title: 4-aminoquinolone piperidine amides: noncovalent inhibitors of DprE1 with long residence time and potent antimycobacterial activity.
abstract: 4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biosciences, and §DMPK (Drug Metabolism and Pharmacokinetics) and Animal Sciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore 560024, India.
authors.forename: Maruti
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authors.forename: Vaishali
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authors.lastname: Humnabadkar
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authors.forename: Vijayashree
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authors.lastname: Achar
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authors.lastname: Narayan
authors.forename: Sudha
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authors.lastname: Ravishankar
authors.forename: Prashanti
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authors.forename: Jitendar
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authors.forename: Ramanatha
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authors.forename: Monalisa
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authors.lastname: Chatterji
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authors.lastname: Whiteaker
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authors.lastname: McLaughlin
authors.forename: Laurent R
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authors.lastname: Chiarelli
authors.forename: Giovanna
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authors.lastname: Riccardi
authors.forename: Maria Rosalia
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authors.lastname: Pasca
authors.forename: Claudia
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authors.lastname: Binda
authors.forename: João
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authors.lastname: Neres
authors.forename: Neeraj
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authors.lastname: Dhar
authors.forename: François
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authors.lastname: Signorino-Gelo
authors.forename: John D
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authors.lastname: McKinney
authors.forename: Vasanthi
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authors.lastname: Ramachandran
authors.forename: Radha
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authors.lastname: Shandil
authors.forename: Ruben
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authors.lastname: Tommasi
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Iyer
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.forename: Vinayak
authors.initials: V
authors.lastname: Hosagrahara
authors.forename: Stefan
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authors.lastname: Kavanagh
authors.forename: Neela
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authors.lastname: Dinesh
authors.forename: Sandeep R
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mesh_terms: D000429:Alcohol Oxidoreductases; D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D024881:Drug Resistance, Bacterial; D016680:Genome, Bacterial; D006801:Humans; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D015363:Quinolones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010880:Piperidines; D015363:Quinolones; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C583625:DprE1 protein, Mycobacterium tuberculosis