The Synthesis and Reactivity of Naphthoquinonynes.

The first systematic exploration of the synthesis and reactivity of naphthoquinonynes is described. Routes to two regioisomeric Kobayashi-type naphthoquinonyne precursors have been developed, and the reactivity of the ensuing 6,7- and 5,6-aryne intermediates has been investigated. Remarkably, these studies have revealed that a broad range of cycloadditions, nucleophile additions and difunctionalizations can be achieved while maintaining the integrity of the highly sensitive quinone unit. The methodologies offer a powerful diversity oriented approach to C6 and C7 functionalized naphthoquinones, which are typically challenging to access. From a reactivity viewpoint, the study is significant because it demonstrates that aryne-based functionalizations can be utilized strategically in the presence of highly reactive and directly competing functionality.

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease Mpro and Papain-like Protease PLpro of SARS-CoV-2.

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC50) values between 0.41 µM and 9.0 µM. In addition, three compounds inhibited PLpro with IC50 ranging from 1.9 µM to 3.3 µM. To verify the specificity of Mpro and PLpro inhibitors, our experiments included an assessment of common causes of false positives such as aggregation, high compound fluorescence, and inhibition by enzyme oxidation. Altogether, we confirmed novel classes of specific Mpro and PLpro inhibitors. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.

Raman spectra-based structural classification analysis of quinoidal and derived molecular systems.

This work reports a classification analysis method based on the vibrational Raman spectra of 38 quinones and related structures, spectrally ordering and classifying the compounds. The molecular systems are relevant for chemical and biological processes, with applications in pharmacology, toxicology and medicine. The classification strategy uses a combination of principal component analysis with K-means clustering methods. Both theoretical simulations and experimental data are analysed, thus establishing their spectral characteristics, as related to their chemical structures and properties. The protocol introduced here should be broadly applicable in other molecular and solid state systems.

Removal and modification of directing groups used in metal-catalyzed C-H functionalization: the magical step of conversion into 'conventional' functional groups.

Over the past few decades, regioselective catalytic C-H functionalization has provided an attractive tool for unique retrosynthetic disconnections. The advancement of the directing group strategy in metal catalyzed synthetic transformation has contributed significantly to the incorporation of a wide range of functionalization reactions in both aromatic systems and aliphatic backbones. However, the extensive utilization of these methodologies depends on the ease of removal of the directing group to restore the free functional group. In this review, we have summarised the reported approaches for removing/modifying versatile directing groups.

Synthesis of ß-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles.

Desulfonylative alkylation of N-tosyl-1,2,3-triazoles under metal-free conditions leading to ß-triazolylenones is reported here. The present study encompasses the synthesis of triazoles with a new substitution pattern in a single step from cyclic 1,3-dicarbonyl compounds and N-tosyl triazole in moderate to high yields. Our synthesis takes place with complete regioselectivity as confirmed by crystallographic analysis which is rationalized by a suitable mechanistic proposal. This method provides an efficient, versatile and straightforward strategy towards the synthesis of new functionalized 1,2,3-triazoles.

Ruthenium(II)-Catalyzed Double Annulation of Quinones: Step-Economical Access to Valuable Bioactive Compounds.

Double ruthenium(II)-catalyzed alkyne annulations of quinones were accomplished. Thus, a strategy is reported that provides step-economical access to valuable quinones with a wide range of applications. C-H/N-H activations for alkyne annulations of naphthoquinones provided challenging polycyclic quinoidal compounds by forming four new bonds in one step. The singular power of the thus-obtained compounds was reflected by their antileukemic activity.

Strategies towards potent trypanocidal drugs: Application of Rh-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulation and nitroalkene reactions for the synthesis of substituted quinones and their evaluation against Trypanosoma cruzi.

Rhodium-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulations and nitroalkene reactions have been employed for the synthesis of 56 quinone-based compounds. These were evaluated against Trypanosoma cruzi, the parasite that causes Chagas disease. The reactions described here are part of a program that aims to utilize modern, versatile and efficient synthetic methods for the one or two step preparation of trypanocidal compounds. We have identified 9 compounds with potent activity against the parasite; 3 of these were 30-fold more potent than benznidazole (Bz), a drug used for the treatment of Chagas disease. This article provides a comprehensive outline of reactions involving over 120 compounds aimed at the discovery of new quinone-based frameworks with activity against T. cruzi.

Structure-based identification of naphthoquinones and derivatives as novel inhibitors of main protease Mpro and papain-like protease PLpro of SARS-CoV-2.

The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (Mpro) and papain-like protease (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing the polyproteins translated from the viral RNA. In the present work, we virtually screened 688 naphthoquinoidal compounds and derivatives against Mpro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against Mpro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PLpro. Four compounds inhibited Mpro with half-maximal inhibitory concentration (IC 50 ) values between 0.41 µM and 66 µM. In addition, eight compounds inhibited PLpro with IC 50 ranging from 1.7 µM to 46 µM. Molecular dynamics simulations suggest stable binding modes for Mpro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PLpro inhibitors, interactions occur in the S3 and S4 pockets. In summary, our structure-based computational and biochemical approach identified novel naphthoquinonal scaffolds that can be further explored as SARS-CoV-2 antivirals.

It takes two to tango: synthesis of cytotoxic quinones containing two redox active centers with potential antitumor activity.

We report the synthesis of 47 new quinone-based derivatives via click chemistry and their subsequent evaluation against cancer cell lines and the control L929 murine fibroblast cell line. These compounds combine two redox centers, such as an ortho-quinone/para-quinone or quinones/selenium with the 1,2,3-triazole nucleus. Several of these compounds present IC50 values below 0.5 µM in cancer cell lines with significantly lower cytotoxicity in the control cell line L929 and good selectivity index. Hence, our study confirms the use of a complete and very diverse range of quinone compounds with potential application against certain cancer cell lines.

The management of menopause with complementary and alternative medicine using an experimental model: ovariectomized rats.

AIM: The purpose of this research was to assess the effects of the flower essences She Oak and Bush Fuchsia on behavioral anxiety in ovariectomized (OVX) rats. METHODS: For four weeks, OVX rats received the flower essences She Oak, Bush Fuchsia or a combination of the two. After flower therapy, the animals were subjected to an elevated plus maze (EPM) behavioral anxiety-test. Cortisol blood level was also evaluated. RESULTS: OVX rats treated with the flower essence She Oak became less anxious and had more entries in the EPM open arms. On the other hand, OVX rats treated with the Bush Fuchsia essence spent more time in the EPM closed arms. This finding is similar to those obtained with controls. In addition, OVX rats that received She Oak and Bush Fuchsia in combination presented the same results as those receiving the Bush Fuchsia alone. CONCLUSIONS: Our results suggest that the flower essence She Oak could have an anxiolytic effect in OVX rats, but that the combination therapy of the She Oak and Bush Fuchsia could avoid the effects of the She Oak.

Synthesis of quinone imine and sulphur-containing compounds with antitumor and trypanocidal activities: redox and biological implications.

Ortho-Quinones represent a special class of redox active compounds associated with a spectrum of pronounced biological activities, including selective cytotoxicity and antimicrobial actions. The modification of the quinone ring by simple nitrogen and sulphur substitutions leads to several new classes of compounds with their own, distinct redox behaviour and equally distinct activities against cancer cell lines and Trypanosoma cruzi. Some of the compounds investigated show activity against T. cruzi at concentrations of 24.3 and 65.6 µM with a selectivity index of around 1. These results demonstrate that simple chemical modifications on the ortho-quinone ring system, in particular, by heteroatoms such as nitrogen and sulphur, transform these simple redox molecules into powerful cytotoxic agents with considerable "potential", not only in synthesis and electrochemistry, but also, in a broader sense, in health sciences.

Quinonoid compounds via reactions of lawsone and 2-aminonaphthoquinone with α-bromonitroalkenes and nitroallylic acetates: Structural diversity by C-ring modification and cytotoxic evaluation against cancer cells.

Morita-Baylis-Hillman acetates and α-bromonitroalkenes have been employed in cascade reactions with lawsone and 2-aminonaphthoquinone for the one-pot synthesis of heterocycle fused quinonoid compounds. The reactions reported here utilized the 1,3-binucleophilic potential of hydroxy- and aminonaphthoquinones and the 1,2/1,3-bielectrophilic potential of bromonitroalkenes and Morita-Baylis-Hillman acetates for the synthesis of pyrrole and furan fused naphthoquinones. The synthesized compounds were evaluated against HCT-116 (human colon carcinoma cells), PC3 (human prostate cancer cells), HL-60 (human promyelocytic leukemia cells), SF295 (human glioblastoma cells) and NCI-H460 (human lung cancer cells) and exhibited antitumor activity with IC50 values as low as < 2 µM. Selected compounds were also evaluated against OVCAR-8 (ovary), MX-1 (breast) and JURKAT (leukemia) cell lines. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC) and L929 cells.

Quinonoid and phenazine compounds: synthesis and evaluation against H37Rv, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis.

Several quinonoid and phenazine compounds were synthesized in moderate to high yields and showed activity against H(37)Rv, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The cytotoxity of the compounds were evaluated against human peripheral blood mononuclear cells (PBMC) and these substances emerge as promising antitubercular prototypes.