title: Design, synthesis and antimycobacterial activity of some new pyridazine derivatives: bis-pyridazine. Part IV.
abstract: The design, synthesis, structure and the antimycobacterial activities of a new class of nitrogen heterocycles, namely N1-substituted-diphenyl ether-bis-pyridazine (BP), is presented. An efficient, facile and straight applicable method for preparation of BP derivatives is described. The primary cycle high throughput screening reveals that two BP compounds, 2a and 3b, are potent inhibitors against Mycobacterium tuberculosis (Mtb), with their antitubercular activity being superior to the second-line antitubercular drug Pyrimethamine and being equal to Cycloserine. The data from cycle-2 screening confirm the results from cycle-1. The MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation, indicate the intracellular drug effectiveness against Mtb of these compounds, the lack of toxicity, a significant activity against both replicating and non-replicating Mtb and, a bactericidal mechanism of action (for 2b). SAR correlations have been done. Overall, the BP derivatives and especially compound 2b, appeared as a new leading antitubercular structure, which makes it a promising lead for further drug development.
authors.forename: Dorina
authors.initials: D
authors.lastname: Mantu
authors.forename: Vasilichia
authors.initials: V
authors.lastname: Antoci
authors.affiliation: Al. I. Cuza" University of Iasi, Faculty of Chemistry, Bd. Carol 11, 700506 Iasi, Romania. ionelm@uaic.ro.
authors.forename: Ionel I
authors.initials: II
authors.lastname: Mangalagiu
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003523:Cycloserine / Q000494:pharmacology; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011739:Pyrimethamine / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D006571:Heterocyclic Compounds; D011724:Pyridazines; D003523:Cycloserine; D011739:Pyrimethamine