Computer-aided Prediction and Cytotoxicity Evaluation of Bis-Hydrazones as Novel Anticancer Agents

Among several possible novel bioactive compounds, hydrazones provide a rich platform for the design of novel bioactive compounds. They are easily synthesized and show a large variety of biological activities, such as antimicrobial, anti-tubercular and antitumor.1 This work presents the theoretical studies concerning the design and biological activity prediction, the synthesis and antitumor activity of three (thio-)glycolic- and 3,3’-bis-thio-propanoic-bis-hydrazones(3), synthesized as described2. It was performed the prediction of pharmacological activity spectra by Activity-It system3 with 2136 models built from PubChem/ADMET datasets. Several activities already reported for hydrazones were confirmed for our compounds, together with new putative activities against leukemia, trypanosoma and leishmania. The cytotoxic activity of hydrazones was evaluated in vitro (MTT,cell viability) against selected human cancer cell lines: colon (HCT116), leukemia(HL60), prostate(PC3), glioblastoma(SF-295) and breast(MX1). The derivatives1 and 2 are the most potent anticancer agents with cytotoxic activity against all tested cell lines (IC50g/mL and CI 95%,respectively: 7.27-24.08 and 6.79-25.87), but 1 is less toxic (mouse fibroblast L929). The electrochemical studies of 1 and 2 were also performed by cyclic voltammetry in aprotic media (DMF/0.1M Bu4NPF6/glassy carbon) and 1 and 2 showed an electrochemical reduction mechanism related to the nitroaromatic function, with a self-protonation mechanism and oxidation on the thioether function.These substances are promising candidates as novel antitumoral agents for the treatment of cancer.