4‑Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity NaikMaruti HumnabadkarVaishali TantrySubramanyam J. PandaManoranjan NarayanAshwini GupthaSupreeth PandugaVijender ManjrekarPraveena JenaLalit kumar KoushikKrishna ShanbhagGajanan JatheendranathSandesh ManjunathaM. R. GoraiGopinath BathulaChandramohan RudrapatnaSuresh AcharVijayashree SharmaSreevalli AmbadyAnisha HegdeNaina MahadevaswamyJyothi KaurParvinder SambandamurthyVasan K. AwasthyDisha NarayanChandan RavishankarSudha MadhavapeddiPrashanti ReddyJitendar PrabhakarKR SaralayaRamanatha ChatterjiMonalisa WhiteakerJames McLaughlinBob ChiarelliLaurent R. RiccardiGiovanna PascaMaria Rosalia BindaClaudia NeresJoão DharNeeraj Signorino-GeloFrançois McKinneyJohn D. RamachandranVasanthi ShandilRadha TommasiRuben IyerPravin S. NarayananShridhar HosagraharaVinayak KavanaghStefan DineshNeela GhorpadeSandeep R. 2014 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 (IC<sub>50</sub> < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.