title: Novel N-linked aminopiperidine-based gyrase inhibitors with improved hERG and in vivo efficacy against Mycobacterium tuberculosis.
abstract: DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.
authors.affiliation: Department of Medicinal Chemistry; ‡Department of Biosciences and §DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Shahul
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authors.forename: Vikas
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authors.lastname: Patil
authors.forename: Suresh
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authors.lastname: Solapure
authors.forename: Umender
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authors.lastname: Sharma
authors.forename: Prashanti
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authors.lastname: Madhavapeddi
authors.forename: Anandkumar
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authors.lastname: Raichurkar
authors.forename: Murugan
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authors.lastname: Chinnapattu
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authors.lastname: Rudrapatana
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authors.lastname: Awasthy
authors.forename: Radha
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authors.lastname: Nandishaiah
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.forename: Anirban
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authors.lastname: Ghosh
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authors.lastname: Narayan
authors.forename: V K
authors.initials: VK
authors.lastname: Ramya
authors.forename: Parvinder
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authors.lastname: Kaur
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.forename: Jim
authors.initials: J
authors.lastname: Werngren
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.forename: C N Naveen
authors.initials: CN
authors.lastname: Kumar
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.forename: Mahesh
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authors.lastname: Kumar K N
authors.forename: Samit
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authors.lastname: Ganguly
authors.forename: Sowmya
authors.initials: S
authors.lastname: Bharath
authors.forename: Ugarkar
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authors.lastname: Bheemarao
authors.forename: Kakoli
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authors.lastname: Mukherjee
authors.forename: Uma
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authors.lastname: Arora
authors.forename: Sheshagiri
authors.initials: S
authors.lastname: Gaonkar
authors.forename: Michelle
authors.initials: M
authors.lastname: Coulson
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.forename: Sunita M
authors.initials: SM
authors.lastname: de Sousa
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001682:Biological Availability; D002908:Chronic Disease; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D024841:Fluoroquinolones / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; C000606913:KCNH2 protein, human; D010880:Piperidines; D021122:Protein Subunits; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase