Naik, Maruti Humnabadkar, Vaishali Tantry, Subramanyam J. Panda, Manoranjan Narayan, Ashwini Guptha, Supreeth Panduga, Vijender Manjrekar, Praveena Jena, Lalit kumar Koushik, Krishna Shanbhag, Gajanan Jatheendranath, Sandesh Manjunatha, M. R. Gorai, Gopinath Bathula, Chandramohan Rudrapatna, Suresh Achar, Vijayashree Sharma, Sreevalli Ambady, Anisha Hegde, Naina Mahadevaswamy, Jyothi Kaur, Parvinder Sambandamurthy, Vasan K. Awasthy, Disha Narayan, Chandan Ravishankar, Sudha Madhavapeddi, Prashanti Reddy, Jitendar Prabhakar, KR Saralaya, Ramanatha Chatterji, Monalisa Whiteaker, James McLaughlin, Bob Chiarelli, Laurent R. Riccardi, Giovanna Pasca, Maria Rosalia Binda, Claudia Neres, João Dhar, Neeraj Signorino-Gelo, François McKinney, John D. Ramachandran, Vasanthi Shandil, Radha Tommasi, Ruben Iyer, Pravin S. Narayanan, Shridhar Hosagrahara, Vinayak Kavanagh, Stefan Dinesh, Neela Ghorpade, Sandeep R. 4‑Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity 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. MIC;enzyme;compound;scaffold;Long Residence Time;Mtb;cell screen;nM;DprE 1;AQ;IC;DprE 1 inhibition 2014-06-26
    https://acs.figshare.com/articles/dataset/4_Aminoquinolone_Piperidine_Amides_Noncovalent_Inhibitors_of_DprE1_with_Long_Residence_Time_and_Potent_Antimycobacterial_Activity/2279410
10.1021/jm5005978.s002