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Substitution is well-known to modulate the physico-chemical properties of molecules. In this study, a combined, multifactor approach was employed to determine a plethora of substitution patterns using –Br and –O-H in 1,4-naphthoquinone and its derivatives. On the basis of classical Density Functional Theory (DFT), 25 models divided into three groups were developed. The first group contains 1,4-naphthoquinone and its derivatives substituted only by –Br. The second group consists of compounds substituted by –Br and one –O-H group. As a result of the substitution, an intramolecular hydrogen bond was formed. The third group also contains –Br as a substituent, but two –O-H groups were introduced and two intramolecular hydrogen bonds were established. The simulations were performed at the ωB97XD/6-311++G(2d,2p) level of theory. The presence of substituents influenced the electronic structure of the parent compound and its derivatives by inductive effects, but it also affected the geometry of the 2 and 3 groups, due to the intramolecular hydrogen bonding and the formation of a quasi-ring/rings. The static DFT models were applied to investigate the aromaticity changes in the fused rings based on the Harmonic Oscillator Model of Aromaticity (HOMA). The OH stretching was detected for the compounds from groups 2 and 3 and further used to find correlations with energetic parameters. The evolution of the electronic structure was analyzed using Hirshfeld atomic charges and the Substituent Active Region (cSAR) parameter. The proton reaction path was investigated to provide information on the modulation of hydrogen bridge properties by diverse substitution positions on the donor and acceptor sides. Subsequently, Car–Parrinello Molecular Dynamics (CPMD) was carried out in the double-bridged systems (group 3) to assess the cooperative effects in double –O-H-substituted systems. It was determined that the –O-H influence on the core of the molecule is more significant than that of –Br, but the latter has a major impact on the bridge dynamics. The competitive or synergic effect of two –Br substituents was found to depend on the coupling between the intramolecular hydrogen bridges. Thus, the novel mechanism of a secondary (cooperative) substituent effect was established in the double-bridged systems via DFT and CPMD results comparison, consisting of a mediation of the bromine substitutions’ influence by the cooperative proton transfer events in the hydrogen bridges.

1,4-Naphthoquinone derivatives have superior anticancer effects, but their use has been severely limited in clinical practice due to adverse side effects. To reduce the side effects and extend the anticancer effects of 1,4-naphthoquinone derivatives, 2-(butane-1-sulfinyl)-1,4-naphthoquinone (BQ) and 2-(octane-1-sulfinyl)-1,4-naphthoquinone (OQ) were synthesized, and their anticancer activities were investigated. The anti-proliferation effects, determined by MTT assays, showed that BQ and OQ significantly inhibited the viability of gastric cancer cells and had no significant cytotoxic effect on normal cell lines. The apoptotic effect was determined by flow cytometry, and the results showed that BQ and OQ induced cell apoptosis by regulating the mitochondrial pathway and cell cycle arrest at the G2/M phase via inhibition of the Akt signaling pathway in AGS cells. Furthermore, BQ and OQ significantly increased the levels of reactive oxygen species (ROS) and this effect was blocked by the ROS scavenger NAC in AGS cells. BQ and OQ induced apoptosis by upregulating the protein expression of p38 and JNK and downregulating the levels of ERK and STAT3. Furthermore, expression levels of these proteins were also blocked after NAC treatment. These results demonstrated that BQ and OQ induced apoptosis and cell cycle arrest at the G2/M phase in AGS cells by stimulating ROS generation, which caused subsequent activation of MAPK, Akt and STAT3 signaling pathways. Thus, BQ and OQ may serve as potential therapeutic agents for the treatment of human gastric cancer. [ABSTRACT FROM AUTHOR]

The WHO has stated that antibiotic resistance is escalating to perilously high levels globally and that traditional therapies of antimicrobial drugs are futile against infections caused by resistant microorganisms. Novel antimicrobial drugs are therefore required. We report in this study on the inhibitory activity of the 1,4‐naphthoquinone‐2,3‐bis‐sulfides and 1,4‐naphthoquinone sulfides against two bacteria and a fungus to determine their antimicrobial properties. The 1,4‐naphthoquinone sulfides have potent activity with a minimum inhibitory concentration (MIC) of 7.8 μg/mL against Staphylococcus aureus (Gram +ve), an MIC of 23.4 μg/mL against the fungus, Candida albicans, which was better than that of Amphotericin B (MIC = 31.3 μg/mL), and against Escherichia coli (Gram −ve) an MIC of 31.3 μg/mL was obtained. The 1,4‐naphthoquinone had an MIC of 11.7 μg/mL against S. aureus and the 1,4‐naphthohydroquinone also had the same activity against E. coli. Hit, Lead & Candidate Discovery [ABSTRACT FROM AUTHOR]

1,4-Naphthoquinone compounds are a class of organic compounds derived from naphthalene. They exert a wide variety of biological effects, but when used as anticancer drugs, have varying levels of side effects. In the present study, in order to reduce toxicity and improve the antitumor activity, we synthesized two novel 1,4-naphthoquinone derivatives, 2-(butane-1-sulfinyl)-1,4-naphthoquinone (BSQ) and 2-(octane-1-sulfinyl)-1,4-naphthoquinone (OSQ). We investigated the antitumor effects of BSQ and OSQ in human lung cancer cells and the underlying molecular mechanisms of these effects, focusing on the relationship between these compounds and reactive oxygen species (ROS) production. MTT assay and trypan blue exclusion assay results showed that BSQ and OSQ had significant cytotoxic effects in human lung cancer cells. Flow cytometry results indicated that the number of apoptotic cells and the intracellular ROS levels significantly increased after treatment with BSQ and OSQ. However, cell apoptosis was inhibited by pretreatment with the ROS scavenger N-acetyl- l -cysteine (NAC). Western blotting results showed that BSQ and OSQ increased the expression levels of p-p38 kinase and p-c-Jun N-terminal kinase (p-JNK), and decreased the expression levels of p-extracellular signal-regulated kinase (p-ERK), p-protein kinase B (p-Akt), and p-signal transducer and activator of transcription-3 (p-STAT3). These phenomena were blocked by mitogen-activated protein kinase (MAPK) inhibitors, Akt inhibitors and NAC. In conclusion, BSQ and OSQ induce human lung cancer A549 cell apoptosis by ROS-mediated MAPKs, Akt, and STAT3 signaling pathways. Therefore, BSQ and OSQ may be therapeutic potential agents for the treatment of human lung cancer. • To reduce its side effects and improve its antitumor ability, we synthesized two 1,4-naphthoquinone derivatives: BSQ and OSQ. • The derivatives showed potent activity in suppressing human lung cancer cell viability. • They also induced apoptosis by a ROS and MAPK/Akt/STAT3-dependent mechanism. • Based on our findings, BSQ and OSQ may be potential anticancer drugs for human lung cancer therapy. [ABSTRACT FROM AUTHOR]

Derivatives of 1,4-naphthoquinone have excellent anti-cancer effects, but their use has been greatly limited due to their serious side effects. To develop compounds with decreased side effects and improved anti-cancer activity, two novel types of 1,4-naphthoquinone derivatives, 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ) were synthesized and their anti-tumor activities were investigated. The effects of EPDMNQ and ENDMNQ on cell viability, apoptosis and accumulation of reactive oxygen species (ROS) in liver cancer cells were determined by MTT cell viability assay and flow cytometry. The expression levels of mitochondrial, mitogen activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathway-associated proteins in Hep3B liver cancer cells were analyzed by western blot analysis. The results demonstrated that EPDMNQ and ENDMNQ inhibited the proliferation of liver cancer Hep3B, HepG2, and Huh7 cell lines but not that of normal liver L-02, normal lung IMR-90 and stomach GES-1 cell lines. The number of apoptotic cells and ROS levels were significantly increased following treatment with EPDMNQ and ENDMNQ, and these effects were blocked by the ROS inhibitor N-acetyl-L-cysteine (NAC) in Hep3B cells. EPDMNQ and ENDMNQ induced apoptosis by upregulating the protein expression of p38 MAPK and c-Jun N-terminal kinase and downregulating extracellular signal-regulated kinase and STAT3; these effects were inhibited by NAC. The results of the present study demonstrated that EPDMNQ and ENDMNQ induced apoptosis through ROS-modulated MAPK and STAT3 signaling pathways in Hep3B cells. Therefore, these novel 1,4-naphthoquinone derivatives may be useful as anticancer agents for the treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Abstract 1,4-Naphthoquinone derivatives have been widely documented with regard to their biological properties, and particularly their anticancer activities. In the 9,10-anthraquinone family, aza-annulation involving one of the carbonyl oxygen atoms has afforded more potent, possibly less toxic analogues. We recently carried out different modifications on the naphthoquinone skeleton to generate 3-chloro-2-amino- and 3-chloro-2-(N -acetamido)-1,4-naphthoquinone and 3,4-dihydrobenzo[ f ]quinoxalin-6(2 H)-one derivatives. These three series of compounds were now tested against normal human fibroblasts and six human cancer cell lines. Some of the dihydrobenzoquinoxalinone derivatives were not only more potent than their 1,4-naphthoquinone counterparts, but also exhibited 10- to 14-fold selectivity between bladder carcinoma and normal cells and were equipotent with the non-selective reference drug used (etoposide). The fusion of an additional azaheterocycle to the 1,4-naphthoquinone nucleus modulates both the activity, selectivity and mechanism of action of the compounds. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with cytotoxic activity and mechanism of action. Finally, 3D-QSAR CoMFA and CoMSIA models were built on the AGS, J82, and HL-60 cell lines. The best models had values of r2 pred = 0.815; 0.823 and 0.925. The main structural relationships found, suggest that acetylation and alkylation of the amino group with large groups would be beneficial for cytotoxic activity. Highlights • Annulation of the naphthoquinone leads to increased antiproliferative potency. • Hetero-annulation of naphthoquinone modulates the activity and mechanism of action. • Qsar analysis of antiproliferative activities shows the main structural relationships found. [ABSTRACT FROM AUTHOR]

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.

1,4-Naphthoquinone and its derivatives have shown some efficacy as therapeutic compounds for cancer and inflammation, though their clinical application is limited by their side-effects. To reduce the toxicity of these compounds and optimize their effects, we synthesized two 1,4-naphthoquinone derivatives—2-butylsulfinyl- 1,4-naphthoquinone (BSNQ) and 2-octylsulfinyl-1,4-naphthoquinone (OSNQ)—and investigated their effects and underlying mechanisms in hepatocellular carcinoma cells. BSNQ and OSNQ decreased cell viability and significantly induced apoptosis, accompanied by the accumulation of reactive oxygen species (ROS). However, pretreatment with N -acetyl- l -cysteine, a specific ROS scavenger, blocked apoptosis. Western blot results indicated that BSNQ and OSNQ up-regulated the phosphorylation of p38 and JNK, and down-regulated the phosphorylation of ERK, Akt and STAT3, and that these effects were blocked by N-acetyl- l -cysteine. Furthermore, BSNQ and OSNQ suppressed tumor growth and modulated MAPK and STAT3 signaling in mouse xenografts without detectable effects on body weight or hematological parameters. These results indicate that BSNQ and OSNQ induce apoptosis in human hepatoma Hep3B cells via ROS-mediated p38/MAPK, Akt and STAT3 signaling pathways, suggesting that these 1,4-naphthoquinone derivatives may provide promising new anticancer agents to treat HCC. [ABSTRACT FROM AUTHOR]

Two novel 1,4-naphthoquinone derivatives containing salicylic acid and procaine moieties were synthesized and evaluated for their anticancer activity in vitro. The antiproliferative effect was assayed against MDA-MB-231 cells, a human breast adenocarcinoma cell line, using CellTiter-Glo® Luminescent Cell Viability Assay. Both compounds tested proved a growth inhibition effect on this cell line in a dose-dependent manner. Our results showed that the compound with procaine effectively reduces breast cancer MDA-MB-231 cells viability and proliferation at higher concentration while that with salicylic acid had an inhibitory effect at lower concentrations and might be tested as an anticancer agent. [ABSTRACT FROM AUTHOR]

Several synthetic and natural naphthoquinone derivatives have been associated with antifungal activity. Candida albicans is a fungus that is known to exist in the normal human flora, but under certain conditions it can cause mild to fatal infections. Its pathogenicity has been associated with fungus conversion from cellular yeast to filamentous form Y- M. Inhibition of this process by several anilino-, dianilino-, phenoxy-, and diphenoxy-1,4-naphthoquinones was investigated in order to find some correlation between structure, redox properties and biological activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A series of 2-substituted amino-3-chloro-1,4-naphthoquinone derivatives (3-12) were synthesized as anticancer agents and tested against four cancer cell lines including HepG2, HuCCA-1, A549 and MOLT-3. The most potent cytotoxic activity against the HepG2, HuCCA-1 and A549 cell lines was found to be m-acetylphenylamino-1,4-naphthoquinone (8) affording IC50 values of 4.758, 2.364 and 12.279 µM, respectively. On the other hand, p-acetylphenylamino-1,4-naphthoquinone (9) exhibited the most potent cytotoxic activity against the MOLT-3 cell line with an IC50 of 2.118 µM. Quantitative structure-activity relationship (QSAR) investigations provided good predictive performance as observed from cross-validated R of 0.9177-0.9753 and RMSE of 0.0614-0.1881. The effects of substituents at the 2-amino position on the naphthoquinone core structure and its corresponding influence on the cytotoxic activity were investigated by virtually constructing additional 1,4-naphthoquinone compounds (13-36) for which cytotoxic activities were predicted using equations obtained from the previously constructed QSAR models. Interpretation of informative descriptors from QSAR models revealed pertinent knowledge on physicochemical properties governing the cytotoxic activities of tested cancer cell lines. It is anticipated that the QSAR models developed herein could provide guidelines for further development of novel and potent anticancer agents. [ABSTRACT FROM AUTHOR]

The structures of sulphur atom tethered quinone containing flexible carboxylic acid (3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylsulfanyl)acetic acid ( 1) and its molecular complex with 4,4′-bipyridine ( 3) are determined. The compound 1 crystallizes in P-1 (triclinic, a = 7.5378(6) Å, b = 7.6413(7) Å, c = 10.3101(9) Å; α = 89.779 (7)°, β = 81.042 (5)°, γ = 89.101(7)°) and the molecular complex 3 crystallises in P2(1)/ n (monoclinic, a = 9.3383(7) Å, b = 3.970(3) Å, c = 42.130(3) Å, β = 91.056(5)°) space groups, respectively. The R(8) type hydrogen bonding between dicarboxylic acid groups present in the parent compound 1 is lost on interaction with 4, 4′-bipyridine; in the molecular complex 3 R(7) type of O···H-C and O-H···N interactions are present between the pyridine rings and carboxylic acid groups. The molecular complex ( 4) derived from 3-carboxymethylsulfanyl-1,4-dihydroxynaphthalen-2-yl-sulfanyl) acetic acid ( 2) with triphenylphosphine oxide in 1:2 ratio, crystallises in C2/c space group have monoclinic, a = 26.0494(13) Å, b = 10.5402(5) Å, c = 17.1023(8) Å, β = 108.719 (5)°). The triphenylphosphine oxide molecules are preferentially held by O-H···O interactions between carboxylic acid and P=O bond. Graphical Abstract: The structures of (3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-ylsulfanyl) acetic acid , its molecular complex with 4,4′-bipyridine and molecular complex of 3-carboxymethylsulfanyl-1,4-dihydroxy naphthalen-2-yl-sulfanyl)acetic acid with triphenylphosphine oxide are presented[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Mono- and disubstituted [(tetrahydro-2,4-dioxopyrimidin-1(2 H)-yl)phenoxy]naphthalene-1,4-diones were synthesized by the reaction of dihydro-1-(3-hydroxy- and 4-hydroxyphenyl)pyrimidine-2,4(1 H,3 H)-diones and their 5- and 6-methyl derivatives with 2,3-dichloro-1,4-naphthoquinone. Their stability in alkaline and acidic media was investigated. Four of the compounds exhibited good antimicrobial activity against Staphylococcus aureus, Mycobacterium luteum, Candida tenuis, and Aspergillus niger. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Three naphthoquinone derivatives (plumbagin, juglone, and menadione) have been reported with antibacterial, antifungal, and antiviral properties and could potentially be used as anticancer agents because they can provoke apoptosis. However, they are also strong oxidants and cause cytotoxicity and even necrosis, so they are only limited to experimental chemotherapeutic use. In order to understand their physical chemical properties, we used both Fourier Transform Infrared Spectroscopy (FTIR) and Terahertz Time-Domain Spectroscopy (THz-TDS) to study their absorption spectra in wave number ranges of 400∼4000 cm-1 and 6.6 ∼ 92.4 cm-1. We also analyzed their characteristic absorption peaks, and assigned spectra peaks in IR range to their molecular structures. These data will be very useful in future studies of their pharmaceutical mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Selective carbon–sulphur bond cleavage reaction of (3-mercapto-1,4-dioxo-1,4-dihydro-naphthalen-2-ylsulfanyl) acetic acid by copper(II) nitrate tetrahydrate at room temperature to form copper(II) complex of 2-(1,4-dihydro-2-hydroxy-1,4-dioxonaphthalen-3-ylthio) acetic acid is described. [Copyright &y& Elsevier]

Abstract: 1,4-Naphthoquinone derivatives (NQD) containing lipophilic alkyl chains, i.e. 2-((Z)-heptadec-8-enyl)-3-methyl 1,4-naphthoquinone (QMe), 2-((Z)-heptadec-8-enyl)-3-hydroxy-1,4-naphthoquinone (QOH) and (Z)-octadec-9-enyl 1,4-naphthoquinone-2-carboxylate (QE) were synthesized. The redox behavior of these NQD was studied in ethanol and entrapped in the reversed bicontinuous cubic phase of space group type Pn3m (Q224) of aqueous monoolein. In ethanol, cyclic voltammetry curves exhibit two pairs of oxidation–reduction peaks arising from the redox processes controlled by adsorption and molecular diffusion. The NQD molecules are also electrochemically active in the cubic phase, indicating the participation in the 2e−, 2H+-redox cycle at pH<9. Therefore, it was concluded that the head group of the entrapped NQD reaches the lipid bilayer interface of cubic phase during the process. [Copyright &y& Elsevier]

Abstract: A series of 2-chloro-3-arylsulfanyl-[1,4]naphthoquinones (2), 2,3-bis-arylsulfanyl-[1,4]naphthoquinones (3) and 12H-benzo[b]phenothiazine-6,11-diones and their analogs 6–8 were synthesized and evaluated for their antiproliferative activity against human cervical cancer (HeLa) cells. Compounds 3a and 3b were found to possess most potent antiproliferative and cell killing ability. Compounds 1–8 were also evaluated for antifungal activities. The structure–activity relationship of these compounds was studied and the results show that compound 2a (MIC50 =1.56μg/mL) exhibited in vitro potent antifungal activity compared to the clinically useful antifungal drug Fluconazole (MIC50 =2.0μg/mL) against Sporothrix. schenckii. Compound 2a (MIC50 =1.56μg/mL) also exhibited same antifungal activity compared to clinically useful drug Amphotericin-B (MIC50 =1.56μg/mL) against Trichophyton. mentagraphytes. [Copyright &y& Elsevier]

Abstract: A series of (S)-N-(3-chloro-1,4-naphthoquinon-2-yl)-α-amino acid ethyl esters 3 and 1,2,3-trisubstituted-1,4-dihydrobenzo[g]quinoxaline-5,10-diones 6–23 were synthesized and evaluated for antifungal and antibacterial activities. The structure–activity relationship of these compounds was studied and the results show that the compounds 3a and 3b exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii whereas compounds 12 and 22 showed in vitro antibacterial activity against Klebsiella pneumoniae and Escherichia coli. [Copyright &y& Elsevier]

A family of vitamins K (VK), 2-methyl-l,4-naphthoquinone derivatives, especially VK3, have been reported to inhibit the growth of various tumor cell lines. Analysis of cell growth inhibition by novel 1,4-naphthoquinone (NQ) derivatives in the present study was undertaken with two purposes. The first one was to sample new biologically active antitumor compounds, the second being to study the mechanism of cell growth inhibition and death induction by NQ derivatives. Retardation of cell proliferation and cytotoxic activity of synthesized by us five 1,4-naphthoquinones 1-5 containing 2-aminoalkyl moiety with terminal bromo (1, 2), chloro (4), hydroxyl (3) and mercapto (5) groups were examined in the model murine hepatoma cell line MH-22A. Our study showed that four NQ compounds, 1-4, induced both apoptotic and necrotic cell death. The frequency of apoptosis was largely parallel to the potency of growth inhibition. According to our data, the most effective were compounds 2-(2-hydroxyethylamino)-l,4-naphthoquinone (3) and 2-(2-bromoethylamino)-1,4-naphthoquinone (1). Derivative 3 appeared to be particularly active; its antiproliferative activity was about 40% higher than of VK3. In addition, the findings suggest that compound 3, as well as 1, in our study induced overexpression of the c-jun gene, which has been reported to be associated with apoptosis. Meanwhile, transfected MH-22A cells where the c-Jun level was blocked were much more resistant to the treatment with the NQ derivatives 1 and 3. In summary, the novel 1,4-naphthoquinones 1 and 3 containing 2-amino-ethyl functions with terminal bromo (1) and hydroxyl (3) groups exhibited structural requirements for murine hepatoma cell growth inhibitory and cell killing activities. The effects may be related with the induction of c-jun expression. [ABSTRACT FROM AUTHOR]

Abstract: The growth-inhibiting activity of Tabebuia impetiginosa Martius ex DC dried inner bark-derived constituents against Helicobacter pylori ATCC 43504 was examined using paper disc diffusion and minimum inhibitory concentration (MIC) bioassays. The activity of the isolated compounds was compared to that of the commercially available anti-Helicobacter pylori agents, amoxicillin, metronidazole, and tetracycline. The biologically active components of Tabebuia impetiginosa dried inner bark (taheebo) were characterized by spectroscopic analysis as 2-(hydroxymethyl)anthraquinone, anthraquinone-2-carboxylic acid, and 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol). With the paper disc diffusion assay 2-(hydroxymethyl)anthraquinone exhibited strong activity against Helicobacter pylori ATCC 43504 at 0.01mg/disc. Anthraquinone-2-carboxylic acid, lapachol and metronidazole were less effective, exhibiting moderate anti-Helicobacter pylori activity at 0.1mg/disc. Amoxicillin and tetracycline were the most potent compounds tested, displaying very strong activity at 0.005mg/disc. 2-(Hydroxymethyl)anthraquinone exhibited moderate activity at this dose. Tetracycline still had strong activity at 0.001mg/disc while amoxicillin had little activity at this dose. In the MIC bioassay, 2-(hydroxymethyl)anthraquinone (2μg/mL), anthraquinone-2-carboxylic acid (8μg/mL), and lapachol (4μg/mL) were more active than metronidazole (32μg/mL) but less effective than amoxicillin (0.063μg/mL) and tetracycline (0.5μg/mL). The anti-Helicobacter pylori activity of seven 1,4-naphthoquinone derivatives (structurally related to lapachol), 1,4-naphthoquinone, 5,8-dihydroxy-1,4-naphthoquinone (naphthazarin), 2-methyl-1,4-naphthoquinone (menadione), 2-hydroxy-1,4-naphthoquinone (lawsone), 5-hydroxy-2-methyl-1,4-naphthoquinone (plumbagin), 5-hydroxy-1,4-naphthoquinone (juglone), and 2,3-dichloro-1,4-naphthoquinone (dichlone) was also evaluated using the paper disc assay. Menadione and plumbagin were the most potent compounds tested with the later still exhibiting very strong activity at 0.001mg/disc. Menadione, juglone and tetracycline had strong activity at this low dose while the latter two compounds and amoxicillin had very strong activity at 0.005mg/disc. Lawsone was unusual in that it had very strong activity at 0.1 and 0.05mg/disc but weak activity at doses of 0.01mg/disc and lower. Naphthazalin, lapachol and dichlone had similar activities while metronidazole had the lowest activity of all compounds tested. These results may be an indication of at least one of the pharmacological actions of taheebo. The Tabebuia impetiginosa dried inner bark-derived materials, particularly 2-(hydroxymethyl)anthraquinone, merit further study as potential Helicobacter pylori eradicating agents or lead compounds. [Copyright &y& Elsevier]

Substitution is well-known to modulate the physico-chemical properties of molecules. In this study, a combined, multifactor approach was employed to determine a plethora of substitution patterns using –Br and –O-H in 1,4-naphthoquinone and its derivatives. On the basis of classical Density Functional Theory (DFT), 25 models divided into three groups were developed. The first group contains 1,4-naphthoquinone and its derivatives substituted only by –Br. The second group consists of compounds substituted by –Br and one –O-H group. As a result of the substitution, an intramolecular hydrogen bond was formed. The third group also contains –Br as a substituent, but two –O-H groups were introduced and two intramolecular hydrogen bonds were established. The simulations were performed at the ω B97XD/6-311++G(2d,2p) level of theory. The presence of substituents influenced the electronic structure of the parent compound and its derivatives by inductive effects, but it also affected the geometry of the 2 and 3 groups, due to the intramolecular hydrogen bonding and the formation of a quasi-ring/rings. The static DFT models were applied to investigate the aromaticity changes in the fused rings based on the Harmonic Oscillator Model of Aromaticity (HOMA). The OH stretching was detected for the compounds from groups 2 and 3 and further used to find correlations with energetic parameters. The evolution of the electronic structure was analyzed using Hirshfeld atomic charges and the Substituent Active Region (cSAR) parameter. The proton reaction path was investigated to provide information on the modulation of hydrogen bridge properties by diverse substitution positions on the donor and acceptor sides. Subsequently, Car–Parrinello Molecular Dynamics (CPMD) was carried out in the double-bridged systems (group 3) to assess the cooperative effects in double –O-H-substituted systems. It was determined that the –O-H influence on the core of the molecule is more significant than that of –Br, but the latter has a major impact on the bridge dynamics. The competitive or synergic effect of two –Br substituents was found to depend on the coupling between the intramolecular hydrogen bridges. Thus, the novel mechanism of a secondary (cooperative) substituent effect was established in the double-bridged systems via DFT and CPMD results comparison, consisting of a mediation of the bromine substitutions' influence by the cooperative proton transfer events in the hydrogen bridges. [ABSTRACT FROM AUTHOR]

The rate of the GSH conjugate formation, the inhibition of DNA topoisomerasel-1 and the cytotoxic activity against L1210 cells of the naphthoquinones showed the same order; 5,8-dimethoxy-1,4-naphthoquinone (DMNQ)>6-(1-hydroxyethyl)-DMNQ>2-(1-hydroxyethyl)-DMNQ; the steric hindrance of the substituents, particularly 2-substutuent, in reacting with cellular nucleophiles must be the main cause for lowering the bioactivities. Acetylation of 2-(1-hydroxyethyl)-DMNQ producing 2-(acetyloxyethyl)-DMNQ potentiated the bioactivities; 2-(1-hydroxyethyl)-DMNQ did not react with GSH and the enzyme, and showed ED50 of 0.680 μg/ml, whereas the values of 2-(1-acetyloxyethyl)-DMNQ were the conjugate formation of 0.14 μM, IC50 value of 81 μM for the enzyme inhibition and ED50 of 0.146 μg/ml for the cytotoxcity. Furthermore, the acetylation 2-(1-hydroxyethyl)-DMNQ (T/C, 119%) enhaced the T/C values for the mice bearing S-180 tumor [T/C of 2-(1-acetyloxyethyl)-DMNQ, 276%]. It was assumed that the difference in bioactivities ensued by acetylation was based on the mechanism of the so-called bioreductive alkylation. [ABSTRACT FROM AUTHOR]