Received: 24 August 2017 | Revised: 12 February 2018 | Accepted: 13 February 2018 DOI: 10.1002/ardp.201700272 FULL PAPER Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation Merve Ertas 1 | Zafer Sahin 1 | Barkin Berk 1 | Leyla Yurttas 2 | Sevde N. Biltekin 3 | Seref Demirayak 1 1 Department of Pharmaceutical Chemistry, School of Pharmacy, İstanbul Medipol University, İstanbul, Turkey 2 Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University, Eskisehir, Turkey 3 Department of Pharmaceutical Microbiology, School of Pharmacy, İstanbul Medipol University, İstanbul, Turkey Correspondence Merve Ertas, Department of Pharmaceutical Chemistry, School of Pharmacy, İstanbul Medipol University, Kavacık street no. 19, 34810 İstanbul, Turkey. Email: mertas@medipol.edu.tr Funding information Anadolu University Scientific Research Projects Commission, Grant number: 1410S422 Abstract Drugs used in breast cancer treatments target the suppression of estrogen biosynthesis. During this suppression, the main goal is to inhibit the aromatase enzyme that is responsible for the cyclization and structuring of estrogens either with steroid or non-steroidal-type inhibitors. Non-steroidal derivatives generally have a planar aromatic structure attached to the triazole ring system in their structures, which inhibits hydroxylation reactions during aromatization by coordinating the heme group. Bioisosteric replacement of the triazole ring system and development of aromatic/ cyclic structures of the side chain can increase the selectivity for aromatase enzyme inhibition. In this study, pyridine-substituted thiazolylphenol derivatives, which are non-steroidal triazole bioisosteres, were synthesized using the Hantzsch method, and physical analysis and structural determination studies were performed. The IC 50 values of the compounds were determined by a fluorescence-based aromatase inhibition assay. Then, their antiproliferative activities on the MCF7 and HEK 293 cell lines were evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Furthermore, the crystal structure of human placental aromatase was subjected to a series of docking experiments to identify the possible interactions between the most active structure and the active site. Lastly, an in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules. KEYWORDS anticancer activity, aromatase, breast cancer, MCF-7, non-steroidal inhibitor 1 | INTRODUCTION Breast cancer is the most common cancer among women worldwide. [1] Most breast cancers in postmenopausal women are estrogen receptor positive (ER + ) [2,3] and adjuvant endocrine therapy has an important role in treating this type. Efficacy of suppression treatment is based on the idea that estrogens stimulate the growth of residual cancer cells or contribute to the initiation of a new primary cancer over time. Selective estrogen-receptor modulators (SERMs) and aromatase inhibitors (AIs) are two basic regimes used in clinics. During the final step of estrogen biosynthesis, the aromatase enzyme plays a crucial role by both enhancing the aromatic feature of Arch Pharm Chem Life Sci. 2018;e1700272. wileyonlinelibrary.com/journal/ardp © 2018 Deutsche Pharmazeutische Gesellschaft | 1 of 11 https://doi.org/10.1002/ardp.201700272