Molecular structures, Hirshfeld analysis and biological investigations of isatin based thiosemicarbazones Sivaraj Saranya a, 1 , Jebiti Haribabu b, c, 1 , Vishnunarayanan Namboothiri Vadakkedathu Palakkeezhillam b , Peter Jerome b , Kannayiram Gomathi a , Kodagala Kameswara Rao d , Velakaturi Hari Hara Surendra Babu d , Ramasamy Karvembu b, * , Dasararaju Gayathri e, ** a Department of Biotechnology, Dr. MGR Educational and Research Institute University, Maduravoyal, Chennai 600095, India b Department of Chemistry, National Institute of Technology, Tiruchirappalli, 620015, India c Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, 278-8510 Japan d Department of Physics, Sri Venkateswara Arts College, Tirupati, 517501, India e Centre of Advanced Study in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, 600025, India article info Article history: Received 29 April 2019 Received in revised form 26 July 2019 Accepted 5 August 2019 Available online 8 August 2019 Keywords: Thiosemicarbazones Antioxidant Cytotoxicity Anti-inflammatory Phospholipase A2 Molecular docking abstract The synthesized isatin thiosemicarbazone compounds (1e10) were well characterized by elemental analysis, and UVeVisible, FT-IR and NMR spectroscopic methods. The crystal structure of two of the compounds (6 and 9) was confirmed by single crystal X-ray crystallography. Hirshfeld surface analysis was performed to analyze the intermolecular interactions. The compounds were evaluated for their in vitro antioxidant and cytotoxicity against MCF-7 (breast) cancer cell line through DPPH and MTT as- says, respectively. The results clearly indicated that compounds 5, 6, 7 and 8 showed significant anti- oxidant property and compound 7 exhibited greater cytotoxicity than the other compounds. Anti- inflammatory activity of the compounds was determined by in vitro PLA2 inhibition assay and in silico molecular docking study, which showed promising results for all the compounds. © 2019 Elsevier B.V. All rights reserved. 1. Introduction Thiosemicarbazide when condensed with aldehyde or ketone with potential donor site(s) yields Schiff base termed as thio- semicarbazone. Thiosemicarbazone compounds and their metal complexes have been studied over the last 50 years for their tremendous biological applications. The presence of sulfur atom and its ability to bind with the metals in the biological system is believed to be the major reason for their biological activities [1] such as anticancer [2], antitumor, antifungal [3], antibacterial [4], antimalarial, antiviral [5] and anti-HIV [6]. Thiosemicarbazone (TSC) derivatives such as marboran, amithiozone, cutisone, ambazone and anisaldehyde thio- semicarbazone were proved to possess antituberculosis or anti- tumor effect (Fig. 1)[7]. Recent studies on the antitumor property of thiosemicarbazone derivative DP44 mT (di-2-pyridylketone-4,4- dimethyl-3-thiosemicarbazone) have proved that the compound can actively bind iron in a tight chelate complex and deplete tumors as cancer cells need more iron than normal body cells to sustain their abnormally rapid growth [8]. In addition, cytotoxicity effect of a series of cyclohexyl thiosemicarbazones was reported against HER-2 over expressed SKBr-3 cells [9]. Thiosemicarbazone de- rivatives were reported to possess anticancer activity against various cell lines, cholangiocarcinoma (HuCCA-1), liver carcinoma (HepG2), lung carcinoma (A549) and acute lymphoblastic carci- noma (MOLT-3) [10]. More importantly, N-heterocyclic TSCs showed broad range of activities, which are believed to be at least partially due to their RNR inhibition property [11]. To date, several TSC compounds, namely, 3-amino-2-pyridinecarboxaldehyde TSC (triapine) [12e14], di-2-pyridylketone-4-cyclohexyl-4-methyl-3- * Corresponding author. ** Corresponding author. E-mail addresses: kar@nitt.edu (R. Karvembu), gayathri@unom.ac.in (D. Gayathri). 1 Both the authors contributed equally to this work. Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc https://doi.org/10.1016/j.molstruc.2019.126904 0022-2860/© 2019 Elsevier B.V. All rights reserved. Journal of Molecular Structure 1198 (2019) 126904