ABSTRACT
Tumor necrosis factor-alpha (TNF-[Formula: see text] is an important pro-inflammatory cytokine responsible for a diverse range of inflammatory diseases including rheumatoid arthritis. In the present manuscript, our medicinal chemistry efforts on the design, synthesis and TNF-[Formula: see text] evaluation of a series of 3, 6-disubstituted imidazo[1,2-b]pyridazine is described. The best compounds were 3-pyridyl and (4-(methylsulfonyl)phenyl) analogs 8q and 8w, showing inhibition of TNF-[Formula: see text] production with IC[Formula: see text]values of 0.9 and 0.4 [Formula: see text]M, respectively. The identified leads have potential for further development for treatment of inflammatory diseases.
Subject(s)
Leukocytes, Mononuclear/drug effects , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Cell Survival/drug effects , Cells, Cultured , Humans , Leukocytes, Mononuclear/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh's disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups', a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC50â¯=â¯0.5⯵M and 0.3⯵M respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions.
Subject(s)
Sulfonamides/chemistry , Tumor Necrosis Factor-alpha/metabolism , Binding Sites , Catalytic Domain , Cells, Cultured , Drug Design , Humans , Hydrogen Bonding , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/toxicity , Molecular Docking Simulation , Pyridazines/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
A series of novel 4 and 5-substituted methylsulfonyl benzothiazole (MSBT) compounds having amide, alkoxy, sulfonamide, nitro and amine functionality were synthesized from sequential reactions on 5-ethoxy-2-(methylsulfonyl)benzo[d]thiazole such as nitration, reduction, sulfonation, dealkylation, etc. All synthesized compounds were screened against antimicrobial and selected screened for anticancer activity. Antimicrobial activities studies reveled that among all compounds screened, out of MSBT-07, MSBT-11, MSBT-12, MSBT-14, MSBT-19, and MSBT-27 were found to have promising antimicrobial activity at MIC range of 4-50µg/ml against selected bacterial as well as fungal species. Compounds having good antimicrobial activity were screened for cervical cancer (HeLA cell lines). Of these MSBT-07 and MSBT-12 significantly reduced the cell growth. Consequently their calculated GI50 values were found to be 0.1 or <0.1µM.
