title: Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration.
abstract: High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure-activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (ΔcydKO) was hyper-susceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cytochrome bc1 complex, a validated drug target in M. tuberculosis.
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Renier
authors.initials: R
authors.lastname: van der Westhuyzen
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Susan
authors.initials: S
authors.lastname: Winks
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Wilson
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Boyle
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gessner
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Candice
authors.initials: C
authors.lastname: Soares de Melo
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.affiliation: South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Mathew
authors.initials: M
authors.lastname: Njoroge
authors.affiliation: South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Christel
authors.initials: C
authors.lastname: Brunschwig
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Nina
authors.initials: N
authors.lastname: Lawrence
authors.affiliation: Novartis Institute for Tropical Diseases (NITD) , 10 Biopolis Road, Chromos no. 05-01, Singapore 138670, Singapore.
authors.forename: Srinivasa P S
authors.initials: SP
authors.lastname: Rao
authors.affiliation: DST/NRF Centre of Excellence in Biomedical TB Research, SA MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Health Sciences, Stellenbosch University , Tygerberg 7505, South Africa.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sirgel
authors.affiliation: DST/NRF Centre of Excellence in Biomedical TB Research, SA MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Health Sciences, Stellenbosch University , Tygerberg 7505, South Africa.
authors.forename: Paul
authors.initials: P
authors.lastname: van Helden
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Ronnett
authors.initials: R
authors.lastname: Seldon
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Atica
authors.initials: A
authors.lastname: Moosa
authors.affiliation: MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town , Rondebosch 7701, South Africa.|Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Digby F
authors.initials: DF
authors.lastname: Warner
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Arista
authors.affiliation: Novartis Institute for Tropical Diseases (NITD) , 10 Biopolis Road, Chromos no. 05-01, Singapore 138670, Singapore.
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.affiliation: Novartis Institute for Tropical Diseases (NITD) , 10 Biopolis Road, Chromos no. 05-01, Singapore 138670, Singapore.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Street
authors.affiliation: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.|South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.|Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D011728:Pyridones; D011758:Pyrroles; D014450:Electron Transport Complex III