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.
Antimycobacterial, Bis-pyridazine, diphenyl ether linker, LORA, MBC, MIC, MTT, SAR.
Al. I. Cuza” University of Iasi, Faculty of Chemistry, Bd. Carol 11, 700506 Iasi, Romania.