Oxindole–benzothiazole hybrids as CDK2 inhibitors and anticancer agents: design, synthesis and biological evaluation

• Published in: BMC chemistry Vol. 18; no. 1; pp. 169 - 19
• Main Author: Abdel-Mohsen, Heba T.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 13.09.2024; BioMed Central Ltd; Springer Nature B.V; BMC
• Subjects: Amino acids; Anticancer activity; Anticancer properties; Binding; Bonding agents; Cancer; Care and treatment; CDK2 inhibitory activity; Cell cycle; Chemical bonds; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Design; Drug therapy; Health aspects; Hydrogen; Hydrogen bonding; Hydrophobicity; Molecular docking; Necrosis; Oxindole–benzothiazole; Prevention; Prostate cancer; Synthesis; Design; CDK2 inhibitory activity; Oxindole–benzothiazole; Synthesis; Molecular docking; Anticancer activity
• ISSN: 2661-801X; 2661-801X
• DOI: 10.1186/s13065-024-01277-1

In the current study, molecular hybridization between the oxindole core and benzothiazole system through an acetohydrazide moiety was accomplished for the design of a new series of oxindole–benzothiazole hybrids 9a – r targeting CDK2 for cancer therapy. The afforded hybrids displayed promising growth inhibitory activity on NCI cancer cell lines at 10 µM. Compound 9o displayed mean GI% = 55.91%. Based on the potent activity of 9o , it was further assessed for its cytotoxic activity at five dose level and it demonstrated GI 50 reaching 2.02 µM. Analysis of the cell cycle of the prostate cancer cell line DU145 after treatment with 9o confirmed its ability to arrest its cell cycle at the G1 phase. Moreover, 9o proved its ability to potentiate the apoptosis and necrosis of the same cell line. Furthermore, the oxindole–benzothiazole hybrids 9b , 9f and 9o showed IC 50  = 0.70, 0.20 and 0.21 µM, respectively on CDK2. Besides, molecular docking simulation of the synthesized oxindole–benzothiazole hybrid 9o proved the expected binding mode which involves the accommodation of the oxindole moiety in the ATP binding pocket where it is involved in hydrogen bonding and hydrophobic interactions with the essential amino acids in the hinge region while the benzothiazole moiety is oriented toward the solvent region. Investigation of the physicochemical properties of the hybrids 9a – r highlights their acceptable ADME properties that can be somewhat developed for the discovery of new anticancer agents.