Synthesis, molecular modelling and evaluation of (-)-isopulegol-based 2,4-diaminopyrimidines as promising aurora...

A library of (-)-isopulegol-based 2,4-diaminopyrimidines was prepared from commercially available (-)-isopulegol. Aminodiols, derived from (-)-isopulegol according to literature methods, were added to 5-substituted 2,4-dichloropyrimidines; the resulting products were then subjected to microwave-assisted S_NAr coupling reactions with aniline derivatives to produce 2,4-diaminopyrimidines. All 2,4-diaminopyrimidine adducts were evaluated for their in vitro cytotoxicity against human colon adenocarcinoma cell lines, including Colo205 and Colo320. Among these derivatives, compounds 6a and 7b exhibited significantly greater efficacy against the two cancer cell lines within concentrations around 2.0 μM. Furthermore, these derivatives displayed higher selectivity for cancer cells over normal cells (SI > 44) compared to the positive controls, doxorubicin (SI > 2) and cisplatin (SI = 5). Molecular docking analysis indicated that these compounds (6a and 7b) form interactions with the aurora A kinase receptor both from structural and energetic perspectives. These results suggest that derivatives 6a and 7b have potential for further development as aurora A kinase inhibitors for colorectal cancer treatment.