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

ACS Med Chem Lett. 2019 Dec 10;11(5):638-644. doi: 10.1021/acsmedchemlett.9b00515.

Meir Touitou ¹ ², Fabrizio Manetti ³, Camila Maringolo Ribeiro ⁴, Fernando Rogerio Pavan ⁴, Nicolò Scalacci ¹, Katarina Zrebna ¹, Neelu Begum ⁵, Dorothy Semenya ¹, Antima Gupta ⁶, Sanjib Bhakta ⁶, Timothy D McHugh ⁵, Hanoch Senderowitz ², Melina Kyriazi ¹, Daniele Castagnolo ¹

Affiliations

1 School of Cancer and Pharmaceutical Sciences, King's College London, 150 Stamford Street, London SE1 9NH, U.K.
2 Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University Ramat-Gan 5290002, Israel.
3 Dipartimento di Biotecnologie, Chimica e Farmacia, via A. Moro 2, I-53100 Siena, Italy.
4 Tuberculosis Research Laboratory, School of Pharmaceutical Sciences, Sao Paulo State University (UNESP), Rod. Araraquara-Jau, km1, 14800-903 Araraquara, Brazil.
5 Centre for Clinical Microbiology, University College London, London NW3 2PF, U.K.
6 Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, U.K.

PMID: 32435364 DOI: 10.1021/acsmedchemlett.9b00515

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.

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