Design and evaluation of sulfadiazine derivatives as potent dual inhibitors of EGFRWT and EGFRT790M: integrating biological, molecular docking, and ADMET analysis

Abstract

A series of derivatives (5–14) were synthesized through the diazotization of sulfadiazine with active methylene compounds. The chemical structures of these newly designed compounds were validated through spectral and elemental analysis techniques. The antiproliferative potential of derivatives 5–14 was assessed against three distinct cancer cell lines (A431, A549, and H1975) using the MTT assay. The results revealed that compounds 8, 12, and 14 exhibited the most potent antiproliferative activity, with IC₅₀ values ranging from 2.31 to 7.56 μM. Notably, these values were significantly lower than those of known EGFR inhibitors, including erlotinib, gefitinib, and osimertinib, suggesting the potential of these derivatives as novel antiproliferative agents. Furthermore, compound 12 was identified as the most potent inhibitor of both EGFR^WT and EGFR^T790M protein kinases, with IC₅₀ values of 14.5 and 35.4 nM, respectively. These results outperformed those of gefitinib and osimertinib, which exhibited IC₅₀ values of 18.2 and 368.2 nM, and 57.8 and 8.5 nM, respectively. Molecular docking studies of compounds 8, 12, and 14 within the ATP-binding sites of both EGFR^WT and EGFR^T790M corroborated the in vitro results when compared to erlotinib, gefitinib, and osimertinib. The docking results indicated that compound 8 exhibited a favorable binding affinity for both EGFR^WT and EGFR^T790M, with binding scores of −6.40 kcal mol⁻¹ and −7.53 kcal mol⁻¹, respectively, which were comparable to those of gefitinib and osimertinib, with binding scores of −8.01 and −8.72 kcal mol⁻¹, respectively. Furthermore, an assessment of the most promising EGFR inhibitors (8, 12, and 14) using the egg-boiled method for their in silico ADME properties revealed significant lipophilicity, blood–brain barrier (BBB) penetration, and gastrointestinal (GIT) absorption. Collectively, our designed analogs, particularly compounds 8, 12, and 14, exhibit promising dual antiproliferative and EGFR^WT and EGFR^T790M kinase inhibitory properties, positioning them as efficient candidates for further therapeutic development.