Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

Sanjib Bhakta; Nicolò Scalacci; Arundhati Maitra; Alistair K Brown; Saiprasad Dasugari; Dimitrios Evangelopoulos; Timothy D McHugh; Parisa N Mortazavi; Alexander Twist; Elena Petricci; Fabrizio Manetti; Daniele Castagnolo

doi:10.1021/acs.jmedchem.6b00031

Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

J Med Chem. 2016 Mar 24;59(6):2780-93. doi: 10.1021/acs.jmedchem.6b00031. Epub 2016 Mar 8.

Authors

Affiliations

¹ Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London , Malet Street, London WC1E 7HX, U.K.
² Department of Applied Sciences, Northumbria University Newcastle , Ellison Place, NE1 8ST, Newcastle upon Tyne, U.K.
³ Institute of Pharmaceutical Science, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
⁴ School of Medicine, Pharmacy and Health, Durham University , Queen's Campus, Stockton-on-Tees, TS17 6BH, U.K.
⁵ Centre for Clinical Microbiology, University College London , London, NW3 2PF U.K.
⁶ Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via Aldo Moro 2, I-53100 Siena, Italy.

PMID: 26907951
DOI: 10.1021/acs.jmedchem.6b00031

Abstract

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 C5 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adamantane / analogs & derivatives*
Adamantane / chemical synthesis
Adamantane / pharmacology
Antitubercular Agents / chemical synthesis*
Antitubercular Agents / pharmacology*
Carrier Proteins / drug effects
Cell Line
Cell Survival / drug effects
Computational Biology
Drug Design
Drug Resistance, Multiple, Bacterial / drug effects*
Ethylenediamines / chemical synthesis*
Ethylenediamines / pharmacology*
Humans
Microbial Sensitivity Tests
Models, Molecular
Mycobacterium / drug effects
Mycobacterium tuberculosis / drug effects*
Pharmaceutical Preparations / metabolism
Piperazines / chemical synthesis*
Piperazines / pharmacology*
Pyrroles / chemical synthesis*
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

Antitubercular Agents
Carrier Proteins
Ethylenediamines
N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine
Pharmaceutical Preparations
Piperazines
Pyrroles
Adamantane
BM 212

Abstract

Publication types

MeSH terms

Substances

Grants and funding