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A series of cyano- and amidino-substituted imidazo[4,5-b]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound 10, which contained an unsubstituted amidino group, and compound 14, which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC50 0.4 and 0.7 μM, respectively). All tested compounds lacked antibacterial activity, with the exception of compound 14, which showed moderate activity against E. coli (MIC 32 μM). Bromo-substituted derivative 7, which contained an unsubstituted phenyl ring (EC50 21 μM), and para-cyano-substituted derivative 17 (EC50 58 μM) showed selective but moderate activity against respiratory syncytial virus (RSV). ispartof: MOLECULES vol:28 issue:1 ispartof: location:Switzerland status: published

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.

Within this work we describe the synthesis of versatile substituted 2-phenyl benzothiazole 3–10 and 2-phenylbenzimidazole 12–19 derivatives bearing amidino groups. Furthermore, the synthesized compounds were explored for their antiproliferative activity in vitro on three cancer cell lines. Tested compounds showed moderate to strong antiproliferative activity. Furthermore, the type of the attached amidino group on benzazole nuclei has the significant impact on the antiproliferative activity only within benzimidazole derivatives with 2-imidazolinyl substituted derivatives being more active in comparison to amidino substituted analogues. All obtained results revealed that this type of benzothiazole derivatives have a great potential for further optimization and development of more efficient potential antiproliferative agents. This work is licensed under a Creative Commons Attribution 4.0 International License.

We present the synthesis of a range of benzimidazole/benzothiazole-2-carboxamides with a variable number of methoxy and hydroxy groups, substituted with nitro, amino, or amino protonated moieties, which were evaluated for their antiproliferative activity in vitro and the antioxidant capacity. Antiproliferative features were tested on three human cancer cells, while the antioxidative activity was measured using 1,1-diphenyl-picrylhydrazyl (DPPH) free radical scavenging and ferric reducing antioxidant power (FRAP) assays. Trimethoxy substituted benzimidazole-2-carboxamide 8 showed the most promising antiproliferative activity (IC50 = 0.6&ndash, 2.0 &micro, M), while trihydroxy substituted benzothiazole-2-carboxamide 29 was identified as the most promising antioxidant, being significantly more potent than the reference butylated hydroxytoluene BHT in both assays. Moreover, the latter also displays antioxidative activity in tumor cells. The measured antioxidative capacities were rationalized through density functional theory (DFT) calculations, showing that 29 owes its activity to the formation of two [O&bull, ∙∙∙H&ndash, O] hydrogen bonds in the formed radical. Systems 8 and 29 were both chosen as lead compounds for further optimization of the benzazole-2-carboxamide scaffold in order to develop more efficient antioxidants and/or systems with the antiproliferative activity.

New cis- and trans-3-aryl-4-[2-(2-vinylphenyl)ethenyl]sydnones 2 , aryl = phenyl, p-tolyl were prepared and transformed on irradiation in the presence of acrolein to a pyrazoline derivative that aromatized during isolation to trans-1-tolyl-3-[2-(2-vinylphenyl)ethenyl]pyrazole 7 and trans-5-formyl-1-tolyl-3-[2-(2-vinylphenyl)ethenyl]pyrazole 8 .

New trans- and cis-o-stilbene-methylene-sydnones 3a,b were synthesized by transforming the trans- and cis-o-aminomethylstilbene derivative, obtained by reduction of corresponding o-cyano derivatives, into glycine ester derivatives (43 and 31% yield) followed by hydrolysis (90 and 96% yield), nitrosation and ring closure with acetic acid anhydride (30 and 40% yield). The products were submitted to photochemical and thermal intramolecular [3 + 2] cycloadditions to afford diverse heteropolycyclic compounds. Photochemical reactions afforded cis-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (11, 12.5% yield) and trans-3-(4-methylphenyl)-3a,8-dihydro-3H-pyrazolo[5,1-a]isoindole (12, 5% yield). Thermal reactions afforded 3-(4-methylphenyl)-3,3a,8,8a-tetrahydroindeno[2,1-c]pyrazole (14, 50% yield) and 11-(4-methylphenyl)-9,10-diazatricyclo[7.2.1.02,7]dodeca-2,4,6,10-tetraene (15, 22% yield).

Macrolides with 14- and 15-membered ring are characterized by high and extensive tissue distribution, as well as good cellular accumulation and retention. Since macrolide structures do not fit the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we describe the development of the first models for macrolide cellular pharmacokinetics. By comparison of cellular accumulation and retention in six human primary cell cultures of leukocytic and lung origin, as well as in lung carcinoma cell line NCI-H292, this cell line was found to be an adequate representative cell type for modeling macrolide cellular pharmacokinetics. Accumulation and retention in the NCI-H292 cells, as well as various physicochemical properties, were determined for a set of 48 rationally designed basic macrolide compounds. Classification models for predicting macrolide cellular accumulation and retention were developed using relatively easily determined and conceptually simple descriptors: experimentally determined physicochemical parameters ChromlogD and CHI IAM, as well as a calculated number of positively charged atoms (POS). The models were further tested and improved by addition of 37 structurally diverse macrolide molecules.

Stilbeneylsydnone derivatives were synthesized by a sequence of reactions in good yields. Irradiation of 3-stilbeneyl-4-methylsydnone 4 gives 1H-1, 2-benzodiazepine derivative 7 as the main product along with 2-methylquinoline derivative 20. Irradiation of 3-stilbeneyl-4-phenylsydnone 5 afforded only 1H-1, 2-benzodiazepine derivative 8 whereas on irradiation of 4-unsubstituted 3-stilbeneylsydnone 3 no benzodiazepine derivative was detected. An efficient novel photochemical approach to 1H-1, 2-benzodiazepines has been found from the new 3-(o-stilbeneyl)-4-substituted-sydnones via intramolecular 1, 7-electrocyclization reaction of the photogenerated nitrile imines.

1H and 13C NMR spectra of cis- and trans-3-(2-[2-(4-methylphenyl)ethenyl]phenyl])sydnones, the first stilbene-substituted mezoionic oxadiazolium rings, were fully assigned combining the information in various solvents, such as deuterated benzene, acetone and chloroform, using 2D NMR techniques.