| Autor: |
Monalisa Chatterji, João Neres, Sreevalli Sharma, Prashanti Madhavapeddi, Vijender Panduga, James D. Whiteaker, Suresh Rudrapatna, Chandan Narayan, Krishna Koushik, Laurent R. Chiarelli, Gajanan Shanbhag, Vaishali Humnabadkar, Gopinath Gorai, Claudia Binda, Sandeep R. Ghorpade, Radha Shandil, Neeraj Dhar, Maria Rosalia Pasca, Stefan Kavanagh, Vasan K. Sambandamurthy, M. R. Manjunatha, K.R. Prabhakar, Vijayashree Achar, John D. McKinney, Neela Dinesh, Naina Hegde, Praveena Manjrekar, François Signorino-Gelo, Parvinder Kaur, Shridhar Narayanan, Jitendar Reddy, Subramanyam J. Tantry, Ashwini Narayan, Sandesh Jatheendranath, Lalit kumar Jena, Tommasi Ruben A, Jyothi Mahadevaswamy, Disha Awasthy, Ramanatha Saralaya, Manoranjan Panda, Bob McLaughlin, Anisha Ambady, Vinayak Hosagrahara, Pravin Iyer, Chandramohan Bathula, Maruti Naik, Giovanna Riccardi, Supreeth Guptha, Sudha Ravishankar, Vasanthi Ramachandran |
| Rok vydání: |
2014 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 57(12) |
| ISSN: |
1520-4804 |
| Popis: |
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-beta-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 similar to 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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