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Description
The present work is aimed at designing, synthesizing, and evaluating a library of 2-amino-1,3,4-thiadiazole based compounds as anticancer agents through their inhibitory action against Cyclin-Dependent Kinase (CDK2) enzyme. CDK2 is a member of the protein kinase family, which plays a major role in regulating various events of the eukaryotic cell division cycle. It is overexpressed in cancer cells, resulting in abnormal regulation of the cell cycle and hyperproliferation. Thus, CDK2 is regarded as a potential therapeutic target for cancer therapy. The 2-amino-1,3,4-thiadiazole nucleus is a privileged scaffold in drug discovery due to its diverse biological activity. One of its derivatives, 2-(4-fluorophenylamino)-5-(2,4 dihydroxyphenyl)-1,3,4-thiadiazole (FABT, 1), was shown to inhibit the extracellular signal-regulated kinase pathway to induce cell cycle arrest in human non-small lung carcinoma cells (NSCLC). A series of compounds containing the 1,3,4 thiadiazole scaffold was designed through molecular hybridization of FABT (1) with the experimental tyrosine kinase inhibitor Semaxanib (2). The designed compounds were synthesized by conventional methodologies and characterized by NMR and IR characterization techniques, followed by evaluation for their antitumor activity against C6 neuroblastoma cell line by MTT assay with doxorubicin as the reference standard. Molecular docking of each synthesized compound was done in the active site of CDK2 (PDB ID: 4LYN) using AutoDock4.2, and the binding energy was calculated. A library of compounds having general structure 3 (as shown in Figure 1) has been designed, synthesized, and evaluated for CDK2 inhibitory potential. The most potent compound of the series (compound 4) is shown to inhibit CDK2 with an IC$_{50}$ of 0.005 µM. It shows binding energy of -9.62 kcal/mol when docked with CDK2 active site (PDB ID: 4LYN) and interactions with PHE82, LEU183, ILE10, ALA31, LEU134, VAL164, ALA144, and GLU81 residues and pi-pi interaction with PHE82 and LEU83.On the basis of the above findings, it can be postulated that this rigid scaffold 3 could serve as a template for the design of potential drug candidates in cancer therapy by modulating CDK2 activity.
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