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ATP acts in the extracellular environment as an important signal, activating a family of receptors called purinergic receptors. In recent years, interest in the potential therapeutics of purinergic components, including agonists and antagonists of receptors, has increased. Currently, many observations have indicated that ATP acts as an important mediator of inflammatory responses and, when found in high concentrations in the extracellular space, is related to the activation of the P2X7 purinergic receptor. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Sulfonamide derivatives have been reported to be potent inhibitors of P2X receptors. In this study, ten naphthoquinone sulfonamide derivatives and five naphthoquinone sulfonate ester derivatives were tested for their inhibitory activity on the P2X7 receptor expressed in peritoneal macrophages. Some compounds showed promising results, displaying IC50 values lower than that of A740003. Molecular docking and dynamic studies also indicated that the active compounds bind to an allosteric site on P2X7R. The binding free energy indicates that sulfonamides have an affinity for the P2X7 receptor similar to A740003. Therefore, the compounds studied herein present potential P2X7R inhibition. [ABSTRACT FROM AUTHOR]

14 new naphthoquinones were prepared and tested against human cancer cell lines PC-3 (prostate), HCT-116 (colon carcinoma), SNB-19 (glioblastoma), HL-60 (leukemia) and MCF-7 (breast), and a nontumor cell line L929 (murine fibroblasts) to determine cytotoxicity with the MTT assay. 8-OH-β-lapachones (14a, 14c, 14d) presented best results, showing low IC50 values and high selectivity for HCT-116 and HL-60 tumor cells. [ABSTRACT FROM AUTHOR]

Four cobalt(iii)–TPA complexes with 2-hydroxy-3-X-1,4-naphthoquinones (HNQ-X), X = methyl (1), chlorine (2), bromine (3) and iodine (4), were designed and investigated as potential bioreductively activated carriers for naphthoquinone-based drugs. The substituents X were used in order to avoid dimerization of the naphthoquinone ligands and evaluate their effect on the Co3+/Co2+ potential. The expected [Co(TPA)(NQ-X)]2+ species was obtained for the NQ-CH3 ligand in 1, while the chlorine, bromine and iodine derivatives fostered the attachment of a methoxide to the C(1)carbonyl atom to produce complexes 2, 3 and 4, respectively. The structure and electronic properties of the complexes were investigated by single crystal X-ray diffraction analysis and DFT calculations. Cyclic voltammetry analysis showed that the Co3+/Co2+ potential is 0.21 V for complex 1 and 0.32 V vs. SHE for complexes 2–4. Redox activation with dissociation of the naphthoquinones was successfully achieved by reduction of the complexes with the biologically relevant reducing agent ascorbic acid. [ABSTRACT FROM AUTHOR]

Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis. [ABSTRACT FROM AUTHOR]

Abstract: Two complementary methodologies involving olefin ring-closing metathesis and Knoevenagel-electrocyclization were utilized for the synthesis of α-xyloidones and fused chromene-1,4-naphthoquinones 5f–n and 6. The latter methodology was performed under acid catalysis or microwave irradiation allowing the synthesis of α-xyloidones 5f–j in moderate to good yield, which could not be obtained via the Knoevenagel-electrocyclization method. On the other hand, the lawsone bis-alkylation (C and O) then RCM olefin enabled the preparation of simple xyloidone 5m–n and the oxepin-1,4-naphthoquinones 6. [Copyright &y& Elsevier]

Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are considered inadequate, especially because of undesirable side effects and low efficacy in the chronic stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small library of compounds (1a–i and 2a–j) was designed based on the structural optimization of a Hit compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness profile, as a promising compound against Trypanosoma cruzi. SAR analysis also revealed 1g as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and 1g were unable to reduce parasite load, and did not prevent mouse mortality in T. cruzi acute infection. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile. [ABSTRACT FROM AUTHOR]

Dengue virus infection is a serious public health problem in endemic areas of the world where 2.5 billion people live. Clinical manifestations of the Dengue infection range from a mild fever to fatal cases of hemorrhagic fever. Although being the most rapidly spreading mosquito-borne viral infection in the world, until now no strategies are available for effective prevention or control of Dengue infection. In this scenario, the development of compounds that specifically inhibit viral replication with minimal effects to the human hosts will have a substantial effect in minimizing the symptoms of the disease and help to prevent viral transmission in the affected population. The aim of this study was to screen compounds with potential activity against dengue virus from a library of synthetic naphthoquinones. Several 1,2- and 1,4-pyran naphthoquinones were synthesized by a three-component reaction of lawsone, aldehyde (formaldehyde or arylaldehydes) and different dienophiles adequately substituted. These compounds were tested for the ability to inhibit the ATPase activity of the viral NS3 enzyme in in vitro assays and the replication of dengue virus in cultured cells. We have identified two 1,4-pyran naphthoquinones, which inhibited dengue virus replication in mammal cells by 99.0% and three others that reduced the dengue virus ATPase activity of NS3 by two-fold in in vitro assays. [ABSTRACT FROM AUTHOR]

The aims of this study were the planning, synthesis and in vitro evaluation of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Gram-negative and Gram-positive strains, searching for potential lead compounds against bacterial biofilm formation. A series of 12 new analogs of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones were synthesized by adding a thiol and different substituents to a ο -quinone methide using microwave irradiation. The compounds were tested against Gram-positive ( Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. simulans ATCC 27851, S. epidermidis ATCC 12228 and a hospital Methicillin-resistant S. aureus (MRSA) strain), as well as Gram-negative ( Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa ATCC 15442, Proteus mirabilis ATCC 15290, Serratia marcescens ATCC 14756, Klebsiella pneumoniae ATCC 4352 and Enterobacter cloacae ATCC 23355) strains, using the disk diffusion method. Ten compounds showed activity mainly against Gram-negative strains with a minimal inhibitory concentration (MIC = 4–64 μg/mL) within the Clinical and Laboratory Standards Institute (CLSI) levels. The biofilm inhibition data showed compounds, 9e , 9f , 9j and 9k , are anti-biofilm molecules when used in sub-MIC concentrations against P. aeruginosa ATCC 15442 strain. Compound ( 9j ) inhibited biofilm formation up to 63.4% with a better profile than ciprofloxacin, which is not able to prevent biofilm formation effectively. The reduction of P. aeruginosa ATCC 15442 mature biofilms was also observed for 9e and 9k . The structure modification applied in the series resulted in 12 new naphthoquinones with antimicrobial activity against Gram-negative bacteria strains ( E. coli ATCC 25922, P. aeruginosa ATCC 27853 and ATCC 15442). Four compounds decreased P. aeruginosa biofilm formation effectively. [ABSTRACT FROM AUTHOR]

Purinergic receptors are transmembrane proteins responsive to extracellular nucleotides and are expressed by several cell types throughout the human body. Among all identified subtypes, the P2×7 receptor has emerged as a relevant target for the treatment of inflammatory disease. Several clinical trials have been conducted to evaluate the effectiveness of P2×7R antagonists. However, to date, no selective antagonist has reached clinical use. In this work, we report the pharmacological evaluation of eleven N, S -acetal juglone derivatives as P2×7R inhibitors. Using in vitro assays and in vivo experimental models, we identified one derivative with promising inhibitory activity and low toxicity. Our in silico studies indicate that the 1,4-naphthoquinone moiety might be a valuable molecular scaffold for the development of novel P2×7R antagonists, as suggested by our previous studies. [Display omitted] • P2X7 receptor (P2X7R) is an ATP-gated ion channel involved in several inflammatory diseases and neuropathic pain. • P2X7R activation triggers several pro-inflammatory mechanisms, such as NLRP3 inflammasome assembly and release of IL-1β. • Despite the key role of P2X7R in inflammatory disorders, no inhibitor is approved for clinical use yet. • Juglone-derived N,S -acetal compounds showed good in vitro and in vivo P2X7R inhibitory activity. • In silico studies corroborates that 1,4-naphthoquinones might be valuable synthetic platforms for novel P2X7 antagonists. [ABSTRACT FROM AUTHOR]

We report herein a straightforward and efficient one-step reaction to prepare new nor-β-lapachone derivatives tethered with phenylthio groups at position 3 of the furan ring. We have screened the compounds on bloodstream trypomastigotes of Trypanosoma cruzi , the causative agent of Chagas disease, aimed at finding a new prototype with high trypanocidal activity. The new compounds possess a broad range of activity (IC 50 /24 h from 9.2 to 182.7 μM), higher than the original quinone (391.5 μM) and four of them higher than standard drug benznidazole (103.6 μM). The most active was compound 13b (9.2 μM), being 11 times active than benznidazole and the less toxic derivative to heart muscle cells. [ABSTRACT FROM AUTHOR]

Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy-resistant cases. Naphthoquinones (NQ) are considered privileged structures in medicinal chemistry due to their plethora of biological activities, including antimicrobial and anticancer effects. Nitrogen-containing heterocycles such as 1,2,3-1H-triazoles have been identified as general scaffolds for generating glycosidase inhibitors. In the present study, the NQ and 1,2,3-1H-triazole cores have been combined to chemically synthesize 18 new 1,2-furanonaphthoquinones tethered to 1,2,3-1H-triazoles (1,2-FNQT). Their cytotoxicities were evaluated against four different leukemia cell lines, including MOLT-4 and CEM (lymphoid cell lines) and K562 and KG1 (myeloid cell lines), as well as normal human peripheral blood mononucleated cells (PBMCs). The new 1,2-FNQT series showed high cytotoxic potential against all leukemia cell lines tested, and some compounds (12o and 12p) showed even better results than the classical therapeutic compounds such as doxorubicin or cisplatin. Others compounds, such as 12b, are promising because of their high selectivity against lymphoblastic leukemia and their low activity against normal hematopoietic cells. The cells of lymphoid origin (MOLT and CEM) were generally more sensitive than the myeloid cell lines to this series of compounds, and most of the compounds that showed the highest cytotoxicity were similarly active against both cell lines. [ABSTRACT FROM AUTHOR]

Abstract: A series of 36 new phenylsulfanylmethyl[1,4]naphthoquinones (7–42) were synthesized by a three-component reaction that involves lawsone, the appropriate aldehyde and thiols with variable substitution patterns. These reactions involve the in situ generation of o-quinone methides (o-QM) via Knoevenagel condensation and 1,4-nucleophilic addition under conventional heating or microwave irradiation. The new naphthoquinones obtained by this methodology were shown to have moderate to good in vitro antimalarial activity against Plasmodium falciparum (3D7). [Copyright &y& Elsevier]