New quinoline-2-one/pyrazole derivatives; design, synthesis, molecular docking, anti-apoptotic evaluation, and caspase-3 inhibition assay

• Published in: Bioorganic chemistry 2020-01, Vol.94, p.103348, Article 103348
• Main Authors: Aly, Ashraf A., Sayed, Samia M., Abdelhafez, El-Shimaa M.N., Abdelhafez, Sara Mohamed Naguib, Abdelzaher, Walaa Yehia, Raslan, Mohamed A., Ahmed, Amira E., Thabet, Khaled, El-Reedy, Ahmed A.M., Brown, Alan B., Bräse, Stefan
• Format: Article
• Language: English
• Subjects: Animals; Anti-apoptotic quinoline; Antioxidant; Apoptosis - drug effects; Caspase 3 - drug effects; Caspase-3; Colon; Docking; Drug Design; Histopathology; Molecular Docking Simulation; NAC; Pyrazole; Pyrazoles - chemistry; Pyrazoles - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Rats
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103348

[Display omitted] •Synthesis of new pyrazolo-quinoline-2-ones.•NMR spectra as effective tool to elucidate the given structure.•Some compounds showed significant improvement for oxidative stress parameters MDA, SOD, GSH and NOx in comparison with model group and greater than NAC.•Colonic histopathological investigation was performed on all targeted compounds.•H&E sections of some compounds revealed apparent normal colonic cells compared with NAC.•Docking studies with caspase-3 revealed that most of the tested compounds showed good binding with the enzyme. We report the synthesis of new quinoline-2-one/pyrazole hybrids and their antiapoptotic activity. This effect was studied in sight of decreasing tissue damage induced by I/R in colon of rats using N-acetylcysteine (NAC) as anti-apoptotic reference. Compounds 6a, 6c and 6f showed significant improvement for oxidative stress parameters MDA, SOD, GSH and NOx in comparison with model group and greater than the reference NAC (N-acetylcysteine), whereas compounds 6d and 6e exhibited weaker antioxidant activity when compared with the reference NAC. Moreover, compounds 6a, 6c and 6f showed significant decrease in inflammatory mediators TNFα and CRB greater than NAC when compared to the model group especially compound 6c whose found CRB conc 1.90 (mg/dL) in comparison to NAC of conc 2.13 mg/dL. Additionally, colonic histopathological investigation was performed to all targeted compounds that indicates H&E sections of compounds 6a and 6f revealed apparent normal colonic cells while compound 6e showed dilated blood vessels with more apoptotic cells if compared with NAC. Caspase-3 inhibition assay revealed that compounds 6a, 6b and 6d weaken caspase-3 expression to an extent higher than NAC (1.063, 0.430, 0.731 and 1.115, respectively). Docking studies with caspase-3 revealed that most of the tested compounds showed good binding with the enzyme especially for compound 6d make several interactions better than that of the reference NAC.