Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria

Meir Touitou; Fabrizio Manetti; Camila Maringolo Ribeiro; Fernando Rogerio Pavan; Nicolò Scalacci; Katarina Zrebna; Neelu Begum; Dorothy Semenya; Antima Gupta; Sanjib Bhakta; Timothy D. Mchugh; Hanoch Senderowitz; Melina Kyriazi; Daniele Castagnolo

doi:10.1021/acsmedchemlett.9b00515

Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria

Meir Touitou, Fabrizio Manetti, Camila Maringolo Ribeiro, Fernando Rogerio Pavan, Nicolò Scalacci, Katarina Zrebna, Neelu Begum, Dorothy Semenya, Antima Gupta, Sanjib Bhakta, Timothy D. Mchugh, Hanoch Senderowitz, Melina Kyriazi, Daniele Castagnolo

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

11 Scopus citations

Abstract

A series of N-phenyl-2,5-dimethylpyrrole derivatives, designed as hybrids of the antitubercular agents BM212 and SQ109, have been synthesized and evaluated against susceptible and drug-resistant mycobacteria strains. Compound 5d, bearing a cyclohexylmethylene side chain, showed high potency against M. tuberculosis including MDR-TB strains at submicromolar concentrations. The new compound shows bacteriostatic activity and low toxicity and proved to be effective against intracellular mycobacteria too, showing an activity profile similar to isoniazid.

Original language	English
Pages (from-to)	638-644
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00515
State	Published - 14 May 2020

Bibliographical note

Publisher Copyright:
Copyright © 2019 American Chemical Society.

Funding

We gratefully acknowledge EPSRC (Global Challenges Competition King’s College London), Global Challenges Research Fund at Birkbeck, University of London and Royal Society (RG160870) for research funding and financial support. MT acknowledge King’s College London for a period of leave. DS acknowledges the South African National Research Foundation-SARChI for financial support. We gratefully acknowledge NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research, NC/T001240/1) for financial support and Carolyn Lam and Simona di Blasio for their help and training on Galleria mellonella assays. FRP and CMR acknowledge Sao Paulo Research Foundation (FAPESP - grant 2018/00163-0) for financial support.

Funders	Funder number
South African National Research Foundation-SARChI
Engineering and Physical Sciences Research Council
Royal Society	RG160870
University of London
National Centre for the Replacement, Refinement and Reduction of Animals in Research	NC/T001240/1
Fundação de Amparo à Pesquisa do Estado de São Paulo	2018/00163-0
National Centre for the Replacement Refinement and Reduction of Animals in Research

Keywords

Tuberculosis
antimycobacterial drug
drug resistance
intracellular tuberculosis
pyrroles

UN SDGs

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

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10.1021/acsmedchemlett.9b00515

Cite this

Touitou, M., Manetti, F., Ribeiro, C. M., Pavan, F. R., Scalacci, N., Zrebna, K., Begum, N., Semenya, D., Gupta, A., Bhakta, S., Mchugh, T. D., Senderowitz, H., Kyriazi, M., & Castagnolo, D. (2020). Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria. ACS Medicinal Chemistry Letters, 11(5), 638-644. https://doi.org/10.1021/acsmedchemlett.9b00515

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doi = "10.1021/acsmedchemlett.9b00515",

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Touitou, M, Manetti, F, Ribeiro, CM, Pavan, FR, Scalacci, N, Zrebna, K, Begum, N, Semenya, D, Gupta, A, Bhakta, S, Mchugh, TD, Senderowitz, H, Kyriazi, M & Castagnolo, D 2020, 'Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria', ACS Medicinal Chemistry Letters, vol. 11, no. 5, pp. 638-644. https://doi.org/10.1021/acsmedchemlett.9b00515

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AU - Touitou, Meir

AU - Manetti, Fabrizio

AU - Ribeiro, Camila Maringolo

AU - Pavan, Fernando Rogerio

AU - Scalacci, Nicolò

AU - Zrebna, Katarina

AU - Begum, Neelu

AU - Semenya, Dorothy

AU - Gupta, Antima

AU - Bhakta, Sanjib

AU - Mchugh, Timothy D.

AU - Senderowitz, Hanoch

AU - Kyriazi, Melina

AU - Castagnolo, Daniele

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Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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