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.