Four New Menadione Thioderivatives, Potential Antineoplastic Candidates: In Silico and PARP-1 Inhibition Studies

The design, production, and study of new poly[ADP-ribose] polymerase 1 (PARP-1) inhibitors have emerged as an interesting exploration area, since PARP-1 is an overexpressed enzyme in several carcinomas. In this sense, menadione, or vitamin K3, is well known for its use in correct blood clotting, and for the generation of reactive oxygen species, but it is important to mention that it has been used as an antineoplastic agent against several cell lines. Related to the last commentary, in this work, four novel molecules (<b>2</b>-<b>5</b>) were produced from menadione through a Michael addition protocol, using 1,2-ethanedithiol, cysteamine, benzene-1,4-dithiol, and 4-aminobenzenethiol as nucleophiles, and menadione (<b>1</b>) as substrate, to evaluate them as plausible candidates to inhibit PARP-1. It is convenient to note that after their production and spectroscopic characterization, both docking and theoretical studies for each compound were conducted, using density functional theory (DFT) with the hybrid method B3LYP with the 6-311G(d,p) basis set. As a complement, the reactivity properties determined by DFT calculations were obtained for all compounds; the results revealed that <b>2</b> has the best properties to bind with PARP-1, and <b>3</b> offered good results. Hence, the target compounds were evaluated in vitro, determining their activity against PARP-1, using olaparib as a reference. Molecules <b>2</b> and <b>3</b> displayed the free binding energy values -7.97 and -9.35 kcal/mol, respectively, but <b>2</b> has the best IC₅₀ value, 13.76 µM. It is important to highlight that <b>2</b> and <b>3</b> must be considered as potential new inhibitor agents against PARP-1, exhibiting competitive IC₅₀ values with olaparib.