Exploring the Antibacterial and Antiparasitic Activity of Phenylaminonaphthoquinones-Green Synthesis, Biological Evaluation and Computational Study.

Organic compounds with antibacterial and antiparasitic properties are gaining significance for biomedical applications. This study focuses on the solvent-free synthesis (green synthesis) of 1,4-naphthoquinone or 2,3-dichloro-1,4-naphthoquinone with different phenylamines using silica gel as an acid solid support. The study also includes in silico PASS predictions and the discovery of antibacterial and antiparasitic properties of phenylaminonaphthoquinone derivatives 1-12, which can be further applied in drug discovery and development. These activities were discussed in terms of molecular descriptors such as hydrophobicity, molar refractivity, and half-wave potentials. The in vitro antimicrobial potential of the synthesized compounds 1-12 was evaluated against a panel of six bacterial strains (three Gram-positive: Staphylococcus aureus, Proteus mirabilis, and Enterococcus faecalis; and three Gram-negative bacteria: Escherichia coli, Salmonella typhimurium, and Klebsiella pneumoniae). Six compounds (1, 3, 5, 7, 10, and 11) showed better activity toward S. aureus with MIC values between 3.2 and 5.7 µg/mL compared to cefazolin (MIC = 4.2 µg/mL) and cefotaxime (MIC = 8.9 µg/mL), two cephalosporin antibiotics. Regarding in vitro antiplasmodial activity, compounds 1 and 3 were the most active against the Plasmodium falciparum strain 3D7 (chloroquine-sensitive), displaying IC50 values of 0.16 and 0.0049 µg/mL, respectively, compared to chloroquine (0.33 µg/mL). In strain FCR-3 (chloroquine-resistant), most of the compounds showed good activity, with compounds 3 (0.12 µg/mL) and 11 (0.55 µg/mL) being particularly noteworthy. Additionally, docking studies were used to better rationalize the action and prediction of the binding modes of these compounds. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed.

Design, synthesis and biological evaluation of marine naphthoquinone-naphthol derivatives as potential anticancer agents.

1'-Hydroxy-4',8,8'-trimethoxy-[2,2'-binaphthalene]-1,4-dione (compound 5), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regarding the anticancer activities and biological mechanisms of its derivatives remains limited. Herein, a series of novel naphthoquinone-naphthol derivatives were designed, synthesised, and evaluated for their anticancer activity against cancer cells of different origins. Among these, Compound 13, featuring an oxopropyl group at the ortho-position of quinone group, exhibited the most potent inhibitory effects on HCT116, PC9, and A549 cells, with IC50 values decreasing from 5.27 to 1.18 µM (4.5-fold increase), 6.98 to 0.57 µM (12-fold increase), and 5.88 to 2.25 µM (2.6-fold increase), respectively, compared to compound 5. Further mechanistic studies revealed that compound 13 significantly induced cell apoptosis by increasing the expression levels of cleaved caspase-3 and reducing Bcl-2 proteins through downregulating the EGFR/PI3K/Akt signalling pathway, leading to the inhibition of proliferation in HCT116 and PC9 cells. The present findings suggest this novel naphthoquinone-naphthol derivative may hold potential as an anticancer therapeutic lead.

Natural Product-Inspired Discovery of Naphthoquinone-Furo-Piperidine Derivatives as Novel STAT3 Inhibitors for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and STAT3 has emerged as an effective drug target for TNBC treatment. Herein, we employed a scaffold-hopping strategy of natural products to develop a series of naphthoquinone-furopiperidine derivatives as novel STAT3 inhibitors. The in vitro assay showed that compound 10g possessed higher antiproliferative activity than Cryptotanshinone and Napabucasin against TNBC cell lines, along with lower toxicity and potent antitumor activity in a TNBC xenograft model. Mechanistically, 10g could inhibit the phosphorylation of STAT3 and the binding affinity was determined by the SPR assay (KD = 8.30 µM). Molecule docking studies suggested a plausible binding mode between 10g and the SH2 domain, in which the piperidine fragment and the terminal hydroxy group of 10g played an important role in demonstrating the success of this evolution strategy. These findings provide a natural product-inspired novel STAT3 inhibitor for TNBC treatment.

1H-1,2,3-triazol-1,4-naphthoquinone Derivatives: Novel Inhibitors Targeting Pyocyanin Biosynthesis for P. Aeruginosa Infection Treatment Advances.

BACKGROUND: This study investigates the potential of eleven 1H-1,2,3-triazol-1,4-naphthoquinone conjugates as virulence factor inhibitors (like Pyocyanin) and their affinity for PhzM, a crucial enzyme for Pyocyanin biosynthesis in Pseudomonas aeruginosa infections. METHODS: A straightforward synthetic pathway enabled the production of these compounds, which were characterized and structurally confirmed through spectroscopic analyses. Evaluation of their impact on PhzM thermal stability identified promising candidates for PhzM binders. RESULTS: Concentration-response behavior elucidated their binding affinity, revealing them as the first reported micromolar affinity ligands for PhzM. Structure-activity relationship analysis emphasized the role of specific molecular moieties in binding affinity modulation, paving the way for future advanced inhibitors' development. CONCLUSION: These findings highlight the potential of naphthoquinone-triazole derivatives as leads for novel therapeutics against P. aeruginosa infections.

Total syntheses of borolithochromes H1, H2, I1, and I2.

Total syntheses of borolithochromes H1, H2, I1, and I2, the red pigments isolated from fossils of Jurassic putative red alga Solenopora jurassica, have been achieved. The naphthoquinone possessing a chiral sec-butyl side chain has been synthesized from (S)-2-methylbutanol. The Diels-Alder reaction of the chiral naphthoquinone and the previously reported diene was followed by one pot S-methylation/intramolecular Corey-Chaykovsky reaction/epoxide rearrangement to provide the benzo[gh]tetraphene skeleton. Complexation of the resulting ligand with trimethyl borate and the following O-demethylation furnished a 1:1 mixture of borolithochromes I1 and I2, which were separated by HPLC using CHIRALPAK IC® to afford optically pure borolithochromes I1 (6) and I2 (7). On the other hand, borolithochromes H1 and H2 were not separated by HPLC in our laboratory. Fortunately, the mixture of the methyl ethers of borolithochromes H1 and H2 were separated and O-demethylation with magnesium iodide furnished optically pure borolithochromes H1 (4) and H2 (5).

Synthesis of amino juglone derivatives with adjuvant activity against clinical isolated methicillin-resistant staphylococcus aureus strains.

1,4-naphthoquinones hydroxyderivatives belong to an important class of natural products and have been known as a favored scaffold in medicinal chemistry due to their multiple biological properties. Juglone is one of the most important 1,4-naphthoquinone extracted from juglandaceae family showing a good antibacterial activity. In this study, we report the synthesis of aminojuglone derivatives through Michael addition reaction using Cerium (III) chloride heptahydrate (CeCl3·7H2O) as catalyst. The synthesized aminojuglone derivatives were evaluated for their antibacterial properties against sensitive, clinical resistant Gram-positive and Gram-negative bacterial strains. Compound 3c showed a good antibacterial activity similar to cloxacillin (2 µg/mL) against the clinically resistant S.aureus. The antibiotic adjuvant activity of compounds was evaluated in combination with three clinically use antibiotics. The combination of compounds 3a, 3b, 3e, 3 h-3 l, 3n and 3o with cloxacillin showed remarkable adjuvant activity against clinically resistant S. aureus (66-fold potentiation of cloxacillin activity). 3e is the only compound consistent with the concept of antibiotic adjuvant, presenting insufficient antibacterial activity (MIC > 128 µg/mL) and potentiate the activity of cloxacillin (66-fold) with synergistic effect. A structural characterization of 3e was carried out for the first time using X-ray diffraction technic. Moreover, compound 3e did not show a cytotoxic activity on sheep red blood cells.

Synthesis and biological evaluation of novel isoxazoloquinone derivatives as potent STAT3-targeting antipsoriasis agents.

Psoriasis is a troublesome scaling skin disease with no high-effective medication available by far. Signal transducer and activator of transcription 3 (STAT3) has recently been revealed as a crucial player in the pathogenesis and progression of psoriasis and emerged as an intriguing antipsoriatic drug target. Naturally occurring lapachol and its quinone analogs had been discovered as effective STAT3 inhibitors, however, their antipsoriatic effects are not well investigated. Previously, we have reported a series of isothiazoloquinone lapachol derivatives. Here, the antipsoriastic potentials of these isothiazoloquinones were investigated and, in addition, 35 novel isoxazoloquinone derivatives were prepared and studied for their anti-psoriasis properties. Among them, the most potent antipsoriatic compound B20 determined by in vitro test on HaCaT cells could directly bind to STAT3, reduce STAT3 level and inhibit STAT3 nuclear translocation. In vivo studies showed that topical application of B20 could effectively alleviate IMQ-induced psoriasis in mice with no obvious side effects. In addition, B20 inhibited the production of interleukin 17 (IL-17A), a STAT3-downstream cytokine essential for the progression of psoriasis, both in vitro and in vivo. Thus, isoxazoloquinone B20 is a potent STAT3-targeting antipsoriatic agent worth of further investigation.

Design, synthesis and biological evaluation of novel naphthoquinothiazole derivatives as potent antitumor agents through inhibiting STAT3.

The signal transducer and activator of transcription 3 (STAT3) has been established as a crucial drug target in the development of antitumor agents. In this study, a series of 21 derivatives of the STAT3 inhibitor napabucasin were designed and synthesized. Through preliminary screening against tumor cell lines, SZ6 emerged as the most potent compound with half maximal inhibitory concentration (IC50) values of 46.3 nM, 66.4 nM, and 53.8 nM against HCT116, HepG2, and Hela cells respectively. Furthermore, SZ6 effectively suppressed tumor invasion and migration in HCT116 cell assays by inducing S-phase arrest and apoptosis through inhibition of Protein Kinase B (PKB/AKT) activity and induction of reactive oxygen species (ROS). The mechanism underlying SZ6's action involves inhibition of STAT3 phosphorylation, which was confirmed by western blotting analysis. Additionally, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) demonstrated direct binding between SZ6 and STAT3. Notably, in vivo studies revealed that SZ6 significantly inhibited tumor growth without any observed organ toxicity. Collectively, these findings identify SZ6 as a promising STAT3 inhibitor for colorectal cancer treatment.

Synthesis and biochemical characterization of naphthoquinone derivatives targeting bacterial histidine kinases.

Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized. These compounds were tested for their inhibitory activity (IC50) against WalK, an essential HK for Bacillus subtilis growth, and their minimum inhibitory concentrations (MIC) against B. subtilis. As a result, 11 novel HK inhibitors were obtained as naphthoquinone derivatives (IC50: 12.6-305 µM, MIC: 0.5-128 µg ml-1). The effect of representative compounds on the expression of WalK/WalR regulated genes in B. subtilis was investigated. Four naphthoquinone derivatives induced the expression of iseA (formerly yoeB), whose expression is negatively regulated by the WalK/WalR system. This suggests that these compounds inhibit WalK in B. subtilis cells, resulting in antibacterial activity. Affinity selection/mass spectrometry analysis was performed to identify whether these naphthoquinone derivatives interact with WalK in a manner similar to waldiomycin. Three compounds were found to competitively inhibit the binding of waldiomycin to WalK, suggesting that they bind to the H-box region conserved in HKs and inhibit HK activity.

Design, synthesis and identification of novel molecular hybrids based on naphthoquinone aromatic hydrazides as potential trypanocide and leishmanicidal agents.

In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.

Anilino-1,4-naphthoquinones as potent mushroom tyrosinase inhibitors: in vitro and in silico studies.

Tyrosinase, a pivotal enzyme in melanin synthesis, is a primary target for the development of depigmenting agents. In this work, in vitro and in silico techniques were employed to identify novel tyrosinase inhibitors from a set of 12 anilino-1,4-naphthoquinone derivatives. Results from the mushroom tyrosinase activity assay indicated that, among the 12 derivatives, three compounds (1, 5, and 10) demonstrated the most significant inhibitory activity against mushroom tyrosinase, surpassing the effectiveness of the kojic acid. Molecular docking revealed that all studied derivatives interacted with copper ions and amino acid residues at the enzyme active site. Molecular dynamics simulations provided insights into the stability of enzyme-inhibitor complexes, in which compounds 1, 5, and particularly 10 displayed greater stability, atomic contacts, and structural compactness than kojic acid. Drug likeness prediction further strengthens the potential of anilino-1,4-naphthoquinones as promising candidates for the development of novel tyrosinase inhibitors for the treatment of hyperpigmentation disorders.

Improved synthesis, molecular modeling and anti-inflammatory activity of new fluorinated dihydrofurano-naphthoquinone compounds.

A series of new fluorinated dihydrofurano-napthoquinone compounds were sucessfully synthesized in good yields using microwave-assisted multi-component reactions of 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, and pyridinium bromide. The products were fully characterized using spectroscopic techniques and evaluated for their anti-inflammatory activity using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Among 12 new compounds, compounds 8b, 8d, and 8e showed high potent NO inhibitory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC50 values ranging from 1.54 to 3.92 µM. The levels of pro-inflammatory cytokines IL-1ß and IL-6 in LPS-stimulated RAW264.7 macrophages were remarkably decreased after the application of 8b, 8d, 8e and 8k. Molecular docking simulations revealed structure-activity relationships of 8b, 8d, and 8e toward NO synthase, cyclooxygenase (COX-2 over COX-1), and prostaglandin E synthase-1 (mPGES-1). Further physicochemical and pharmacokinetic computations also demonstrated the drug-like characteristics of synthesized compounds. These findings demonstrated the importance of fluorinated dihydrofurano-napthoquinone moieties in the development of potential anti-inflammatory agents.

Shikonin N-benzyl matrinic acid ester derivatives as novel telomerase inhibitors with potent activity against lung cancer cell lines.

In this study, a series of novel shikonin N-benzyl matrinic acid ester derivatives (PMMB-299-PMMB-310) were synthesized and tested for their ability to inhibit the proliferation of cancer cells. Compared with shikonin and matrine, some of the ester derivatives were found to exhibit better anti-proliferative activity against seven different cancer cell lines, with less cytotoxicity toward non-cancerous cells. The strongest anti-proliferative activity was exhibited by PMMB-302, which had an IC50 value of 2.71 µM against A549 cells. The compound caused cell cycle arrest in the G2/M phase and induced apoptosis. Effects on the expression of apoptosis-related molecules such as Bcl2, Bcl-XL, caspase-3, caspase-9 and FADD suggested that PMMB-302 has tumor suppressive roles in lung cancer cells. In addition, PMMB-302 inhibited expression of telomerase core proteins, dyskerin and NHP2, and telomerase reverse transcriptase RNA. Moreover, molecular docking of PMMB-302 was subsequently conducted to determine the probable binding mode with telomerase. Taken together, the results indicate that PMMB-302 acts as a tumor suppressor in lung cancer cells by negatively regulating telomerase expression.

Synthetic enamine naphthoquinone derived from lawsone as cytotoxic agents assessed by in vitro and in silico evaluations.

We synthesized ten enamine naphthoquinones with yields ranging from 43 to 76%. These compounds were screened for their in vitro antiproliferative activities by MTT assay against four types of human cancer cell lines: HCT116, PC3, HL60 and SNB19. The naphthoquinones bearing the picolylamine (7) and quinoline (12) moieties were the most actives (IC50 < 24 µM for all the cell lines), which were comparable or better to the values obtained for the control drugs. In silico evaluations allowed us to develop a qualitative Structure-Activity Relationship which suggest that electrostatic features, particularly the C2-C3 internuclear repulsion and the molecular dipole moment, relate to the biological response. Furthermore, Molecular Docking simulations indicate that the synthetic compounds have the potential to act as anticancer molecules by inhibiting topoisomerase-II and thymidylate synthase.

Natural and Synthetic Naphthoquinones as Potential Anti-Infective Agents.

BACKGROUND: Naphthoquinones are a class of aromatic compounds relevant for their chemical characteristics, structural properties, and biological activity. These compounds are found in nature with a wide range of effects, highlighting their antibacterial, antifungal, and antiprotozoal properties. Additionally, naphthoquinones are used as a scaffold to obtain new derivatives with pharmacological potential, mainly compounds against parasitic diseases. OBJECTIVE: The purpose of this work was to carry out a comprehensive review of naphthoquinones and their derivatives obtained from both natural and synthetic sources, also, to analyze their biological activity against Leishmania spp. (Leishmaniasis), Trypanosoma cruzi (Chagas disease), Plasmodium falciparum (Malaria), Toxoplasma gondii (Toxoplasmosis), and Toxocara canis (Toxocariasis). All of these agents are responsible for relevant diseases worldwide. RESULTS: Natural naphthoquinones, such as plumbagin, diospyrin, burmanin, lapachol, lawsone and psychorubrin, show an antiprotozoal activity similar or enhanced antiprotozoal activity to reference drugs. Some naphthoquinones obtained by synthesis or semi-synthesis showed better biological activity or less toxic effects than natural compounds. CONCLUSION: In this review, natural and synthetic naphthoquinones showed antiparasitic activity, in most cases, with improved results than current drugs currently used in clinical trials. A modification of their structure with different functional groups can enhance their biological effects, improve solubility, and reduce undesirable side effects. Therefore, naphthoquinones are important molecules in the development of new chemotherapeutic agents against parasitic diseases.

Structure-Activity Relationship Studies of Antimicrobial Naphthoquinones Derived from Constituents of Tabebuia avellanedae.

In this study, based on our previous study, derivatives of naphtho[2,3-b]furan-4,9-diones were synthesized and their antimicrobial activities were evaluated. The screening of these naphthoquinones revealed that the fluorine-containing NQ008 compound exhibited potent and broad antimicrobial activities against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative bacteria, and fungi. The results of the ratio of the minimum bactericidal concentration (MBC) to the minimum inhibitory concentrations (MICs) and time-kill assays suggest that the mode of action of NQ008 is bactericidal. Additionally, the results of a drug resistance study revealed that NQ008 exhibited potent antibacterial activity and may delay the development of bacteria resistance. Furthermore, NQ008 exhibited preliminary antiviral activity against the swine influenza virus and Feline calicivirus.

Synthesis and comparison of in vitro dual anti-infective activities of novel naphthoquinone hybrids and atovaquone.

A principal factor that contributes towards the failure to eradicate leishmaniasis and tuberculosis infections is the reduced efficacy of existing chemotherapies, owing to a continuous increase in multidrug-resistant strains of the causative pathogens. This accentuates the dire need to develop new and effective drugs against both plights. A series of naphthoquinone-triazole hybrids was synthesized and evaluated in vitro against Leishmania (L.) and Mycobacterium tuberculosis (Mtb) strains. Their cytotoxicities were also evaluated, using the human embryonic kidney cell line (HEK-293). The hybrids were found to be non-toxic towards human cells and had demonstrated micromolar cellular antileishmanial and antimycobacterial potencies. Hybrid 13, i.e. 2-{[1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl]methoxy}naphthalene-1,4-dione was the most active of all. It was found with MIC90 0.5 µM potency against Mtb in a protein free medium, and with half-maxima inhibitory concentrations (IC50) of 0.81 µM and 1.48 µM against the infective promastigote parasites of L. donavani and L. major, respectively, with good selectivity towards these pathogens (SI 22 - 65). Comparatively, the clinical naphthoquinone, atovaquone, although less cytotoxic, was found to be two-fold less antimycobacterial potent, and six- to twelve-fold less active against leishmania. Hybrid 13 may therefore stand as a potential anti-infective hit for further development in the search for new antitubercular and antileishmanial drugs. Elucidation of its exact mechanism of action and molecular targets will constitute future endeavour.

Exploration of Benzo[b]carbazole-6,11-diones as anticancer agents: Synthesis and studies of hTopoIIα inhibition and apoptotic effects.

Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoIIα inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative CN and Pd-catalyzed CC bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoIIα inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- κß signaling cascade, relatively less cytotoxicity to normal cells, and hTopoIIα inhibition with more efficiency compared to an anticancer drug etoposide.

An Update on the Synthesis and Applications of Bis(Naphthoquinones): An Important Class of Molecules against Infectious Diseases and other Conditions.

Naphthoquinones are important molecules belonging to the general class of quinones, and many of these compounds have become drugs that are in the pharmaceutical market for the treatment of several diseases. A special subclass of compounds is that of the bis(naphthoquinones), which have two linked naphthoquinone units. In the last few years, several synthetic approaches toward such valuable compounds have been described, as well as their evaluation against numerous important biological targets. In this review, we provide a thorough discussion on the various synthetic methods reported for the synthesis of bis(naphthoquinone) analogues, also highlighting the biological activities of these substances.

Rational designed highly sensitive NQO1-activated near-infrared fluorescent probe combined with NQO1 substrates in vivo: An innovative strategy for NQO1-overexpressing cancer theranostics.

Since NQO1 is overexpressed in many cancer cells, it can be used as a biomarker for cancer diagnosis and targeted therapy. NQO1 substrates show potent anticancer activity through the redox cycle mediated by NQO1, while the NQO1 probes can monitor NQO1 levels in cancers. High sensitivity of probes is needed for diagnostic imaging in clinic. In this study, based on the analysis of NQO1 catalytic pocket, the naphthoquinone trigger group 13 rationally designed by expanding the aromatic plane of the benzoquinone trigger group 10 shows significantly increased sensitivity to NQO1. The sensitivity of the naphthoquinone trigger group-based probe A was eight times higher than that of benzoquinone trigger group-based probe B in vivo. Probe A was selectively and efficiently sensitive to NQO1 with good safety profile and plasma stability, enabling its combination with NQO1 substrates in vivo for NQO1-overexpressing cancer theranostics for the first time.