Synthesis, molecular docking and biological evaluation of 2,4-diaminopyrimidines and pyrazoles as aurora kinase...

Aurora kinases (AURKs) constitute a family of serine/threonine protein kinases that regulate cell cycle progression and are frequently overexpressed in various cancers, thereby contributing to tumorigenesis. A series of pyrazoles and 2,4-diaminopyrimidines were designed and synthesized as potential cytotoxic entities in ovarian, brain, and leukemia cancer. Molecular docking studies were conducted on AURKA (PDB IDs: 3UP7) and AURKB (PDB IDs: 4AF3). Compounds exhibiting favorable interaction with the ATP binding site and key residues (Ala213 and Glu211 in AURKA; Ala157 and Glu155 in AURKB) were identified as potential candidates. Compounds 2j, 2l, 2p, 9a, and 10a showed dose-dependent cytotoxicity in SKOV3, C6, and THP1 cell lines. Of them, 2l, 9a, and 10a effectively suppressed the growth of SKOV3, C6, and THP1 cells with IC₅₀ values of 8.63 µM, 0.019 µM and 0.084 µM, respectively. Compounds 2l, 2p, 9a, and 10a showed promising inhibitory activity in AURKA and AURKB. 2p and 10a exhibited comparable potency to the standard Barasertib at 10 µM (2p: 68.14 %, 10a: 55.64 %, Barasertib: 78.42 %) highlighting their potential as novel therapeutic agents. The compounds 2j and 2p displayed potent inhibitory activity in AURKB. At 10µM, these compounds achieved inhibition rates comparable to standard Barasertib (2j: 56.36 %, 2p: 56.39 %, Barasertib: 68.62 %). Molecular docking and ADME prediction studies indicated these compounds to have good drug likeliness scores. The results of this study indicated that 2l, 2p, 9a, and 10a can be used as lead compounds targeting AURK for development as anti-cancer agents. See also the graphical abstract(Fig. 1).