Reaction conditions optimized for (3a) a.

A series of novel derivatives of 3-(arylamino) quinazoline-2,4(1H,3H)-dione were synthesized with moderate to good yields (20%−70%) using t-butyl hydroperoxide (TBHP) and iodine. Their efficacy against MutT homologue 1 (MTH1) was evaluated using in silico methods. Density functional theory (DFT) analysis, utilizing the B3LYP/6-311G (2df, p) basis set, indicated a promising reactivity profile for the synthesized compounds. The highest occupied molecular orbital (HOMO) regions associated with the phenylhydrazine group serve as sites for electron donation, functioning as electron-rich nucleophiles. Docking analysis with MTH1 enzymes revealed that all compounds exhibited docking scores ranging from −5.77 to −7.24, indicating favorable binding affinities. Among these, compound (3d), with an energy of −7.24 kcal/mol, demonstrated the strongest binding affinity. Importantly, the Generalized Born and Surface Area Solvation (MM-GBSA) rescoring aligned with the docking data, reinforcing the reliability of the predicted binding modes and highlighting these compounds as promising MTH1 inhibitors. Molecular dynamics (MD) simulations indicated that Tyr7, Thr8, Lys23, and Trp117 exhibited a notably high interaction fraction, suggesting that these residues might be critical for the binding affinity of compound (3d). The analysis of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties indicated that all compounds possess a favorable pharmacological profile and comply with Lipinski’s Rule of Five (Ro5), as well as the Ghose, Veber, and Egan rules. Additionally, they are capable of human intestinal absorption (HIA) and exhibit no liver toxicity, whereas BAY-707 is anticipated to exhibit hepatotoxicity.