Merck

Antitubercular activity of quinolizidinyl/pyrrolizidinylalkyliminophenazines.

Bioorganic & medicinal chemistry (2014-12-04)
Michele Tonelli, Federica Novelli, Bruno Tasso, Anna Sparatore, Vito Boido, Fabio Sparatore, Sara Cannas, Paola Molicotti, Stefania Zanetti, Silvia Parapini, Roberta Loddo
RESUMO

Novel riminophenazine derivatives, characterized by the presence of the basic and cumbersome quinolizidinylalkyl and pyrrolizidinylethyl moieties, have been synthesized and tested (Rema test) against Mycobacterium tuberculosis H37Rv and H37Ra, and six clinical isolates of Mycobacterium avium and Mycobacterium tuberculosis. Most compounds exhibited potent activity against the tested strains, resulting more active than clofazimine, isoniazid and ethambutol. The best compounds (4, 5, 12 and 13) exhibited a MIC in the range 0.82-0.86μM against all strains of Mycobacterium tuberculosis and, with the exception of 4 a MIC around 3.3μM versus M. avium. The corresponding values for clofazimine (CFM) were 1.06 and 4.23μM, respectively. Cytotoxicity was evaluated against three cell lines and compound 4 displayed a selectivity index (SI) versus the human cell line MT-4 comparable with that of CFM (SI=5.23 vs 6.4). Toxicity against mammalian Vero 76 cell line was quite lower with SI=79.

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