Pyridazin-3(2H)-one as New FABP4 Inhibitors Suggested by Molecular Growing Experiments (original) (raw)
Related papers
Bioorganic & Medicinal Chemistry Letters, 2004
The synthesis and biological evaluation of novel human A-FABP inhibitors based on the 6-(trifluoromethyl)pyrimidine-4(1H)-one scaffold is described. Two series of compounds, bearing either an amino or carbon substituent in the 2-position of the pyrimidine ring were investigated. Modification of substituents and chain length optimization led to novel compounds with low micromolar activity and good selectivity for human A-FABP.
Pyridazin-3(2H)-ones: the versatile pharmacophore of medicinal significance
Medicinal Chemistry Research, 2013
Pyridazin-3(2H)-one derivatives have attracted the attention of medicinal chemists during the last decade due to their diverse pharmacological activities. Easy functionalization of various ring positions of pyridazinones makes them an attractive synthetic building block for designing and synthesis of new drugs. The incorporation of this versatile biologically accepted pharmacophore in established medicinally active molecules results in wide range of pharmacological effects. Pyridazinones constitute an interesting group of compounds, many of which possess wide spread pharmacological properties such as antihypertensive, platelet aggregation inhibitory, cardiotonic activities and some are also well known for their pronounced analgesic, anti-inflammatory, antinociceptive, and antiulcer activities. Recently pyridazinones have also been reported as antidiabetic, anticonvulsant, antiasthmatic, and antimicrobial agents. These encouraging reports suggest that this privileged skeleton should be extensively studied for the therapeutic benefits. In view of this, a detailed and updated account of the pharmacological properties of pyridazinones is described in this review. The wide range of synthesized pyridazinone analogs along with their medicinal significance is also presented. Keywords Pyridazin-3(2H)-one Á Pharmacological activity Á Anti-inflammatory Á Cardiovascular effects Diverse pharmacological properties Pyridazinones show a diverse range of agrochemical and pharmacological activities including cardiotonic, bronchodilatory, anti-inflammatory, antiulcer, antidiabetic, and antiplatelet activity. Specially, the introduction of alkyl and aryl substituents on the 4-, 5-, and 6-positions may lead to products with diversified activities such as analgesic, antiinflammatory and antipyretic, antihypertensive, antiulcer, antithrombotic, and bronchospasmodic activities (Dal Piaz et al., 1994).
Synthesis and Cytotoxic Activities of Pyrrole[2,3-d]pyridazin-4-one Derivatives
CHEMICAL & PHARMACEUTICAL BULLETIN, 2002
In continuation of our studies on compounds with a resveratrol-based scaffold two compounds with N-containing functional groups have been synthesized and screened for their inhibitory effect on the growth of the human cancer cell lines HT29, 518A2, AsPC-1, BxPC-3, and PC-3. Compound 4, but not 1, demonstrated pronounced in vitro cytotoxicity against all these cancer cell lines, thus making this compound a promising candidate for further preclinical in vivo studies.
Pyridazinones are widely recognized as versatile scaffolds with a wide spectrum of biological activities. In the present work, a series of new 4-chloro-2-(3-chloro-4-fluorophenyl)-5-(aliphatic/cyclic saturated amino)pyridazin-3(2H)-one derivatives 4a-i were synthesized and characterized by spectral techniques. The inhibitory effects of the synthesized compounds 4a-i on the viability of three human cancer cell lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds 4a-i screened, 4g and 4i exhibited inhibitory activity very close to the standard methotrexate; therefore, these lead compounds were further tested for their potential to inhibit the proangiogenic cytokines involved in tumor progression. Compound 4g was found to be a potent antiangiogenic agent against TNFa, VEGF, FGFb, and TGFb, whereas 4i showed potent antiangiogenic activity against TNFa, VEGF, FGFb, and leptin. All the compounds 4a-i were screened for their antioxidant activities using 2,2-diphenyl-1-picryl hydrazine (DPPH), OH, and superoxide anion radicals. Compound 4f showed better OH radical scavenging activity than the standard ascorbic acid.
Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors
Bioorganic & Medicinal Chemistry Letters, 2014
New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines.
Pharmaceutical Chemistry Journal, 2018
Systemic toxicity associated with drug resistance continues to be the major obstacle to curative therapy of cancer. Tumor cell resistance to chemotherapeutic drugs often results in coordinate resistance to other structurally and functionally unrelated drugs and the subsequent development of cross resistance phenotype. Therefore, it seems necessary to identify new molecules as anticancer agents. In this process, we synthesized a series of new pyridazin-3(2H)-one derivatives and evaluated their antitumor potential. These cyclic molecules were synthesized and designed as a combination of benzofuran with pyridazinones. All final compounds have been characterized by spectral and elemental analyses to confirm successful synthesis reactions. To evaluate their anticancer activity, all derivatives were assessed against the human breast adenocarcinoma cell line (MCF-7) and the murine mastocytoma cell line (P815) using the methyl tetrazolium Test (MTT assay). The cytotoxic activity was found to be dose-dependent and the IC 50 values of the synthesized compounds ranged from 14.5 to 40 mM against MCF-7 and from 35 to 82.5 mM against P815. At the same time, no cytotoxic activity was observed against normal cells. In order to investigate the molecular mechanism of the most cytotoxic product (6f), apoptosis induction was measured against MCF-7 cells. Using the annexin-V FITC staining technique, we showed that the cytotoxic effect of this product is associated with apoptosis induction.