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4‑Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity

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posted on 26.06.2014, 00:00 by Maruti Naik, Vaishali Humnabadkar, Subramanyam J. Tantry, Manoranjan Panda, Ashwini Narayan, Supreeth Guptha, Vijender Panduga, Praveena Manjrekar, Lalit kumar Jena, Krishna Koushik, Gajanan Shanbhag, Sandesh Jatheendranath, M. R. Manjunatha, Gopinath Gorai, Chandramohan Bathula, Suresh Rudrapatna, Vijayashree Achar, Sreevalli Sharma, Anisha Ambady, Naina Hegde, Jyothi Mahadevaswamy, Parvinder Kaur, Vasan K. Sambandamurthy, Disha Awasthy, Chandan Narayan, Sudha Ravishankar, Prashanti Madhavapeddi, Jitendar Reddy, KR Prabhakar, Ramanatha Saralaya, Monalisa Chatterji, James Whiteaker, Bob McLaughlin, Laurent R. Chiarelli, Giovanna Riccardi, Maria Rosalia Pasca, Claudia Binda, João Neres, Neeraj Dhar, François Signorino-Gelo, John D. McKinney, Vasanthi Ramachandran, Radha Shandil, Ruben Tommasi, Pravin S. Iyer, Shridhar Narayanan, Vinayak Hosagrahara, Stefan Kavanagh, Neela Dinesh, Sandeep R. Ghorpade
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.

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