Electrochemical study, on mercury, of a Meta-nitroarylamine derivative of nor-β-lapachone, an antitumor and trypanocidal compound

Souza, Ademária Aparecida de; Moura, Maria Aline Barros Fidelis de; Abreu, Fabiane Caxico de; Goulart, Marília Oliveira Fonseca; Silva, Eufrânio N. da; Pinto, Antônio V.; Ferreira, Vı́tor F.; Moscoso, R.; Núñez‐Vergara, Luis J.; Squella, J.A.

doi:10.1590/s0100-40422010001000013

Cited by 6 publications

(1 citation statement)

References 13 publications

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“…The compounds listed in Group 1 are ortho-quinones with different substitution patterns. In general, we evaluated compounds containing arylamino, − alcohol and alkoxy groups, , selenium and sulfur, − the basic chalcone framework, among simple ortho-quinones. ,− …”

Section: Resultsmentioning

confidence: 99%

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M^pro and Papain-like Protease PL^pro of SARS-CoV-2

Santos

Kronenberger

Almeida

et al. 2022

J. Chem. Inf. Model.

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The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. The main protease (M pro ) and papain-like protease (PL pro ) 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 M pro of SARS-CoV-2. Twenty-four derivatives were selected and evaluated in biochemical assays against M pro using a novel fluorogenic substrate. In parallel, these compounds were also assayed with SARS-CoV-2 PL pro . Four compounds inhibited M pro with half-maximal inhibitory concentration (IC 50 ) values between 0.41 μM and 9.0 μM. In addition, three compounds inhibited PL pro with IC 50 ranging from 1.9 μM to 3.3 μM. To verify the specificity of M pro and PL pro 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 M pro and PL pro inhibitors. Molecular dynamics simulations suggest stable binding modes for M pro inhibitors with frequent interactions with residues in the S1 and S2 pockets of the active site. For two PL pro 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.

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Section: Resultsmentioning

confidence: 99%

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M^pro and Papain-like Protease PL^pro of SARS-CoV-2

Santos

Kronenberger

Almeida

et al. 2022

J. Chem. Inf. Model.

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1,2,3-Triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: Potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones

Cruz

Hussene

Dias

et al. 2014

Bioorganic & Medicinal Chemistry

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1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2 μM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.

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Growth inhibitory effects of 3′-nitro-3-phenylamino nor-beta-lapachone against HL-60: A redox-dependent mechanism

Araújo

Souza

Júnior

et al. 2012

Toxicology in Vitro

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In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2). QPhNO(2) caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO(2) treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry.

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Electrochemical study, on mercury, of a Meta-nitroarylamine derivative of nor-β-lapachone, an antitumor and trypanocidal compound

Cited by 6 publications

References 13 publications

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M^pro and Papain-like Protease PL^pro of SARS-CoV-2

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M^pro and Papain-like Protease PL^pro of SARS-CoV-2

1,2,3-Triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: Potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones

Growth inhibitory effects of 3′-nitro-3-phenylamino nor-beta-lapachone against HL-60: A redox-dependent mechanism

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Electrochemical study, on mercury, of a Meta-nitroarylamine derivative of nor-β-lapachone, an antitumor and trypanocidal compound

Cited by 6 publications

References 13 publications

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

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

1,2,3-Triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: Potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones

Growth inhibitory effects of 3′-nitro-3-phenylamino nor-beta-lapachone against HL-60: A redox-dependent mechanism

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Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M^pro and Papain-like Protease PL^pro of SARS-CoV-2

Structure-Based Identification of Naphthoquinones and Derivatives as Novel Inhibitors of Main Protease M^pro and Papain-like Protease PL^pro of SARS-CoV-2