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Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.

A Brønsted acid-catalyzed reaction between isoindolinone-derived propargylic alcohols and external aromatic nucleophiles for the construction of spiroisoindolinone indenes is described. The reaction proceeds rapidly with a broad range of substrates to generate spiroindenes chemoselectively and regioselectively in moderate to high yields. Key to the success of this transformation is an intercepted Meyer-Schuster rearrangement/intramolecular Friedel-Crafts alkylation relay that offers a modular approach in the synthesis of target compounds.

Amides are common molecules which are most often prepared using benzotriazole oxide coupling reagents. Such amides can be derivatised with compounds that contain a triple carbon–carbon bond in order to facilitate easy introduction of the amide fragment into a target molecule via cycloaddition reactions. In this paper, a previously unknown tandem reaction consisting of amide coupling and hydroamination of a triple C–C bond is described. The reaction occurs when the TBTU/HOBt coupling reagent pair is used for coupling of propiolic acid with mono-Boc-diaminocyclohexane. The hydroamination can be circumvented by using COMU as the coupling reagent. The addition reaction was further explored by using methyl propiolate with TBTU/HOBt which yielded a plethora of different products including O- and N-addition products and also a product of formal methyl propiolate dimerization. Due to high symmetry and low number of non-equivalent protons and carbons, most of the products were difficult to characterise by NMR spectroscopy, so it was necessary to obtain X-ray single crystal structures for most of them. In addition, the identification of the products was further supported by very good agreement of NMR spectra collected experimentally with NMR spectra calculated by DFT.

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 21/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF4. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6, monoclinic, space group P 21/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 21/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.

Praziquantel (PZQ) is a biopharmaceutical classification system (BCS) class II anthelmintic drug characterized by poor solubility and a bitter taste, both of which can be addressed by inclusion complexation with cyclodextrins (CD). In this work, a comprehensive investigation of praziquantel/cyclodextrin (PZQ/CD) complexes was conducted by means of UV–vis spectroscopy, spectrofluorimetry, NMR spectroscopy, liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS), and molecular modeling. Phase solubility studies revealed that among four CDs tested, the randomly methylated β-CD (RMβCD) and the sulfobutylether sodium salt β-CD (SBEβCD) resulted in the highest increase in PZQ solubility (approximately 16-fold). The formation of 1:1 inclusion complexes was confirmed by HRMS, NMR, and molecular modeling. Both cyclohexane and the central pyrazino ring, as well as an aromatic part of PZQ are included in the CD central cavity through several different binding modes, which exist simultaneously. Furthermore, the influence of CDs on PZQ stability was investigated in solution (HCl, NaOH, H2O2) and in the solid state (accelerated degradation, photostability) by ultra-high-performance liquid chromatography–diode array detection–tandem mass spectrometry (UPLC-DAD/MS). CD complexation promoted new degradation pathways of the drug. In addition to three already known PZQ degradants, seven new degradation products were identified (m/z 148, 215, 217, 301, 327, 343, and 378) and their structures were proposed based on HRMS/MS data. Solid complexes were prepared by mechanochemical activation, a solvent-free and ecologically acceptable method.

A conformational study of branimycin was performed using single-crystal X-ray crystallography to characterize the solid-state form, while a combination of NMR spectroscopy and molecular modeling was employed to gain information about the solution structure. Comparison of the crystal structure with its solution counterpart showed no significant differences in conformation, confirming the relative rigidity of the tricyclic system. However, these experiments revealed that the formerly proposed stereochemistry of branimycin at 17-C should be revised. (Chemical Equation Presented).

Three novel spiroketals were prepared by a one-pot transformation of 6-O-methyl-9(E)-hydroxyiminoerythronolide A. We present the formation of a [4.5]spiroketal moiety within the macrolide lactone ring, but also the unexpected formation of a 10-C=11-C double bond and spontaneous change of stereochemistry at position 8-C. As a result, a thermodynamically stable structure was obtained. The structures of two new diastereomeric, unsaturated spiroketals, their configurations and conformations, were determined by means of NMR spectroscopy and molecular modelling. The reaction kinetics and mechanistic aspects of this transformation are discussed. These rearrangements provide a facile synthesis of novel macrolide scaffolds.

The 16-membered macrolide antibiotics (e.g. tylosin A and josamycin) are mainly used in veterinary medicine, and are much less studied than their 14- and 15-membered erythromycin-based cousins. Although these antibiotics have similar antibacterial profiles, with activity primarily against Gram- positive and a limited range of Gram-negative organisms, the 16–membered macrolides show some advantages. These include better gastrointestinal tolerance, lack of drug-drug interactions, and activity against certain resistant bacterial strains by extension of the peptide tunnel reach allowing additional interactions. In addition to antibacterial activity, the most famous representative of the class, tylosin A, as well as some derivatives of desmycosin (tylosin B), have shown antimalarial activity. Such activity has also been observed in the 14-membered macrolide antibiotics, azithromycin, solithromycin and clindamycin. This antimalarial activity provides the opportunity to investigate these drugs as cheap and effective antimalarials. This is an overview of the latest research on biosynthesis, structure, chemical properties and mode of action of 16-membered macrolides, with special emphasis on their most explored members: tylosin A and josamycin.

In order to optimize Mukaiyama reagent-induced cyclization of vicinal sec-amino alcohols of desosamine origin towards exclusive formation of N′-substituted-2-imino-1,3-thiazolidines via a thiocarbamoyl intermediate, the influence of reaction conditions was studied. A novel, mild, one-pot, two-step method was developed, and the formation of N′-substituted-2-imino-1,3-oxazolidines as side products was minimized. The inversion of configuration at C-2′ was unambiguously established using NMR-based conformational analysis. A reaction mechanism was proposed. A test series of novel desosamine-modified 14- and 15-membered macrolides, bearing N′-alkyl-2-imino-1,3-thiazolidines fused to the desosamine sugar were prepared.

An efficient one-pot method for the synthesis of novel 9a, 11-bridged 15-membered 9a-aza-9-deoxo-9ahomoerythromycin A and its 6-O-methyl analogue has been developed. The novel bicyclic azalide scaffold is characterized by an N'-substituted-2-imino-1, 3-oxazolidine moiety bound to a acrolactone ring between positions 9a and 11. Removal of the cladinose sugar from the starting compounds allows easy preparation of a small series of such bicyclic 3-keto and 3, 6-hemiketal azalide derivatives. A mechanism for the formation of N'-substituted-2-imino-1, 3-oxazolidines is discussed. Antibacterial properties of the prepared compounds were evaluated.

Selective oxidation of diethylene glycol by a ruthenium(VIII) species, obtained in situ from ruthenium(III) chloride-sodium­ periodate in the presence of a catalytic quantity of water, affords a monoaldehyde in the form of the internal acetal 2-hydroxy-1, 4-dioxane. This compound was used in reductive alkylations of selected primary and secondary amines, demonstrating its utility in the preparation of target structures with the 2-(2- hydroxyethoxy)ethylamino unit.

Synthesis of a novel heterocyclic class of compounds, 1-aza-dibenzo[e,h]azulenes [1] (6a-c and 7a-c), derived from dibenzo[b,f]oxepin, its 8-chloro analogue and dibenzo[b,f]thiepin, respectively, is described. Aldol condensation of the starting ketones 4a-c with (dimethyl-hydrazono)-acetaldehyde affords hydrazonoethylidene derivatives 5a-c, which on reduction with sodium dithionite and subsequent cyclization provide the target tetracyclic 1-aza-dibenzo[e,h]azulenes 6a-c. Regiospecific formylation of 6a-c with Vilsmeier reagent leads to 2-formyl derivatives 7a-c. A series of derivatives 6a-c and 7a-c was tested for antiinflammatory activity as potential inhibitors of tumor necrosis factor alpha (TNF-α) production in vitro.

Macrolide aglycons (E)-9-hydroxyimino-6-O-methylerythronolide A (4), 9a-aza-9-deoxo-9, 9-dihydro-9a, 11-O-dimethyl-9a-homoerythronolide A (5) and 9a-aza-9-deoxo-9, 9-dihydro-9a-homoerythronolide A (6) were prepared by multistep syntheses. A conformational study of these new macrolide aglycons was performed using single crystal X-ray crystallography to gain information about the solid state, while a combination of NMR spectroscopy and molecular modelling was employed to study the solution structures. The crystal structures were found to be stabilised by a complex network of hydrogen bonds and van der Waals interactions. To some extent, the same building motif of infinite molecular chains held together by O–H···O hydrogen bonds was present in the crystal structure of all three compounds. Thorough analysis and comparison of the obtained solid state structures with their solution counterparts showed no significant differences between them, confirming the constrained flexibility of the macrocyclic ring. Moreover, in all three compounds, in both solution and solid state, the macrolactone ring adopts energetically more favoured folded-out conformations.

A set of novel macrolones containing the flexible C8 basic linker and quinolone 3-(2'-hydroxyethyl)carboxamido group has been prepared and structurally characterized by NMR and IR spectroscopy, mass spectrometry and molecular modeling. The new compounds were evaluated in vitro against a panel of erythromycin-susceptible and erythromycin-resistant Gram-positive and Gram-negative bacterial strains. Compared to azithromycin, most of the compounds exhibited improved in vitro potency against the key respiratory pathogens.

Selective oxidation of diethylene glycol by a ruthenium(VIII) species, obtained in situ from ruthenium(III) chloride― sodium periodate in the presence of a catalytic quantity of water, affords a monoaldehyde in the form of the internal acetal 2-hydroxy-1,4-dioxane. This compound was used in reductive alkylations of selected primary and secondary amines, demonstrating its utility in the preparation of target structures with the 2-(2-hydroxy-ethoxy)ethylamino unit.

A series of tetracyclic imidazole derivatives 9a–9v and 10a–10h are prepared by multistep route start- ing from the known tricyclic diketones 2a–2d. Intermediary dibenzooxepin[4, 5-d]imidazoles (3a, 3c) and dibenzothiepin[4, 5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formy- lated at C(2) to afford 7a–7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric x-dimethylaminoalkyl derivatives 9a–9v. N-deprotection of 9i–9v led to the compounds 10a–10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their anti- dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be ?11.5 inflammatory activity.

The solution and solid state conformations of several 6-O-methyl homoerythromycins 1–4 were studied using a combination of X-ray crystallography, NMR spectroscopy and molecular modelling calculations. In the solid state 1 was found to exist as the two independent molecules with similar structures termed 3-endo-folded-out. In solution a significant conformational flexibility was noticed especially in the C2 to C5 region. The compounds 1 and 2 unlike 14-membered macrolides adopted the 3-endo-folded-out conformation while 3 and 4 existed in the classical folded-out conformation. TrNOESY and STD experiments showed that 1 and 2 bound to the Escherichia coli ribosome while 3 and 4, lacking the cladinose sugar, did not exhibit binding activities, this being in accordance with biochemical data. The bound conformations were found to be very similar to the free ones, some small differences were observed and discussed. The STD experiments provided evidence on binding epitopes. The structural parts of 1 and 2 in close contact with ribosome were similar, however the degree of saturation transfer was higher for 2. The differences between tr-NOE data and STD enhancements in 1 and 2 arouse as a consequence of structural changes upon binding and a closer proximity of 2 to the ribosome surface. An understanding of the molecular mechanisms involved in the interaction of macrolides with ribosomes can help in developing strategies aiming at design of potential inhibitors.

Synthesis of a novel heterocyclic class of compounds, 1-aza-dibenzo[e,h]azulenes [1] (6a-c and 7a-c), derived from dibenzo[b,f]oxepin, its 8-chloro analogue and dibenzo[b,f]thiepin, respectively, is described. Aldol condensation of the starting ketones 4a-c with (dimethyl-hydrazono)-acetaldehyde affords hydrazonoethylidene derivatives 5a-c, which on reduction with sodium dithionite and subsequent cyclization provide the target tetracyclic 1-aza-dibenzo[e,h]azulenes 6a-c. Regiospecific formylation of 6a-c with Vilsmeier reagent leads to 2-formyl derivatives 7a-c. A series of derivatives 6a-c and 7a-c was tested for antiinflammatory activity as potential inhibitors of tumor necrosis factor alpha (TNF-α) production in vitro.