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Top1. Introduction
One of the major challenges in the field of drug discovery is to design effective drugs against cancer (Hidalgo, Gail Eckhardt, Garrett-Mayer, & Clendeninn, 2011; Siegel, Miller, & Jemal, 2019). Many existing anticancer drugs fail due to lack of selectivity, frequency of adverse events and bioavailability problems (Huggins, Sherman, & Tidor, 2012; Thurston, 2007). Thus, the field of cancer drugs has a particular need for novel therapeutic leads that allow reducing the cancer deaths. Experimental techniques used for drug discovery are costly and time-consuming. Thus, there is a need to develop computational solutions for designing anticancer drugs (Roy, 2017; H. Singh et al., 2016). The use of in silico tools for the development of anticancer drugs with improvements in selectivity and potency would accelerate the drug discovery processes.
Most of the currently used anticancer drugs may be directed at tumor cells or other elements involved in carcinogenesis (Avendaño & Menéndez, 2015). These compounds directly make non-covalent and covalent linkages with the target located at the DNA, RNA, or indirectly by interacting and inhibiting several enzymes that are required for their synthesis, maintenance or repair. In particular, given that the interaction of a drug with its target is a phenomenon that leads to a therapeutic response, in anticancer drug discovery programs the strength of these molecular interactions is maximized by combining concepts of chemical reactivity, which provide the opportunity to create highly selective drugs that would act on the target with less side effects (Misko et al., 2019; Moorthy, Cerqueira, Ramos, & Fernandes, 2013; J. Singh, Petter, Baillie, & Whitty, 2011).
Hydrazone is a scaffold of choice for drug design due to their ease of synthesis, easily tunable electronic properties, denticity and formation of a wide variety of complexes with chemical, structural, biological and industrial importance (Retamosa, Matador, Monge, Lassaletta, & Fernández, 2016). It has a triatomic grouping >C=N-N< where the C-N double bond is conjugated with a lone electron pair of the terminal nitrogen atom. Such functional grouping is very reactive, the two nitrogens have nucleophilic behavior and the carbon atom has both electrophilic and nucleophilic performance.
In the last few years, there has been considerable interest in the development of heterocyclichydrazones as chelating agents via the imine–N, the amine–N and the heterocyclic–O/S/N centers (Arora, Agarwal, & Singhal, 2014; Cardoso et al., 2017; Saini & Gupta, 2018; Savini et al., 2004). These compounds have been proposed to be inhibitors of the enzyme Ribonucleotide Reductase (RR) (Huff et al., 2018), an important target in anticancer drug development, through the inactivation of the iron complex located at subunit often referred as RR2 protein. Particularly, a series of 3- and 5-methylthiophene-2-carboxaldehyde α-(N)-heterocyclichydrazones (Savini et al., 2004) and N-acylhydrazones containing a thiophene nucleus (Cardoso et al., 2017) have been synthesized in an attempt to obtain antitumoral agents with an N–N–S tridentate ligand system. These compounds are planned for optimization of the chelating properties identified in quinolylhydrazones and by molecular hybridization of a series of arylhydrazones with a thiophene nucleus. Although they display a significant activity against a wide range of cancer types, the activity patterns have not been rationalized for their affinity by forming coordinate covalent bonds with their target, by considering variations in the electron distribution of the hydrazone function, and at additional coordinating functionalities present in the molecule.