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 non-covalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ~100 minutes on the enzyme. In general, AQs have excellent lead-like 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, SAR optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 <10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.

4-Aminoquinolone Piperidine Amides: Non-Covalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity.

CHIARELLI, LAURENT;RICCARDI, GIOVANNA;PASCA, MARIA ROSALIA;BINDA, CLAUDIA;
2014-01-01

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 non-covalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ~100 minutes on the enzyme. In general, AQs have excellent lead-like 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, SAR 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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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/873034
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