There has been considerable interest in the development of new molecule with antibacterial activities particularly against tuberculosis because mycobacterium species have developed resistance against currently used drugs, their toxic effect, and longer duration of therapy. The pyridazine derivatives are an important class of compound for new drugs research and development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their antitubercular activity. These observations have been guiding in the development of new molecules that possess potent antitubercular activity with minimum side effects or effective against multidrug-resistant, extensively drug-resistant mycobacterium strains, and also in patient co-infected with HIV/AIDS.
Purpose: In the present study, antitubercular activities and in silico physicochemical toxicities and bioactivity profile of some 3-chloro-6-arylpyridazines (3a-d) and 6-aryl-4,5-dihydropyridazine-3(2H)-thiones (4a-d) are studied. Approach: The compounds (3a-d) and (4a-d) were evaluated as antitubercular agents against Mycobacterium tuberculosis H37Rv by screening through in vitro Microplate Alamar Blue Assay (MABA) method. Findings: In silico physicochemical parameter revealed that the entire compounds follow Lipinski's rule-of-5 to become a "drug like" molecule. ADME (absorption, distribution, metabolism and excretions) profile prediction has shown that all the compounds can be absorbed through human intestine (HIA +), Caco-2 cell (Caco-2 +) and can cross blood brain barrier (BBB +), they all are non-substrate and non-inhibitor of p-glycoprotein. Compounds 4a-d are inhibitor of human microsomal enzyme like CYP 450 1A2, CYP 450 2C19 and CYP 450 3A4. Research limitations/implications: Compounds 4a-4d are better ligand for enzyme inhibition than 3a-d compounds. The MIC of compounds 4a-d and 3a is 6.25 µg/ml. They are potent than compound 3b-d with MIC 12.5 µg/ml. Originality: Toxicity prediction indicated that compounds 3a-3d and 4a-d are non-carcinogenic and non-mutagenic. Bioactivity prediction for compounds 3a-3d and 4a-d indicated better ligand as enzyme inhibitor in comparison to standard.
Several 6-aryl-4-substituted benzylidene/furfurylidene pyridazin(2H)-3-one derivatives (4a-f) were synthesized and evaluated as analgesic and anti-inflammatory agents in mice and rats, respectively. All compounds were tested by using Eddy's hot plate and the carrageenan-induced hind paw oedema method for the evaluation of analgesic and anti-inflammatory activities, respectively. Results showed that compounds 4f, 4b, 4d, and 4e exhibited higher analgesic and anti-inflammatory activities than other remaining compounds. All title compounds (4a-f) were characterized by IR, NMR and Mass spectroscopy.
Some 6-aryl-4,5-dihydropyridazin-3(2H)-one compounds (2a-f) were synthesized and evaluated for their in-vivo anticonvulsant activities against maximal electro shock (MES) and isoniazid (INH) induced seizure methods at 50mg/kg dose level. Neurotoxicity of all compounds (2a-f) was also tested at 50, 100 and 200mg/kg dose level. The in-vitro antitubercular activity was evaluated against Mycobacterium tuberculosis H37Rv by using the Microplate Alamar Blue Assay (MABA) method. The result showed that all compounds (2a-f) showed significant anticonvulsant activity against both MES and INH induced convulsion methods. Among all compounds (2a-f), highest activity was exhibited by compound 2e against MES and compound 2b against INH-induced convulsion methods. In both methods, phenytion sodium (25mg/kg) and sodium valproate (50mg/kg) were used as reference drugs. All compounds did not showed any neurotoxicity up to 200mg/kg dose level. In antitubercular activity, minimum inhibitor concentration of compound 2e and 2f was 12.5μg/ml and other remaining compounds (2a-d) were showed 25μg/ml when compared with reference drugs Isoniazid (3.12μg/ml), Pyrizinamide (3.12μg/ml) and Streptomycin (6.25μg/ml).
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