Discovery of napabucasin derivatives for the treatment of tuberculosis

Li, Chungen; Tang, Yue-Hua; Sang, Zitai; Yang, Yang; Gao, Yurui; Fang, Cuiting; Zhang, Tianyu; Luo, Youfu

doi:10.1039/c9md00295b

Cited by 5 publications

(11 citation statements)

References 20 publications

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“…Previous studies reported the antibacterial activity of 2-acetylfuro-1,4-naphathoquinone against Escherichia coli , Streptococcus faecalis , and Staphylococcus aureus [ 15 , 17 ]. A recent study also showed its antimycobacterial activity for the treatment of tuberculosis [ 18 ]. In addition, the NAP is in phase III clinical trials for the treatment of cancers (i.e., gastric cancer, pancreatic cancer, and colorectal cancer) [ 19 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

Repurposing Napabucasin as an Antimicrobial Agent against Oral Streptococcal Biofilms

Kuang

Zhang

Peng

et al. 2020

BioMed Research International

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Objectives. Disruption of microbial biofilms is an effective way to control dental caries. Drug resistance and side effects of the existing antimicrobials necessitate the development of novel antibacterial agents. The current study was aimed at investigating the antibacterial activities of the repurposed natural compound napabucasin against oral streptococci. Methods. The minimum inhibitory concentration, minimum bactericidal concentration, minimum biofilm inhibition concentration, and minimum biofilm reduction concentration of Streptococcus mutans, Streptococcus gordonii, and Streptococcus sanguinis were examined by a microdilution method. Cytotoxicity of napabucasin against human oral keratinocytes, human gingival epithelia, and macrophage RAW264.7 was evaluated by CCK8 assays. The dead/live bacterium and exopolysaccharide in the napabucasin-treated multispecies biofilms were evaluated by confocal laser scanning microscopy. Microbial composition within the napabucasin-treated biofilms was further visualized by fluorescent in situ hybridization and qPCR. And the cariogenicity of napabucasin-treated biofilms was evaluated by transverse microradiography. Results. Napabucasin exhibited good antimicrobial activity against oral streptococcal planktonic cultures and biofilms but with lessened cytotoxicity as compared to chlorhexidine. Napabucasin reduced the cariogenic S. mutans and increased the proportion of the commensal S. gordonii in the multispecies biofilms. More importantly, napabucasin significantly reduced the demineralization capability of biofilms on tooth enamels. Conclusion. Napabucasin shows lessened cytotoxicity and comparable antimicrobial effects to chlorhexidine. Repurposing napabucasin may represent a promising adjuvant for the management of dental caries.

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Section: Introductionmentioning

confidence: 99%

Repurposing Napabucasin as an Antimicrobial Agent against Oral Streptococcal Biofilms

Kuang

Zhang

Peng

et al. 2020

BioMed Research International

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“…The residue was purified by chromatography on a silica gel column with PE-EA to give pure intermediate 12a (4.9 g, 75%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 General Procedures for the Synthesis of Intermediates 14a−14l. Intermediate 13a (4.0 g, 13.0 mmol, 1.0 equiv) was added to 30 mL solution of EtOH/H 2 O (v/v, 3/1).…”

Section: Synthesis Of Tert-butyl 4-(4-amino-5-isopropoxy-2methylpheny...mentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 9.32 (s, 3H), 8.41 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.06 (dd, J = 7.9, 1.1 Hz, 1H), 6.94 (s, 1H), 4.58−4.48 (m, 1H), 3.36 (d, J = 11.9 Hz, 2H), 3.14−2.95 (m, 3H), 2.26 (s, 3H), 2.12−1.95 (m, 2H), 1.83 (d, J = 12.9 Hz, 2H), 1.21 (d, J = 6.0 Hz, 6H). 13 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.37 (dd, J = 8.7, 2.4 Hz, 1H), 6.83 (s, 1H), 4.57 (dt, J = 12.0, 6.0 Hz, 1H), 3.14 (d, J = 12.2 Hz, 2H), 2.77 (m, 3H), 2.06 (s, 3H), 1.72−1.56 (m, 4H), 1.27 (d, J = 6.0 Hz, 6H). 13…”

Section: -Chloro-n 2 -(3-chlorophenyl)-n 4 -(2-isopropoxy-5-methyl-4-...mentioning

confidence: 99%

“…It remains one of the leading causes of death worldwide. 1 Globally in 2020, TB has claimed an estimated 1.3 million deaths among HIV-negative people and an additional 214 000 deaths among HIV-positive people. 2 The number of deaths caused by TB was increased in 2020 compared to that of 2019, which has been impacted by the COVID-19 pandemic.…”

Section: ■ Introductionmentioning

confidence: 99%

“…C NMR (100 MHz, DMSO-d 6 ) δ 162.75 (d, J = 240.1 Hz), 158.00, 155.97, 154.50, 147.73, 142.78 (d, J = 11.6 Hz), 139.89, 130.21 (d, J = 9.7 Hz), 127.84, 126.89, 125.26 (d, J = 2.3 Hz), 115.12 (d, J = 1.8 Hz), 112.50, 107.87 (d, J = 21.0 Hz), 105.86 (d, J = 26.8 Hz), 105.03, 72.08, 44.30, 35.60, 29.44, 22.49 (2C), 18.68. HRMS (ESI) m/z: calculated for C 25 H 29 ClFN 5 O [M + H] + : 469.2124; found: 470.2118.5-Chloro-N 2 -(4-fluorophenyl)-N 4 -(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)pyrimidine-2,4-diamine (4d) 1. H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (brs, 1H), 8.99 (m, 1H), 8.89−8.79 (m, 1H), 8.66 (brs, 1H), 8.26 (s, 1H), 7.72 (s, 1H), 7.52 (dd, J = 8.8, 5.0 Hz, 2H), 7.05 (t, J = 8.8 Hz, 2H), 6.87 (s, 1H), 4.53 (dt, J = 12.1, 6.0 Hz, 1H), 3.37 (d, J = 11.9 Hz, 2H), 3.04 (m, 3H), 2.23 (s, 3H), 2.04−1.80 (m, 4H), 1.25 (d, J = 6.0 Hz, 6H) 13.…”

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confidence: 99%

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Structure–Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

Tian

Huang

et al. 2023

J. Med. Chem.

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Discovery of novel antitubercular drugs is an effective strategy against drug-resistant tuberculosis (TB). Our previous study has identified LPX-16j as a novel antitubercular compound. Herein, we perform a comprehensive structure−activity relationship (SAR) based on LPX-16j, indicating that the central pyrimidine ring moiety was crucial for the antitubercular activities of its derivatives, and replacing the naphthyl group with hydrophobic substitutes was well tolerated. The representative derivative 5a exhibited potent activity against H37Ra, H37Rv, and clinical drug-resistant TB with minimum inhibitory concentration (MIC) values of 0.5−1.0 μg/mL. Meanwhile, 5a showed an acceptable safety in vivo and displayed a favorable oral bioavailability with a value of 40.7%. The differential scanning fluorescence, isothermal titration calorimetry, and molecular docking assays indicated that PknB could be one of the targets of compound 5a. Overall, this study identified 5a as a novel promising lead compound with the potential to develop candidates for the treatment of drug-resistant TB.

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Manganese(III) Acetate‐Based Radical Cyclization Reactions for Pyranocoumarin and Pyranoquinoline Compounds: Synthesis, DFT and Molecular Docking Studies

et al. 2022

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Pyranofuroquinoline and pyranofurocoumarin derivatives are significant class of compounds due to being useful in many diverse applications. The synthesis of the compounds are succeeded in one step by radical cyclization reaction in the presence of manganese(III) acetate. Furoquinoline and furocoumarin reactants were used together with 1,1‐disubstituted‐, 1,2‐disubstituted and cyclic alkenes giving pyranofuroquinoline and pyranofurocoumarin compounds in moderate to high yields. Also, we were able to isolate alkenyl and acetoxy‐ side‐products in minor low yields. The electronic and optical features of furoquinoline and furocoumarin reactants and pyranofuroquinoline products were inquired using theoretical approaches (DFT and TD‐DFT). Their excitation and emission spectrums were computed. The results revealed that the pyranofuroquinoline molecules did not show the energy transfer feature. It was observed that the behavior of nonlinear optic of furoquinoline is higher than the pyranofuroquinoline and furocoumarin molecules. But the average polarization and the anisotropy of the polarizability of pyranofuroquinoline increased and was found to be 262.7 and 141.9 respectively. Also, according to the calculated docking parameters, the investigated pyranofuroquinoline and pyranofurocoumarin compounds were found to have higher activity than the substances with anticancer and antibacterial standards.

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Discovery of napabucasin derivatives for the treatment of tuberculosis

Abstract: Thirty-one napabucasin derivatives were synthesized and evaluated for their antitubercular activities, as well as for studying the structure–activity relationships.

Cited by 5 publications

References 20 publications

Repurposing Napabucasin as an Antimicrobial Agent against Oral Streptococcal Biofilms

Repurposing Napabucasin as an Antimicrobial Agent against Oral Streptococcal Biofilms

Structure–Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

Manganese(III) Acetate‐Based Radical Cyclization Reactions for Pyranocoumarin and Pyranoquinoline Compounds: Synthesis, DFT and Molecular Docking Studies

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