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In the present paper, we report the synthesis, characterization, and biological evaluation as antifungal, antibacterial, antioxidant, and cytotoxic/anticancer agents of N-, S-, O-substituted-1,4-naphtho-and 2,5-bis(amino-substituted)-1,4-benzoquinone derivatives. In the synthesized compounds, antimicrobial activity at low concentrations against Escherichia coli B-906, Staphylococcus aureus 209-P, and Mycobacterium luteum B-917 bacteria and Candida tenuis VKM Y-70 and Aspergillus niger F-1119 fungi in comparison with controls was identified. 2-(N-Diphenylmethylpiperazin-1-yl)-3-chloro-1,4-naphthoquinone 9a was the most potent, with a minimum inhibitory concentration value of 3.9 µg/mL against test culture M. luteum. Key words quinone; antimicrobial activity; antioxidant activity; cupric-reducing antioxidant capacity method; reactive oxygen species-scavenging activity; cytotoxicity Quinonic compounds are of great importance to understand different processes that are related to biology.1) The quinone structure is common in numerous natural products that are associated with antitumor, antibacterial, antimalarial and antifungal activities.2) Furthermore, several reports have appeared in literature about anticancer activities of quinones against various cancer cell lines. [3][4][5] 1,4-Naphthoquinones are widely distributed in nature and there are many clinically important antitumor drugs containing a quinone nucleus, such as anthracyclines, mitoxantrones and saintopin, that show excellent anticancer activity. These anticancer agents are effective inhibitors of DNA topoisomerase and it is generally accepted that the cytotoxicity of quinone analogues results from the inhibition of DNA topoisomerase-II. 6) Quinone analogues can also induce the formation of semiquinone radicals, which can transfer an electron to oxygen to produce superoxide. The radical process is catalyzed by flavoenzymes such as reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome-P-450 reductase. Both the superoxide and semiquinone radical anions of naphthoquinone analogues can generate the hydroxyl radical, which is known to cause DNA strand breaks.7) Structure-activity relationship studies from quinonoid compounds indicated that the number and position of nitrogen (N) atoms substituted in the heterocyclic ring were considerably important factors to affect the biological activities. 8,9) The presence of amino, thioor chloro-moiety on the quinones was considerably important factor to effect antifungal activity. 10) Quinones, in particular naphthoquinone derivatives, have been repeatedly isolated from lower as well as higher species of plants, and are found frequently in animals. In addition to quinones possessing a biological function in cell metabolism as electron carriers, other compounds of this class have been found active against bacteria and fungi. 11,12)

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New 3-substituted 1-(3-hydroxyphenyl)-5-oxopyrrolidine derivatives containing hydrazone, azole, diazole, oxadiazole fragments, as well as 2-phenoxy- and 2,3-diphenoxy-1,4-naphthoquinone derivatives were synthesized. The structure of all compounds has been confirmed by NMR, IR, mass spectra, and elemental analysis data. Methyl 1-{3-[(3-chloro-1,4-dioxo-1,4-dihydro-2-naphthalenyl)oxy]phenyl}-5-oxo-3-pyrrolidinecarboxylate demonstrated potential antibacterial and antifungal activities as determined by diffusion and serial dilution methods, while N'-[(4-bromophenyl)methylidene]-1-{3-[(3-chloro-1,4-dioxo-1,4-dihydro-2-naphthalenyl)oxy]phenyl}-5-oxo-3-pyrrolidinecarbohydrazide and 2-{3-[4-(1,2,3-oxadiazol-5-yl)-2-oxo-1-pyrrolidinyl]phenoxy}-3-{3-[4-(1,3,4-oxadiazol-2-yl)-2-oxo-1-pyrrolidinyl]phenoxy}naphthoquinone showed antifungal activity against Candida tenuis and Aspergillus niger at low concentrations, as determined by the serial dilution method. The substitution of the methoxy fragment by N-containing substituents in monophenoxy substituted naphthoquinones was found to decrease their activity against Mycobacterium luteum. Besides, introduction of the second phenoxy substituted fragment increased the antifungal activity against Candida tenuis and Aspergillus niger at lower concentrations.

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3-[(2-Hydroxyphenyl)amino]butanoic and 3-[(2-hydroxy-5-methyl(chloro)phenyl)amino]butanoic acids were converted to a series of derivatives containing hydrazide, pyrrole and chloroquinoxaline moieties. The corresponding benzo[b]phenoxazine derivatives were synthesized by the reaction of the obtained compounds with 2,3-dichloro-1,4-naphthoquinone. Five of the synthesized compounds exhibited good antimicrobial activity against Staphylococcus aureus and Mycobacterium luteum, whereas three compounds showed significant antifungal activity against Candida tenuis and Aspergillus niger.

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Anticancer activity as an associated action for a series of dithiocarbamates of 9,10-anthracenedione was predicted using the PASS computer program and analysed with PharmaExpert software. The predicted cytotoxic activity of the dithiocarbamate derivatives of 9,10-anthracenedione was evaluated in vitro on cancer cells of the human lung (A549), prostate (PC3), colon (HT29) and human breast (MCF7) using the sulforhodamine B (SRB) cell viability assay. Among these compounds, 9,10-dioxo-9,10-dihydroanthracen-1-yl pyrrolidin-1-carbodithioate and 9,10-dioxo-9,10-dihydroanthracen-2-yl pyrrolidin-1-carbodithioate were identified as the most potent anticancer agents with cytotoxic activity against the MCF-7 human breast cell line with GI values of 1.40 μM and 1.52 μM, whereas the GI value for the reference anticancer drug mitoxantrone was 3.93 μM. Thus, anticancer activity predicted by PASS with a probability Pa > 30% was confirmed by the experiment. Relatively small Pa values estimated by PASS indicated the novelty of the considered derivatives comparing to the compounds from the PASS training set.