Original article Synthesis, anticancer activity and QSAR study of 1,4-naphthoquinone derivatives Veda Prachayasittikul a , Ratchanok Pingaew b , Apilak Worachartcheewan c , Chanin Nantasenamat c , Supaluk Prachayasittikul c, * , Somsak Ruchirawat d, e, f , Virapong Prachayasittikul a, * a Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand b Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand c Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand d Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand e Program in Chemical Biology, Chulabhorn Graduate Institute, Bangkok 10210, Thailand f Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education (CHE), Ministry of Education, Thailand article info Article history: Received 11 April 2014 Received in revised form 26 June 2014 Accepted 5 July 2014 Available online 9 July 2014 Keywords: Anticancer 1,4-Naphthoquinone derivatives QSAR Structural modification abstract A series of 2-substituted amino-3-chloro-1,4-naphthoquinone derivatives (3e12) were synthesized as anticancer agents and tested against four cancer cell lines including HepG2, HuCCA-1, A549 and MOLT-3. The most potent cytotoxic activity against the HepG2, HuCCA-1 and A549 cell lines was found to be m- acetylphenylamino-1,4-naphthoquinone (8) affording IC 50 values of 4.758, 2.364 and 12.279 mM, respectively. On the other hand, p-acetylphenylamino-1,4-naphthoquinone (9) exhibited the most potent cytotoxic activity against the MOLT-3 cell line with an IC 50 of 2.118 mM. Quantitative structureeactivity relationship (QSAR) investigations provided good predictive performance as observed from cross- validated R of 0.9177e0.9753 and RMSE of 0.0614e0.1881. The effects of substituents at the 2-amino position on the naphthoquinone core structure and its corresponding influence on the cytotoxic activ- ity were investigated by virtually constructing additional 1,4-naphthoquinone compounds (13e36) for which cytotoxic activities were predicted using equations obtained from the previously constructed QSAR models. Interpretation of informative descriptors from QSAR models revealed pertinent knowledge on physicochemical properties governing the cytotoxic activities of tested cancer cell lines. It is antici- pated that the QSAR models developed herein could provide guidelines for further development of novel and potent anticancer agents. © 2014 Published by Elsevier Masson SAS. 1. Introduction There is a continual increase on the incidence of cancer and it is considered to be the leading cause of morbidity and mortality [1]. Recently, considerable attention has been drawn on the search for novel anticancer drugs in order to improve survival rates and well- being. The quinone scaffold is presented in many currently used anti- cancer drugs [2,3]. Particularly, 1,4-naphthoquinones are active quinone derivatives that are widely used as raw materials in pharmaceuticals and agrochemicals industries. A diverse array of bioactivities has been reported for 1,4-naphthoquinone derivatives to exert anticancer [2,4e8], antimicrobial [9e12], antifungal [10,13e15], antiviral [11,16e18], radical scavenging [19], antiplatelet [20e22] and trypanocidal [23] activities. 1,4-Naphthoquinone contains two ketone groups as a crucial chromophore that accounts for its bioactivities owing to their ability to accept electrons [24]. Structureeactivity relationship study indicated that cytotoxic activity of 1,4-naphthoquinones are closely related with their electron accepting capability [25], which gives rise to reactive oxygen species (ROS) production leading to DNA damage and cell death [2,25,26]. Furthermore, enhanced antimicrobial activity was reported in amino derivatives of 1,4- naphthoquinone [13,27]. The findings indicated that the nitrogen atom of the amino substituent could improve the redox potential of the quinone system [25,28]. In addition, insertion of a chlorine substituent into the amino derivative of 1,4-naphthoquinone * Corresponding authors. E-mail addresses: supaluk@swu.ac.th (S. Prachayasittikul), virapong.pra@ mahidol.ac.th (V. Prachayasittikul). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.07.024 0223-5234/© 2014 Published by Elsevier Masson SAS. European Journal of Medicinal Chemistry 84 (2014) 247e263