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Bentham Science Publishers, Medicinal Chemistry, 9(17), p. 945-955, 2021

DOI: 10.2174/1573406416666200817164308

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Naphthoquinone-based hydrazone hybrids: synthesis and potent activity against cancer cell lines

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, and the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β- lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Methods: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Results: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, compounds 3 and 4 being the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.