Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 6, Pages 2780-2793Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00031
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Funding
- Medical Research Council [G0801956]
- Wellcome Trust/Birkbeck Anniversary Scholarship
- Birkbeck Translational Research Award
- Royal Society of Chemistry
- Northumbria University
- MRC [G0801956] Funding Source: UKRI
- Medical Research Council [G0801956] Funding Source: researchfish
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Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the CS aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.
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