Design and Pharmacophore Study of Triazole Analogues as Aromatase Inhibitors.

BACKGROUND: In the current scenario, breast cancer is measured as one of the most dangerous health issues. An effective therapeutic class of drugs known as aromatase inhibitors is dominant against estrogen receptor-positive breast cancer. However, there is an urgent need to create target-specific AIs with better anti-breast cancer profiles due to the increased toxicity and adverse effects related to currently existing anti-breast cancer drugs.

OBJECTIVES: In the present study, we have designed 100 novel tiazole analogues as aromatase inhibitors and their pharmacophoric features are explored.

METHOD: Molecular docking is applied in a series of 4-substituted-1, 2, 3-triazoles containing letrozole for their aromatase inhibitory effects. The aromatase inhibitory activity of the compound in a series varies from the range of (IC50 = 0.008-31.26 µM). A hydrogen atom positioned at R1 of triazole ring in compound (01) is responsible for the most potent compound (IC50 = 0.008µM) in the series of 28 compounds as compared to letrozole. The self-organizing molecular field study was used to assess the molecular characteristics and biological activities of substances in succession. The four models were developed from PLS and MLR methods. The PLS method was good for statistical analysis. The letrozole scaffold based 100 compounds were designed by selecting an effective pharmacophore responsible for aromatase inhibitory activity. The designed compound was placed on the previous SOMFA model as test set and their IC50 values were calculated.

RESULT: Hydrogen bonds were established between the powerful molecule (01) and the essential residues Met 374 and Arg 115, which were responsible for the aromatase-inhibiting action. Cross-validated q2 (0.6349) & noncross-validated r2 (0.7163) were discovered in the statistical findings as having reliable predictive power. Among 100 designed compounds, seven compounds showed good aromatase inhibitory activities.

CONCLUSION: The additional final SOMFA model created for the interactions between the enzyme & the letrozole blocker may be helpful for future modification and enhancement of the inhibitors of this crucial enzyme.