Abstract: Breast cancer is one of the most high-profile malignant diseases in modern society. Among postmenopausal women affected by the disease, a substantial portion has breast tumors that are estrogen-receptor positive. A common therapeutic intervention for this type of cancer is through endocrine therapy. Endocrine agents can act by either diminishing the availability or inhibiting the binding of estrogens to ER. Aromatase catalyzes the conversion of androgens to estrogens in the final step of the biosynthesis of estrogens and is therefore an attractive therapeutic target for inhibition. 3DQSAR pharmacophore modeling studies were undertaken for biphenyl derivatives as aromatase inhibitors in JEG-3 cell lines. A four-point pharmacophore with two H-bond acceptors and two aromatic rings as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R² = 0.977 for training set molecules. The generated model showed excellent predictive power, with a correlation coefficient of Q² = 0.946 for an external test set. The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may help in the design and development of potent biphenyl derivatives as new aromatase inhibitors.

A series of new 10-(alkylamino)-8-methyl-2, 6-dihydroimidazo[1, 2-c]pyrimido[5, 4-e]pyrimidine-5(3H)-thiones (4a-g) were subjected to molecular property prediction (drug-likeness, lipophilicity and solubility parameters) using Osiris Property Explorer, ALOGPS 2.1, Molinspiration and ACD/Chemsketch 12.0 software programmes. The calculated drug-related properties of the designed molecules were similar to those found in most marketed drugs. Amongst the proposed analogues, four promising candidates were chosen (4a-d) for synthesis on the basis of Lipinski's ‘Rule of Five’ and drug-likeness scores. The significant biological activity of the test compounds in two in vitro modes (isolated guinea pig tracheal chain preparation, isolated guinea pig ileum) supports the promise and accuracy of the prediction. Among them, 4a was the most potent antihistaminic (IC50 value of 30.2 μM; standard, chlorpheniramine maleate showed an IC50 of 14.1 μM).