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Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.

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A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting 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 formylated 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 dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be $11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their antiinflammatory activity.

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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.

Analyzed and interpreted data, Wrote the paper; Mirjana Bukvic: Wrote the paper; Vesna Erakovic Haber: Analyzed and interpreted data, Wrote the paper; Radan Spaventi: Designed research and interpreted data. All authors are accountable for accuracy and integrity of the presented results and have given their approval of the version to be published. Conflict of interest statement FJG, SFB, MSM and AK are employees of GSK, and other authors declare that they have no conflict of interest and no commercial associations that might pose a conflict of interest in connection with the submitted article.