title: 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.
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.
authors.affiliation: Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London , Malet Street, London WC1E 7HX, U.K.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Bhakta
authors.affiliation: Department of Applied Sciences, Northumbria University Newcastle , Ellison Place, NE1 8ST, Newcastle upon Tyne, U.K.|Institute of Pharmaceutical Science, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Scalacci
authors.affiliation: Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London , Malet Street, London WC1E 7HX, U.K.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Department of Applied Sciences, Northumbria University Newcastle , Ellison Place, NE1 8ST, Newcastle upon Tyne, U.K.|School of Medicine, Pharmacy and Health, Durham University , Queen's Campus, Stockton-on-Tees, TS17 6BH, U.K.
authors.forename: Alistair K
authors.initials: AK
authors.lastname: Brown
authors.affiliation: Department of Applied Sciences, Northumbria University Newcastle , Ellison Place, NE1 8ST, Newcastle upon Tyne, U.K.
authors.forename: Saiprasad
authors.initials: S
authors.lastname: Dasugari
authors.affiliation: Centre for Clinical Microbiology, University College London , London, NW3 2PF U.K.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Evangelopoulos
authors.affiliation: Centre for Clinical Microbiology, University College London , London, NW3 2PF U.K.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: McHugh
authors.affiliation: Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London , Malet Street, London WC1E 7HX, U.K.
authors.forename: Parisa N
authors.initials: PN
authors.lastname: Mortazavi
authors.affiliation: Department of Applied Sciences, Northumbria University Newcastle , Ellison Place, NE1 8ST, Newcastle upon Tyne, U.K.
authors.forename: Alexander
authors.initials: A
authors.lastname: Twist
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Petricci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via Aldo Moro 2, I-53100 Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.affiliation: Department of Applied Sciences, Northumbria University Newcastle , Ellison Place, NE1 8ST, Newcastle upon Tyne, U.K.|Institute of Pharmaceutical Science, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
authors.forename: Daniele
authors.initials: D
authors.lastname: Castagnolo
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009161:Mycobacterium / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D002352:Carrier Proteins; D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D004364:Pharmaceutical Preparations; D010879:Piperazines; D011758:Pyrroles; D000218:Adamantane; C115651:BM 212