Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study

Authors

  • Veda Prachayasittikul Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
  • Ratchanok Pingaew Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand
  • Apilak Worachartcheewan Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Department of Community Medical Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
  • Somkid Sitthimonchai Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok 10210, Thailand
  • Chanin Nantasenamat Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
  • Supaluk Prachayasittikul Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
  • Somsak Ruchirawat Laboratory of Medicinal Chemistry, Chulabhorn Research Institute and Program in Chemical Biology, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education, Thailand
  • Virapong Prachayasittikul Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand

DOI:

https://doi.org/10.17179/excli2017-309

Keywords:

1,4-naphthoquinones, aromatase inhibitory activity, structural modification, computer-aided drug design, anticancer agents

Abstract

A series of 2-amino(chloro)-3-chloro-1,4-naphthoquinone derivatives (1-11) were investigated for their aromatase inhibitory activities. 1,4-Naphthoquinones 1 and 4 were found to be the most potent compounds affording IC50 values 5.2 times lower than the reference drug, ketoconazole. A quantitative structure-activity relationship (QSAR) model provided good predictive performance (R2CV = 0.9783 and RMSECV = 0.0748) and indicated mass (Mor04m and H8m), electronegativity (Mor08e), van der Waals volume (G1v) and structural information content index (SIC2) descriptors as key descriptors governing the activity. To investigate the effects of structural modifications on aromatase inhibitory activity, the model was employed to predict the activities of an additional set of 39 structurally modified compounds constructed in silico. The prediction suggested that the 2,3-disubstitution of 1,4-naphthoquinone ring with halogen atoms (i.e., Br, I and F) is the most effective modification for potent activity (1a, 1b and 1c). Importantly, compound 1b was predicted to be more potent than its parent compound 1 (11.90-fold) and the reference drug, letrozole (1.03-fold). The study suggests the 1,4-naphthoquinone derivatives as promising compounds to be further developed as a novel class of aromatase inhibitors.

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Published

2017-05-16

How to Cite

Prachayasittikul, V., Pingaew, R., Worachartcheewan, A., Sitthimonchai, S., Nantasenamat, C., Prachayasittikul, S., … Prachayasittikul, V. (2017). Aromatase inhibitory activity of 1,4-naphthoquinone derivatives and QSAR study. EXCLI Journal, 16, 714–726. https://doi.org/10.17179/excli2017-309

Issue

Vol. 16 (2017)

Section

Original articles

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