Computational Design, Synthesis, and Bioevaluation of 2-(Pyrimidin-4-yl)oxazole-4-carboxamide Derivatives: Dual Inhibition of EGFRWT and EGFRT790M with ADMET Profiling

The ongoing research in Cancer treatment underscores the significance of dual epidermal growth factor receptor (EGFR) kinase inhibitors targeting both mutant and wild-type variants. In this study, employing in silico fragment-based drug design (FBDD) and computational analysis, we have successfully developed a novel chemical series of 2-(pyrimidin-4-yl)oxazole-4-carboxamide (16a-j) derivatives designed as dual EGFR kinase inhibitors. A comparative in vitro Anticancer profile of the newly synthesized compounds (16a-j) was tested against a panel of five human Cancer cell lines like prostate Cancer (PC3 & DU-145), lung Cancer (A549), human liver Cancer (HEPG2), and breast Cancer (MDA-MB-468) by employing MTT method. In this experiment a well-known Anticancer agent, Etoposide was used as positive control. Most of the derivatives demonstrated significant cytotoxicity, ranging from excellent to moderate levels. The IC₅₀ values for the synthesized compounds observed between 0.10 ± 0.052 to 9.83 ± 5.96 µM, while the positive control exhibited a range of 1.97 ± 0.45 µM to 3.08 ± 0.135 µM. These results indicate that the synthesized compounds demonstrate higher cytotoxic potency in comparison to the reference compound. Furthermore, all these compounds underwent screening against normal Vero cell lines to assess their cytotoxicity. In each case, the observed cytotoxicity values (IC₅₀) were higher than 22 µM, affirming the compounds selectivity for Cancer cell lines. Among the compounds investigated, three compounds (16a, 16e, and 16i) exhibited notable cytotoxicity, while two compounds (16g and 16h) demonstrated exceptional cytotoxicity. The selectivity index of the tested compounds indicates a pronounced preference for targeting Cancer cell lines over normal cells. Furthermore, all the compounds 16a-j underwent assessment for their EGFR kinase inhibitory activity against both EGFR^WT and mutated EGFR^T790M. The results unveiled the potential eligibility of this new series of compounds as effective EGFR inhibitors. Moreover, compound 16h underwent additional testing for cell cycle analysis, revealing its capability to arrest the cell cycle in the G2/M phase and induce Apoptosis at the IC₅₀ concentration.

Abemaciclib; Anticancer activity; Capecitabine; EGFR inhibitor; Erlotinib; Fragment-based drug discovery (FBDD); Mubritinib; Nilotinib; Oxazole; Pyrimidine; Vero cell lines.