Structure-activity relationships of 1,5-dihydro-2H-benzo[b][1,4]diazepine-2,4(3H)-diones as inhibitors of Trypanosoma cruzi

Michael Thomas; Joanne Dunne; Peter G. Dodd; Emiliana D’Oria; Laura Frame; Adolfo Garcia-Perez; Kate McGonagle; Pilar Manzano-Chinchon; Lorna MacLean; Christy Paterson; Jennifer Riley; John Thomas; Leah S. Torrie; Karolina Wrobel; Kevin Read; Maria Marco; Manu De Rycker

doi:10.1039/D5MD00185D

Structure-activity relationships of 1,5-dihydro-2H-benzo[b][1,4]diazepine-2,4(3H)-diones as inhibitors of Trypanosoma cruzi

Michael Thomas
, Joanne Dunne
, Peter G. Dodd
, Emiliana D’Oria
, Laura Frame
, Adolfo Garcia-Perez
, Kate McGonagle
, Pilar Manzano-Chinchon
, Lorna MacLean
, Christy Paterson
, Jennifer Riley
, John Thomas
, Leah S. Torrie
, Karolina Wrobel
, Kevin Read
, Maria Marco (Lead / Corresponding author)
, Manu De Rycker (Lead / Corresponding author)

Drug Discovery Unit

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

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Abstract

Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), is responsible for a large health burden with around 6 – 8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act via a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC50’s > 6.4 which were progressed to a T. cruzi washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.

Original language	English
Pages (from-to)	4135-4153
Number of pages	16
Journal	RSC Medicinal Chemistry
Volume	16
Issue number	9
Early online date	6 Jun 2025
DOIs	https://doi.org/10.1039/D5MD00185D
Publication status	Published - 1 Sept 2025

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

UN SDGs

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

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10.1039/D5MD00185D

Author accepted manuscriptAccepted author manuscript, 1.07 MBLicence: CC BY
Supplementary (word)Accepted author manuscript, 6.17 MB
Supplementary FileAccepted author manuscript, 1.38 MB

Wellcome Centre for Anti-Infectives Research
Baragana, B. (Investigator), Cook, S. (Investigator), De Rycker, M. (Investigator), Fairlamb, A. (Investigator), Ferguson, M. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Horn, D. (Investigator), Lee, M. (Investigator), Pawlowic, M. C. (Investigator), Read, K. (Investigator), Wyatt, P. (Investigator) & Wyllie, S. (Investigator)
1/04/17 → 1/04/25
Project: Research

Cite this

Thomas, M., Dunne, J., Dodd, P. G., D’Oria, E., Frame, L., Garcia-Perez, A., McGonagle, K., Manzano-Chinchon, P., MacLean, L., Paterson, C., Riley, J., Thomas, J., Torrie, L. S., Wrobel, K., Read, K., Marco, M., & De Rycker, M. (2025). Structure-activity relationships of 1,5-dihydro-2H-benzo[b][1,4]diazepine-2,4(3H)-diones as inhibitors of Trypanosoma cruzi. RSC Medicinal Chemistry, 16(9), 4135-4153. https://doi.org/10.1039/D5MD00185D

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abstract = "Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), is responsible for a large health burden with around 6 – 8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act via a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC50{\textquoteright}s > 6.4 which were progressed to a T. cruzi washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.",

author = "Michael Thomas and Joanne Dunne and Dodd, \{Peter G.\} and Emiliana D{\textquoteright}Oria and Laura Frame and Adolfo Garcia-Perez and Kate McGonagle and Pilar Manzano-Chinchon and Lorna MacLean and Christy Paterson and Jennifer Riley and John Thomas and Torrie, \{Leah S.\} and Karolina Wrobel and Kevin Read and Maria Marco and \{De Rycker\}, Manu",

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language = "English",

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Thomas, M , Dunne, J , Dodd, PG, D’Oria, E, Frame, L, Garcia-Perez, A, McGonagle, K, Manzano-Chinchon, P, MacLean, L, Paterson, C, Riley, J , Thomas, J , Torrie, LS, Wrobel, K, Read, K, Marco, M & De Rycker, M 2025, 'Structure-activity relationships of 1,5-dihydro-2H-benzo[b][1,4]diazepine-2,4(3H)-diones as inhibitors of Trypanosoma cruzi', RSC Medicinal Chemistry, vol. 16, no. 9, pp. 4135-4153. https://doi.org/10.1039/D5MD00185D

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T1 - Structure-activity relationships of 1,5-dihydro-2H-benzo[b][1,4]diazepine-2,4(3H)-diones as inhibitors of Trypanosoma cruzi

AU - Thomas, Michael

AU - Dunne, Joanne

AU - Dodd, Peter G.

AU - D’Oria, Emiliana

AU - Frame, Laura

AU - Garcia-Perez, Adolfo

AU - McGonagle, Kate

AU - Manzano-Chinchon, Pilar

AU - MacLean, Lorna

AU - Paterson, Christy

AU - Riley, Jennifer

AU - Thomas, John

AU - Torrie, Leah S.

AU - Wrobel, Karolina

AU - Read, Kevin

AU - Marco, Maria

AU - De Rycker, Manu

PY - 2025/9/1

Y1 - 2025/9/1

N2 - Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), is responsible for a large health burden with around 6 – 8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act via a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC50’s > 6.4 which were progressed to a T. cruzi washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.

AB - Chagas disease, caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi), is responsible for a large health burden with around 6 – 8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act via a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC50’s > 6.4 which were progressed to a T. cruzi washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.

U2 - 10.1039/D5MD00185D

DO - 10.1039/D5MD00185D

M3 - Article

SN - 2632-8682

VL - 16

SP - 4135

EP - 4153

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

IS - 9

ER -

Structure-activity relationships of 1,5-dihydro-2H-benzo[b][1,4]diazepine-2,4(3H)-diones as inhibitors of Trypanosoma cruzi

Abstract

ASJC Scopus subject areas

UN SDGs

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Wellcome Centre for Anti-Infectives Research

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