochemistry, in vitro and in rats evaluations of a [(18)F] quinuclidine derivative.

In this report, we describe the synthesis of a novel library of α7 nAChR ligands based on the modulation of the quinuclidine, quinazoline and tropane moieties. Spirane derivatives were newly synthesized under stereo specific 1,3 dipolar cylcoadditions. Only amide derivatives bonded efficiently to the receptor with Ki measured between 14 and 133 nM. The best fluorinated candidate was selected and radiolabeled. The potent [(18)F]4 PET tracer was evaluated in rats and its brain accumulation quantified.

Synthesis of 1,8-diazaanthracenes as building blocks for internally functionalized aromatic oligoamide foldamers.

The synthesis of a variety of 9-functionalized 1,8-diazaanthracene diesters and amino acids is described. Derivatization at the 9-position relies on facile reactions performed on the 9-chloro and 9-bromomethyl precursors. This has allowed the incorporation of nucleophilic or sensitive functional groups that otherwise cannot be incorporated under standard methods for synthesizing these compounds. Additionally, the synthesis of the protected amino acids via a high-yielding monosaponification and subsequent Curtius rearrangement has been accomplished on a multigram scale. These units, together with the functionalized derivatives, should prove to be useful monomers in the synthesis of aromatic oligoamide foldamers.

α-Halogenoacetanilides as hydrogen-bonding organocatalysts that activate carbonyl bonds: fluorine versus chlorine and bromine.

α-Halogenoacetanilides (X=F, Cl, Br) were examined as H-bonding organocatalysts designed for the double activation of CO bonds through NH and CH donor groups. Depending on the halide substituents, the double H-bond involved a nonconventional CH⋅⋅⋅O interaction with either a HCXn (n=1-2, X=Cl, Br) or a HCAr bond (X=F), as shown in the solid-state crystal structures and by molecular modeling. In addition, the catalytic properties of α-halogenoacetanilides were evaluated in the ring-opening polymerization of lactide, in the presence of a tertiary amine as cocatalyst. The α-dichloro- and α-dibromoacetanilides containing electron-deficient aromatic groups afforded the most attractive double H-bonding properties towards CO bonds, with a NH⋅⋅⋅O⋅⋅⋅HCX2 interaction.

Efficient metal-free synthesis of various pyrido[2',1':2,3]imidazo- [4,5-b]quinolines.

Dancing with diversity: The synthesis of diverse pyrido[2',1':2,3]imidazo[4,5-b]quinolines bearing several substitution patterns was developed based on combining a multicomponent reaction (Groebke-Blackburn-Bienaymé reaction) with an original cyclization as a secondary transformation (see scheme; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene).

Pharmaceutical development and optimization of azithromycin suppository for paediatric use.

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought.