Unlocking the potential of aromatase inhibitors: recent advances in drug design, synthesis, docking activity, and in vitro bioactivity evaluations

  • Niloufar Moharrer Navaei 1
  • Narvan Moharrer Navaei 2
  • 1 Faculty of Pharmacy, Cyprus International University, Nicosia 99258, Northern Cyprus via Mersin 10, Turkey
  • 2 Faculty of Pharmacy, Eastern Mediterranean University, Famagusta 99628, Northern Cyprus via Mersin 10, Turkey


Breast cancer, a global health concern claiming approximately 685,000 lives in 2020, necessitates continual advancements in therapeutic strategies. Estrogen and aromatase play pivotal roles in hormone-responsive breast cancer, with 80% of patients exhibiting estrogen receptor-positive tumors. Aromatase inhibitors (AIs), notably non-steroidal inhibitors like anastrozole and letrozole, have significantly improved outcomes, yet challenges persist, including side effects. This review focuses on recent developments in AIs, exploring xanthone derivatives, imidazole derivatives, and curcumin derivatives as potential inhibitors of aromatase. Molecular docking studies, employing Auto Dock and other tools, reveal the binding affinities and interactions of these compounds with the aromatase enzyme. Among xanthones, Erythrommone emerges as a potent inhibitor, holding promise for clinical trials. Imidazole derivatives, synthesized through the Debus-Radziszewski reaction, demonstrate anticancer potential, with compounds like 1a exhibiting superior efficacy against MCF7 cells. ADME-Tox analyses indicate promising drug-likeness but reveal potential mutagenic effects and environmental impacts. Curcumin derivatives, particularly 1,5-diaryl-1,4-pentadien-3-ones, present alternatives to address curcumin's bioavailability challenges. A study of 25 compounds (DKC) identifies DKC-10 as a potent inhibitor, outperforming established breast cancer drugs in terms of binding affinity and interactions with aromatase and ERα+ receptors. These findings underscore the importance of exploring diverse chemical structures in developing AIs, paving the way for more effective and well-tolerated therapeutics. The integration of computational techniques, such as molecular docking studies, accelerates drug discovery by predicting interactions at the molecular level. Overall, this comprehensive review provides valuable insights into the evolving landscape of aromatase inhibitors, offering a roadmap for future research and the development of advanced breast cancer therapeutics.


Download data is not yet available.
Keywords: Aromatase inhibitors, Molecular docking, Imidazole, Curcumin, Xhantones, Breast cancer


[1] B. MacMahon, P. Cole, J. Brown, Etiology of human breast cancer: a review, JNCI J. Natl. Cancer Inst. 50 (1973) 21–42. https://doi.org/10.1093/jnci/50.1.21.
[2] F. Ye, S. Dewanjee, Y. Li, N.K. Jha, Z.-S. Chen, et al., Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer, Mol. Cancer. 22 (2023) 105. https://doi.org/10.1186/s12943-023-01805-y.
[3] B. Conte, L. Boni, G. Bisagni, A. Durando, G. Sanna, et al., SNP of Aromatase predict long-term survival and aromatase inhibitor toxicity in patients with early breast aancer: a biomarker analysis of the GIM4 and GIM5 trials, Clin. Cancer Res. (2023) OF1–OF10. https://doi.org/10.1158/1078-0432.CCR-23-1568.
[4] R. Carpenter, W.R. Miller, Role of aromatase inhibitors in breast cancer, Br. J. Cancer. 93 (2005) S1–S5. https://doi.org/10.1038/sj.bjc.6602688.
[5] L. Clusan, F. Ferrière, G. Flouriot, F. Pakdel, A basic review on estrogen receptor signaling pathways in breast cancer, Int. J. Mol. Sci. 24 (2023) 6834. https://doi.org/10.3390/ijms24076834.
[6] C. Palmieri, D.K. Patten, A. Januszewski, G. Zucchini, S.J. Howell, Breast cancer: Current and future endocrine therapies, Mol. Cell. Endocrinol. 382 (2014) 695–723. https://doi.org/10.1016/j.mce.2013.08.001.
[7] A. Singh, N. Tiwari, A. Mishra, M. Gupta, DFT study and docking of xanthone derivatives indicating their ability to inhibit aromatase, a crucial enzyme for the steroid biosynthesis pathway, Comput. Toxicol. 28 (2023) 100289. https://doi.org/10.1016/j.comtox.2023.100289.
[8] H.R.M. Rashdan, I.A. Shehadi, Triazoles synthesis & applications as nonsteroidal aromatase inhibitors for hormone-dependent breast cancer treatment, Heteroat. Chem. 2022 (2022) 1–16. https://doi.org/10.1155/2022/5349279.
[9] R.K. Rej, J.E. Thomas, R.K. Acharyya, J.M. Rae, S. Wang, Targeting the estrogen receptor for the treatment of breast cancer: recent advances and challenges, J. Med. Chem. 66 (2023) 8339–8381. https://doi.org/10.1021/acs.jmedchem.3c00136.
[10] N.B. Sayyad, P.M. Sabale, M.D. Umare, K.K. Bajaj, Aromatase inhibitors: development and current perspectives, Indian J. Pharm. Educ. Res. 56 (2022) 311–320. https://doi.org/10.5530/ijper.56.2.51.
[11] N. Gremke, S. Griewing, S. Chaudhari, S. Upadhyaya, I. Nikolov, et al., Persistence with tamoxifen and aromatase inhibitors in Germany: a retrospective cohort study with 284,383 patients, J. Cancer Res. Clin. Oncol. 149 (2023) 4555–4562. https://doi.org/10.1007/s00432-022-04376-5.
[12] A. Martinetti, N. Zilembo, L. Ferrari, G. Massimini, A. Polli, et al., Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate, Anticancer Res. 23 (2003) 3485–91.
[13] P.E. Lønning, E. Bajetta, R. Murray, M. Tubiana-Hulin, P.D. Eisenberg, et al., Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial, J. Clin. Oncol. 18 (2000) 2234–2244. https://doi.org/10.1200/JCO.2000.18.11.2234.
[14] H. Al-Kelabi, D. Al-Duhaidahawi, K. Al-Khafaji, N.A. Al-Masoudi, New tamoxifen analogs for breast cancer therapy: synthesis, aromatase inhibition and in silico studies, J. Biomol. Struct. Dyn. 41 (2023) 1–10. https://doi.org/10.1080/07391102.2023.2175375.
[15] S. Chumsri, T. Howes, T. Bao, G. Sabnis, A. Brodie, Aromatase, aromatase inhibitors, and breast cancer, J. Steroid Biochem. Mol. Biol. 125 (2011) 13–22. https://doi.org/10.1016/j.jsbmb.2011.02.001.
[16] U. Dutta, K. Pant, Aromatase inhibitors: past, present and future in breast cancer therapy, Med. Oncol. 25 (2008) 113–124. https://doi.org/10.1007/s12032-007-9019-x.
[17] P.E. Goss, J.N. Ingle, K.I. Pritchard, N.J. Robert, H. Muss, et al., Extending aromatase-inhibitor adjuvant therapy to 10 years, N. Engl. J. Med. 375 (2016) 209–219. https://doi.org/10.1056/NEJMoa1604700.
[18] H. Vanden Bossche, H. Moereels, L.M.H. Koymans, Aromatase inhibitors — mechanisms for non-steroidal inhibitors, Breast Cancer Res. Treat. 30 (1994) 43–55. https://doi.org/10.1007/BF00682740.
[19] X. Wang, S. Chen, Aromatase destabilizer: novel action of exemestane, a food and drug administration–approved aromatase inhibitor, Cancer Res. 66 (2006) 10281–10286. https://doi.org/10.1158/0008-5472.CAN-06-2134.
[20] C. Amaral, G. Correia-da-Silva, C.F. Almeida, M.J. Valente, C. Varela, et al., An exemestane derivative, oxymestane-D1, as a new multi-target steroidal aromatase inhibitor for estrogen receptor-positive (ER+) breast cancer: effects on sensitive and resistant cell lines, Molecules. 28 (2023) 789. https://doi.org/10.3390/molecules28020789.
[21] F. Khan, K. Rojas, M. Schlumbrecht, P. Jeudin, Oophorectomy in premenopausal patients with estrogen receptor-positive breast cancer: new insights into long-term effects, Curr. Oncol. 30 (2023) 1794–1804. https://doi.org/10.3390/curroncol30020139.
[22] U.A. Çevik, I. Celik, J. Mella, M. Mellado, Y. Özkay, Z.A. Kaplancıklı, Design, synthesis, and molecular modeling studies of a novel benzimidazole as an aromatase inhibitor, ACS Omega. 7 (2022) 16152–16163. https://doi.org/10.1021/acsomega.2c01497.
[23] D. Osmaniye, S. Levent, B.N. Sağlık, A.B. Karaduman, Y. Özkay, Z.A. Kaplancıklı, Novel imidazole derivatives as potential aromatase and monoamine oxidase-B inhibitors against breast cancer, New J. Chem. 46 (2022) 7442–7451. https://doi.org/10.1039/D2NJ00424K.
[24] G. Çetiner, U. Acar Çevik, I. Celik, H.E. Bostancı, Y. Özkay, Z.A. Kaplancıklı, New imidazole derivatives as aromatase inhibitor: Design, synthesis, biological activity, molecular docking, and computational ADME-Tox studies, J. Mol. Struct. 1278 (2023) 134920. https://doi.org/10.1016/j.molstruc.2023.134920.
[25] N. Suvannang, C. Nantasenamat, C. Isarankura-Na-Ayudhya, V. Prachayasittikul, Molecular docking of aromatase inhibitors, Molecules. 16 (2011) 3597–3617. https://doi.org/10.3390/molecules16053597.
[26] K. Anbarasu, S. Jayanthi, Identification of curcumin derivatives as human LMTK3 inhibitors for breast cancer: a docking, dynamics, and MM/PBSA approach, 3 Biotech. 8 (2018) 228. https://doi.org/10.1007/s13205-018-1239-6.
[27] J. Bhaliya, V. Shah, Identification of potent COVID-19 Main Protease (Mpro) inhibitors from Curcumin analogues by Molecular Docking Analysis, Int. J. Adv. Res. Ideas Innov. Technol. 6 (2020) 664–672.
[28] I.N. Dahmke, S.P. Boettcher, M. Groh, U. Mahlknecht, Cooking enhances curcumin anti-cancerogenic activity through pyrolytic formation of “deketene curcumin”, Food Chem. 151 (2014) 514–519. https://doi.org/10.1016/j.foodchem.2013.11.102.
[29] V. Shah, J. Bhaliya, G.M. Patel, In silico docking and ADME study of deketene curcumin derivatives (DKC) as an aromatase inhibitor or antagonist to the estrogen-alpha positive receptor (Erα+): potent application of breast cancer, Struct. Chem. 33 (2022) 571–600. https://doi.org/10.1007/s11224-021-01871-2.
[30] A. Kohyama, H. Yamakoshi, S. Hongo, N. Kanoh, H. Shibata, Y. Iwabuchi, Structure-activity relationships of the antitumor C5-Curcuminoid GO-Y030, Molecules. 20 (2015) 15374–15391. https://doi.org/10.3390/molecules200815374.

Cited By

Crossref Google Scholar
Unlocking the potential of aromatase inhibitors: recent advances in drug design, synthesis, docking activity, and in vitro bioactivity evaluations
Available online
How to Cite
Moharrer Navaei, N., & Moharrer Navaei, N. (2023). Unlocking the potential of aromatase inhibitors: recent advances in drug design, synthesis, docking activity, and in vitro bioactivity evaluations. Synthesis and Sintering, 3(4), 234-240. https://doi.org/10.53063/synsint.2023.34183