Soluble epoxide hydrolase (sEH), a member of the α/β hydrolase fold family, catalyzes the hydrolysis of epoxy eicosatrienoic acids to vicinal diol which are involved in the regulation of blood pressure and inflammation. In this study, 2D and 3D‐QSAR analysis of novel N,N′‐disubstituted urea derivatives as sEH inhibitors were performed by stepwise multiple linear regressions (SW‐MLR), stepwise artificial neural networks (SW‐ANN), Comparative Molecular Field Analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). It was found that SW‐MLR model with r2 of 0.954 for the training set and r2 of 0.876 for the test set were more favorable than model established by CoMFA method with r2=0.983, r2pred=0.602 and CoMSIA with r2=0.987, r2pred=0.751 in 3D‐QSAR. In addition, obtaining models were validated by cross validation with cut off value of q2> 0.5. These developed models could be a useful guideline to design and predict the activity of novel compounds with enhanced sEH inhibitory activities.

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In addition, obtaining models were validated by cross validation with cut off values of q2 > 0.5 and r2pred > 0.6.

: Impaired cell cycle regulation and disturbance in signal transduction pathway are two major causes of a condition defined as cancer, one of the significant reasons for mortality worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been commonly used as anticancer agents, and the majority of this medications possess quinazoline moiety as a heteroaromatic core. In this study, two novel series of EGFR-TKIs containing quinazolinone core were designed and synthesized. Most compounds showed reasonable inhibitory activity against EGFR-TK compared to that of erlotinib, a reversible inhibitor of this enzyme. Compound 8b, 2-((2-chlorobenzyl)amino)-6-phenoxyquinazolin-4(1H)-one, with an IC50 value of 1.37 nM exhibited the highest potency. Molecular docking study of compound 8b showed that it had the same direction of erlotinib and formed proper hydrogen bonds and hydrophobic interactions with the important amino acid residues of the active site. Based on in-silico calculations of ADME properties, our novel compounds have the potential to be orally active agents.