Synthesis, Biological Evaluation and Ligand Based Pharmacophore Modeling of New Aromatic Thiosemicarbazones as Potential Anticancer Agents
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Two series of new aromatic thiosemicarbazone derivatives were synthesized by condensation of N-(4-cyanophenyl)hydrazine carbothioamide (I) and N-(4-methylsulfanylphenyl)hydrazine carbothioamide (II) with appropriate aromatic aldehydes in order to investigate their antiviral and cytostatic potency. The chemical structures of all compounds were fully characterized by elemental analysis and spectroscopic techniques. The results of the bioassays indicated that compounds Id, Ie, If and IIf proved inhibitory against influenza virus A (EC50 = 13 – 27 μg/mL for strain H1N1 and 9.3 – 18 μg/mL for strain H3N2). Compounds Ig and IIg were the most cytostatic compounds with inhibition of HeLa cell proliferation at an IC50 = 0.3 μg/mL for Ig and 1.9 μg/mL for IIg. Especially, compound Ig showed the highest cytostatic activity with IC50 of 0.30, 0.70 and 2.50 μg/mL against HeLa, CEM and L1210 cell lines, respectively. This inhibition range was within the same order of magnitude as that for cisplatin. Furthermore, molecular modeling was carried out to examine the cytostatic activity and determine the best pharmacophore model as a guide for the design and development of potential prodrugs in future studies.
Keywordsaromatic thiosemicarbazone antiviral activity cytostatic activity anti-influenza activity pharmacophore modeling
The present work was supported by the Scientific Research Projects Governing Unit Council of Gaziantep University (Grant No. FEF.08.10), Gaziantep, Turkey and by the KU Leuven (GOA 10/14). The authors are grateful to Leentje Persoons, Frieda De Meyer, Leen Ingels, Anita Camps, Steven Carmans, Lies Van den Heurck and Lizette van Berckelaer for excellent technical assistance and Dr. Annelies Stevaert for statistical analysis.
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