Design and Discovery of Potent Benzofuran Oxadiazole MAT2A Inhibitors: Synthesis, Structure Activity Relationships, and Molecular Modeling

Background/Objectives: Methionine adenosyltransferase 2A (MAT2A) has emerged as a promising therapeutic target in cancers harboring methylthioadenosine phosphorylase (MTAP) deletion. However, the development of potent, drug-like MAT2A inhibitors with favorable pharmacokinetic profiles remains challenging. This study aimed to design, synthesize, and evaluate a library of benzofuran-based oxadiazole derivatives as novel MAT2A inhibitors and to elucidate their molecular basis of action through integrated computational studies. Methods: A series of benzofuran-based oxadiazole derivatives (10a–10j and 16–19) was designed, synthesized, and characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). All compounds were evaluated for MAT2A inhibitory activity, with AZ-28 used as the reference inhibitor. The most active compounds were subjected to molecular docking, 200 ns molecular dynamics (MD) simulations, density functional theory (DFT) calculations, and in silico ADME/toxicity prediction. No preregistration was applicable, and no animals were used in this study. Results: The synthesized compounds exhibited a broad range of MAT2A inhibition, with IC50 values from 0.0116 ± 0.0020 to 28.77 ± 1.79 μM, benchmarked against AZ-28 (IC50 = 0.0419 ± 0.0032 μM). Compounds 10g (IC50 = 0.0116 ± 0.0020 μM), 10a (IC50 = 0.0883 ± 0.0060 μM), and 19 (IC50 = 0.158 ± 0.015 μM) were the most potent. Docking revealed favorable binding orientations within the MAT2A active site, supported by hydrogen-bonding and hydrophobic interactions. MD simulations showed stable protein–ligand complexes with favorable RMSD profiles, and binding free-energy calculations supported complex stability. DFT analyses (HOMO–LUMO and MEP) provided insight into electronic properties and reactive sites. Furthermore, in silico ADME and toxicity assessments provided preliminary insights into the drug-likeness and pharmacokinetic properties of the studied compounds. Nevertheless, these computational predictions remain preliminary and require experimental validation. Conclusions: Compounds 10g, 10a, and 19 are promising MAT2A inhibitors, with 10g identified as the most favorable lead. These computational predictions remain preliminary and require experimental validation. Further pharmacokinetic, toxicological, and in vivo studies of 10g are warranted.