title: Antitubercular activity of quinolizidinyl/pyrrolizidinylalkyliminophenazines.
abstract: 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.
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy. Electronic address: michele.tonelli@unige.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Tonelli
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tasso
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Boido
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sparatore
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Sassari, Viale San Pietro, 07100 Sassari, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cannas
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Sassari, Viale San Pietro, 07100 Sassari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Molicotti
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Sassari, Viale San Pietro, 07100 Sassari, Italy. Electronic address: zanettis@uniss.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Zanetti
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Via C. Pascal 36, 20133 Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.affiliation: Dipartimento di Scienze Biomediche, Università di Cagliari, Cittadella Universitaria, 09042 Monserrato (CA), Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D006801:Humans; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects / Q000302:isolation & purification; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000302:isolation & purification; D010619:Phenazines / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D011759:Pyrrolidines / Q000737:chemistry; D054837:Quinolizidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000382:microbiology; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D010619:Phenazines; D011759:Pyrrolidines; D054837:Quinolizidines
keywords: Antitubercular activity; Clinical isolates of Mycobacterium tuberculosis; Mycobacterium avium; Mycobacterium tuberculosis; Quinolizidinyl- and pyrrolizidinyl-alkyliminophenazine derivatives