Comparative evaluation of in silico and in vitro pharmacological activity of some 5-nitrosalicylaldehyde-derived hydrazones

Aroylhydrazones derived from salicylaldehyde are compounds with interesting biological properties including a high anticancer activity. Salicylaldehyde benzoylhydrazone (SBH) is an unusually potent inhibitor of DNA synthesis and cell growth in a variety of cultured human and rodent cells. Various derivatives of SBH have been synthesized in order to discover new more effective antiproliferative agents. In the present paper we report the comparative evaluation of in silico and in vitro biological activity of three recently synthesized 5-nitrosalicylaldehyde-derived hydrazones, namely 5nitrosalicylaldehyde benzoylhydrazone (5nSBH), 5-nitrosalicylaldehyde-4-hydroxy-benzoylhydrazone (5nShBH) and 5-nitrosalicylaldehyde isonicotinoylhydrazone (5nSIH). The molecular properties of the studied compounds, important for drug pharmacokinetics in the human body, were evaluated with the Lipinski's rule of five. The value of logP and the remaining parameters of drug similarity were calculated by the method based on group contributions. All 5-nitro-derivatives observed boundary conditions of the rule and theoretically can be successful oral drugs. The rule is used only as a first step in drug discovery, to find the lead candidates for further elaboration and quickly eliminate the compounds with poor pharmacological properties. In order to examine the antiproliferative effects of the investigated compounds they were tested for in vitro cytotoxicity on a HL-60 acute myeloid leukemia and BV-173 chronic myeloid leukemia cell lines. 5-nitro-derivatives exhibited concentration dependent cytotoxic effect on the leukemia cell lines. The values of IC50 for 5-nitrosalicylaldehyde benzoylhydrazone are comparable with these for the referent cytotoxic drug cisplatin, whereas the IC50 values for 5nShBH and 5nSIH are higher. Based on the results of the MTT-dye reduction assay the compound 5nSBH deserves more detailed toxicological and pharmacological investigation for the development of new anticancer drug. Keywords—nitro-salicylaldehyde benzoylhydrazone; Lipinski's rule; oral drugs; lipophilicity; cytotoxic activity