Synthesis of 3-(arylamino) quinazoline-2,4(1H,3H)-dione derivatives via TBHP/I2: Molecular docking, MD simulation, DFT, and pharmacological evaluation as MTH1 inhibitors
Moeid Goudarzi Karim, Morteza Mehrdad, Davood Gheidari, Nazanin Zahra Gheidari
TL;DR
This paper describes the synthesis and evaluation of new quinazoline derivatives as potential MTH1 inhibitors with promising pharmacological properties.
Contribution
The paper introduces a novel synthetic method and evaluates new quinazoline derivatives as MTH1 inhibitors using multiple computational and pharmacological approaches.
Findings
Compound 3d showed the strongest binding affinity to MTH1 with a docking score of −7.24 kcal/mol.
Molecular dynamics simulations identified key residues (Tyr7, Thr8, Lys23, Trp117) involved in compound 3d binding.
All compounds met pharmacological rules (Lipinski, Ghose, Veber, Egan) and showed no liver toxicity.
Abstract
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…
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Taxonomy
TopicsQuinazolinone synthesis and applications · Enzyme function and inhibition · Cancer therapeutics and mechanisms