Naphthoquinones are among the most active natural products obtained from plants and microorganisms. Naphthoquinones exert their biological activities through pleiotropic mechanisms that include reactivity against cell nucleophiles, generation of reactive oxygen species (ROS) and inhibition of proteins. Here we report a mechanistic antiproliferative study performed in the yeast Saccharomyces cerevisiae for several derivatives of three important natural naphthoquinones: lawsone, juglone and β-lapachone. We have found that (i) the free hydroxyl group of lawsone and juglone modulates toxicity; (ii) lawsone and juglone derivatives differ in their mechanisms of action, being ROS generation more important for the former; and (iii) a subset of derivatives possess the capability to disrupt mitochondrial function, being β-lapachones the most potent compounds in this respect. In addition, we have cross-compared yeast results with antibacterial and antitumor activities. We discuss the relationship between the mechanistic findings, the antiproliferative activities and the physicochemical properties of the naphthoquinones.

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure–activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC₅₀ of 0.8 and 1.2 μM, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

Four indole-3-carbaldehyde semicarbazone derivatives, 2-((5-bromo-1H-indol-3-yl)methylene)hydrazinecarboxamide (1), 2-((5-chloro-1H-indol-3-yl)methylene)hydrazinecarboxamide (2), 2-((5-methoxy-1H-indol-3-yl)methylene)hydrazinecarboxamide (3), and 2-((4-nitro-1H-indol-3-yl)methylene)hydrazinecarboxamide (4) were synthesized and characterized by ESI-MS and spectroscopic (FT-IR, ¹H NMR, and ¹³C NMR) techniques. The two-dimensional NMR (in acetone-d₆) spectral data revealed that the molecules 1 and 2 in solution are in the cisE isomeric form. This evidence is supported by DFT calculations at the B3LYP/6-311++G(d,p) level of theory where it was shown that the corresponding most stable conformers of the synthesized compounds have a cisE geometrical configuration, in both the gas and liquid (acetone and DMSO) phases. The in vitro antibacterial activity of compounds 1–4 was determined against Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria. Among all the tested semicarbazones, 1 and 2 exhibited similar inhibitory activities against Staphylococcus aureus (MIC = 100 and 150 μg/mL, respectively) and Bacillus subtilis (MIC = 100 and 150 μg/mL, respectively). On the other hand, 3 and 4 were relatively less active against the tested bacterial strains compared with 1, 2, and tetracycline.