Novel thiosemicarbazide derivatives with 4-nitrophenyl group as multi-target drugs: a-glucosidase inhibitors with antibacterial and antiproliferative activity Maciej Wos a , Małgorzata Miazga-Karska b , Agnieszka A. Kaczor c,d , Katarzyna Klimek b , Zbigniew Karczmarzyk e , Dorota Kowalczuk f , Waldemar Wysocki e , Grazyna Ginalska b , Zofia Urbanczyk-Lipkowska g , Maja Morawiak g , Monika Pitucha a, * a Department of Organic Chemistry, Medical University, 4A Chodzki St., PL-20093, Lublin, Poland b Department of Biochemistry and Biotechnology, Medical University,1 Chodzki St., PL-20093, Lublin, Poland c Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Medical University,1 Chodzki St., PL- 20093, Lublin, Poland d University of Eastern Finland, School of Pharmacy, Department of Pharmaceutical Chemistry, Yliopistonranta 1, P.O. Box 1627, FI-70211, Kuopio, Finland e Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54 St., PL-08110, Siedlce, Poland f Department of Medicinal Chemistry, Medical University of Lublin, Jaczewskiego 4 St., PL-20090, Lublin, Poland g Institute of Organic Chemistry, Polish Academy of Sciences,Kasprzaka 44/52 St., PL-01224, Warsaw, Poland A R T I C L E I N F O Article history: Received 6 April 2017 Received in revised form 12 June 2017 Accepted 11 July 2017 Keywords: Antibacterial activity Antiproliferative activity a-glucosidase inhibitor Molecular docking Thiosemicarbazide A B S T R A C T A series of thiosemicarbazides with 4-nitrophenyl group was obtained in the reaction of carboxylic acid hydrazides with isothiocyanates. All compounds were checked for their antibacterial and antiprolifer- ative activity. Our results have shown that derivatives 6-8 possessed antibacterial activity against S. aureus, S. epidermidis, S. mutans and S. sanguinis, moderate cytotoxicity and good therapeutic safety in vitro. Additionally, compounds 1 and 4 significantly inhibited A549, HepG2 and MCF-7 cell division. Moreover, PASS software indicated that newly obtained compounds are potential a-glucosidase inhibitors. This was confirmed by in vitro studies. To investigate the mode of interaction with the molecular target compounds were docked to glucose binding site of the enzyme and exhibited a similar binding mode as glucose. © 2017 Elsevier Masson SAS. All rights reserved. 1. Introduction In recent years the organo-nitrogen compounds are commonly designed and synthesized as biologically active compounds [1–3]. Small heterocyclic molecules, such as derivatives of pyrazole, pyridine, triazole, thiazole derivatives have interesting bioactivity profiles [4–6]. Moreover, linear derivatives of these compounds [7– 9], including thiosemicarbazide derivatives can result in ground breaking discovery of new class of therapeutic agents [10]. Conjugated N-N-S tridentate ligand system of thiosemicarbazide (NH 2 -C(S)-NH-NH 2 ) is very important for antibacterial, antituber- cular, anticonvulsant, antifungal, antiproliferative and anticancer activity [11–15]. On the other hand, nitro group is a structural moiety that is often found in biologically active compounds. Nitroheterocyclic derivatives have a wide spectrum of activity including antibacte- rial, antifungal or anticancer properties [16,17]. A significant number of compounds have been found to be adequate in drug discovery process and pharmaceutical research exhibiting anti- inflammatory, anti-HIV, anti-tubercular, antiprotozoal, antibacte- rial, antifungal, antiproliferative and anticancer activity [18–24]. The nitro group affects biological properties of chemical com- pounds, usually by increasing their bactericidal ability and toxicity. In the light of above, the aim of this study was to design, synthesize and study multi-target compounds containing thio- semicarbazide and nitro moieties with antibacterial and anti- proliferative activity. Due to the limited amount of information on the activity of these compounds as a a-glucosidase inhibitors [25– 30], we decided to test this mode of activity. The rationale of this study can be summarized as follows: (1) the possibility of * Corresponding author. E-mail address: monika.pitucha@umlub.pl (M. Pitucha). http://dx.doi.org/10.1016/j.biopha.2017.07.049 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved. Biomedicine & Pharmacotherapy 93 (2017) 1269–1276 Available online at ScienceDirect www.sciencedirect.com