Infectious Disorders - Drug Targets

(Formerly Current Drug Targets - Infectious Disorders)

Jean-Marc Sabatier  
Laboratoire ERT 62 'Ingénierie des peptides à visée thérapeutique' 
Université de la Méditerranée
Faculté de Médecine Nord
Boulevard Pierre Dramard
13916 - MARSEILLE, Cedex 20


Design, Synthesis and Antimycobacterial Activity of Some New Pyridazine Derivatives: Bis-pyridazine. Part IV12-14

Author(s): Dorina Mantu, Vasilichia Antoci, Ionel I. Mangalagiu.


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.

Keywords: Antimycobacterial, Bis-pyridazine, diphenyl ether linker, LORA, MBC, MIC, MTT, SAR.

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Article Details

Year: 2013
Page: [344 - 351]
Pages: 8
DOI: 10.2174/1871526514666140217144707
Price: $58