Identification of potential anticancer 1,3,4–oxadiazole compounds through molecular docking, biological evaluation, DFT, and ADME–Tox computations

The increasing prevalence of cancer and the emergence of drug resistance demonstrate the critical need for new therapeutic approaches. In order to gain insight into their potential as anticancer scaffolds, this study synthesized and assessed novel pyrrolo[2,3- d ]pyrimidine–1,3,4–oxadiazole hybrids for their cytotoxic selectivity and safety profile. Eleven new pyrrolo[2,3- d ]pyrimidine–based compounds were produced in good yields (65–88%) and assessed using in vitro and in silico methods. HRMS, FT-IR, 1 H NMR, and 13 C NMR were among the spectroscopic techniques used to confirm the compounds [ 5a–f & 7a–e ], which were produced using recognized organic synthesis processes. Interestingly, compounds 5c , 7a and 7e exhibited potent antiproliferative activities, particularly against breast and colon cancer cell lines, with IC 50 values of 6.74 ± 1.42–13.78 ± 2.10 µ M. Importantly, compounds 5c , 7a , and 7e exhibited enhanced selectivity for HCT-116 cancer cells with IC 50 values of 8.74 ± 2.51, 8.62 ± 1.16, and 7.01 ± 2.75 µ M, respectively, relative to 5-fluorouracil (5-FU) (IC 50 = 31.61 ± 4.23 µ M). Several electronic features, including frontier molecular orbitals (FMOs), global reactivity parameters, and geometry optimization, were investigated using density functional theory (DFT). Additionally, after pharmacological network research, ADME–T predictions were used in conjunction with in-silico molecular docking and DFT to evaluate interactions between this derivative and the active sites of colon cancer. With a binding energy score of − 7.44, − 8.23, and − 7.31 kcal. mol -1 , the results showed a good binding affinity of the synthesized 1,3,4–oxadiazole hybrids 5c , 7a , and 7e with colon cancer therapy (PDB code: 2HQ6). Collectively, these findings underscore the potential of 1,3,4-oxadiazole hybrids, particularly compounds 7a and 7e , as promising leads for the development of new anticancer agents.