Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis

Manisha Singh; Sarah M. Batt; Christian S. C. Canales; Fernando R. Pavan; Sethu Arun Kumar; Handattu S. Akshatha; Meduri Bhagyalalitha; Karthik G. Pujar; Durgesh Bidye; Gurubasavaraj V. Pujar; Gurdyal S. Besra

doi:10.1080/14756366.2024.2403744

Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis

Manisha Singh, Sarah M. Batt, Christian S. C. Canales, Fernando R. Pavan, Sethu Arun Kumar, Handattu S. Akshatha, Meduri Bhagyalalitha, Karthik G. Pujar, Durgesh Bidye, Gurubasavaraj V. Pujar^*, Gurdyal S. Besra^*

^*Corresponding author for this work

Biosciences

Research output: Contribution to journal › Article › peer-review

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Abstract

Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC 50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.

Original language	English
Article number	2403744
Number of pages	16
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	39
Issue number	1
Early online date	27 Sept 2024
DOIs	https://doi.org/10.1080/14756366.2024.2403744
Publication status	Published - 31 Dec 2024

Keywords

Triazoles/chemistry
Benzoxazoles/chemistry
Enzyme Inhibitors/pharmacology
Drug Design
Structure-Activity Relationship
Dose-Response Relationship, Drug
Mycobacterium tuberculosis/drug effects
Molecular Structure
Fluorometry
Bacterial Proteins/antagonists & inhibitors
Models, Molecular
Microbial Sensitivity Tests
Alcohol Oxidoreductases/antagonists & inhibitors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/14756366.2024.2403744Licence: Creative Commons: Attribution (CC BY)

SinghM2024NovelFinal published version, 3.56 MBLicence: Creative Commons: Attribution (CC BY)

The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways
Besra, D. (Principal Investigator), Bhatt, A. (Co-Investigator), Futterer, K. (Co-Investigator), Alderwick, L. (Co-Investigator) & Zhang, J. (Co-Investigator)
Medical Research Council
1/03/19 → 28/02/25
Project: Research Councils
MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery
Besra, D. (Principal Investigator), Cox, L. (Co-Investigator) & Futterer, K. (Co-Investigator)
Medical Research Council
1/04/18 → 31/03/22
Project: Research Councils

Cite this

Singh, M., Batt, S. M., Canales, C. S. C., Pavan, F. R., Kumar, S. A., Akshatha, H. S., Bhagyalalitha, M., Pujar, K. G., Bidye, D., Pujar, G. V., & Besra, G. S. (2024). Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis. Journal of Enzyme Inhibition and Medicinal Chemistry, 39(1), Article 2403744. https://doi.org/10.1080/14756366.2024.2403744

@article{6fa98f054d0643b9b3cb081b971a17f5,

title = "Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis",

abstract = "Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC 50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment. ",

keywords = "Triazoles/chemistry, Benzoxazoles/chemistry, Enzyme Inhibitors/pharmacology, Drug Design, Structure-Activity Relationship, Dose-Response Relationship, Drug, Mycobacterium tuberculosis/drug effects, Molecular Structure, Fluorometry, Bacterial Proteins/antagonists & inhibitors, Models, Molecular, Microbial Sensitivity Tests, Alcohol Oxidoreductases/antagonists & inhibitors",

author = "Manisha Singh and Batt, {Sarah M.} and Canales, {Christian S. C.} and Pavan, {Fernando R.} and Kumar, {Sethu Arun} and Akshatha, {Handattu S.} and Meduri Bhagyalalitha and Pujar, {Karthik G.} and Durgesh Bidye and Pujar, {Gurubasavaraj V.} and Besra, {Gurdyal S.}",

year = "2024",

month = dec,

day = "31",

doi = "10.1080/14756366.2024.2403744",

language = "English",

volume = "39",

journal = "Journal of Enzyme Inhibition and Medicinal Chemistry",

issn = "1475-6366",

publisher = "Informa Healthcare",

number = "1",

}

Singh, M, Batt, SM, Canales, CSC, Pavan, FR, Kumar, SA, Akshatha, HS, Bhagyalalitha, M, Pujar, KG, Bidye, D, Pujar, GV & Besra, GS 2024, 'Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis', Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 39, no. 1, 2403744. https://doi.org/10.1080/14756366.2024.2403744

Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis. / Singh, Manisha; Batt, Sarah M.; Canales, Christian S. C. et al.
In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 39, No. 1, 2403744, 31.12.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Novel hybrids of 1,2,3-triazole-benzoxazole

T2 - design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis

AU - Singh, Manisha

AU - Batt, Sarah M.

AU - Canales, Christian S. C.

AU - Pavan, Fernando R.

AU - Kumar, Sethu Arun

AU - Akshatha, Handattu S.

AU - Bhagyalalitha, Meduri

AU - Pujar, Karthik G.

AU - Bidye, Durgesh

AU - Pujar, Gurubasavaraj V.

AU - Besra, Gurdyal S.

PY - 2024/12/31

Y1 - 2024/12/31

N2 - Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC 50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.

AB - Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC 50 values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.

KW - Triazoles/chemistry

KW - Benzoxazoles/chemistry

KW - Enzyme Inhibitors/pharmacology

KW - Drug Design

KW - Structure-Activity Relationship

KW - Dose-Response Relationship, Drug

KW - Mycobacterium tuberculosis/drug effects

KW - Molecular Structure

KW - Fluorometry

KW - Bacterial Proteins/antagonists & inhibitors

KW - Models, Molecular

KW - Microbial Sensitivity Tests

KW - Alcohol Oxidoreductases/antagonists & inhibitors

U2 - 10.1080/14756366.2024.2403744

DO - 10.1080/14756366.2024.2403744

M3 - Article

C2 - 39329328

SN - 1475-6366

VL - 39

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

IS - 1

M1 - 2403744

ER -

Novel hybrids of 1,2,3-triazole-benzoxazole: design, synthesis, and assessment of DprE1 enzyme inhibitors using fluorometric assay and computational analysis

Abstract

Keywords

UN SDGs

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Projects

The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways

MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery

Cite this