Discovery of Novel N-Acetylpyrazolines as Microtubule Inhibitors: Design, Synthesis, Anticancer Evaluation, and Molecular Docking Study

Ali, Islam; El Kerdawy, Ahmed M; Batran, Rasha Zakaria; Allam, Rasha Mosa; Abo-elfadl, Mahmoud Taha; Sciandra, Francesca; Ghannam, Iman Ahmed Youssef

doi:10.21608/ejchem.2024.288226.9691

Discovery of Novel N-Acetylpyrazolines as Microtubule Inhibitors: Design, Synthesis, Anticancer Evaluation, and Molecular Docking Study

Document Type : Original Article

Authors

¹ National Research Centre (NRC)

² Pharmaceutical chemistry department, Faculty of Pharmacy Cairo University

³ Department of pharmacology - National Research Centre

⁴ Cancer Biology and Genetics Laboratory Centre of Excellence for Advanced Sciences, National Research Centre

⁵ CNR - Italy

10.21608/ejchem.2024.288226.9691

Abstract

In the current study, a new series of N-acetylpyrazolines (6a-d) were designed and synthesized from their corresponding chalcones and hydrazine hydrate in acidic medium. The N-acetylpyrazolines (6a-d) were tested for their anti-hepatocellular activity against liver cancer (Huh-7, and HepG-2), and normal BNL cell lines and compared with paclitaxel, colchicine, and combrestatin A-4 (CA-4), as standards, and their IC50 values were determined. The 3’,4’,5’-trimethoxyphenyl N-acetylpyrazoline derivative 6d was the found the most potent N-acetylpyrazoline derivative IC50 = 0.30, and 77.30 µM, respectively, and found non-cytotoxic to the normal BNL cell line. While compounds 6b, and 6c revealed lower anticancer activity against Huh-7 cell line IC50 = 14.50, and 11.00 µM, respectively. Moreover, the N-acetylpyrazolines 6a-d were evaluated for their anticancer screening against different cancer cell lines at 10 µM by the Developmental Therapeutic Program (DTP) - NCI - USA, and they showed mean GI% ranges 8.87-64.54%. The 3’,4’,5’-trimethoxyphenyl N-acetylpyrazolines 6c, and 6d revealed potent anticancer activities and lethal effects against lung cancer cell line (HOP-92) for 6c and melanoma cell line (SK-MEL-5) for 6d with GI% values of 104.80, and 109.52%, respectively. Furthermore, the N-acetylpyrazolines 6a-d enhanced tublin polymerization, and showed tubulin-stabilizing effects as paclitaxel at 50 µM. A molecular docking study was performed for the N-acetylpyrazolines 6a-d to investigate the binding pattern at the Taxol-binding site of microtubules.

Keywords

Main Subjects