3 research outputs found
Quinolinyl Pyrimidines: Potent Inhibitors of NDH-2 as a Novel Class of Anti-TB Agents
NDH-2 is an essential respiratory enzyme in <i>Mycobacterium
tuberculosis</i> (Mtb), which plays an important role in the
physiology of Mtb. Herein, we present a target-based effort to identify
a new structural class of inhibitors for NDH-2. High-throughput screening
of the AstraZeneca corporate collection resulted in the identification
of quinolinyl pyrimidines as the most promising class of NDH-2 inhibitors.
Structure–activity relationship studies showed improved enzyme
inhibition (IC<sub>50</sub>) against the NDH-2 target, which in turn
translated into cellular activity against Mtb. Thus, the compounds
in this class show a good correlation between enzyme inhibition and
cellular potency. Furthermore, early ADME profiling of the best compounds
showed promising results and highlighted the quinolinyl pyrimidine
class as a potential lead for further development
Biarylmethoxy Nicotinamides As Novel and Specific Inhibitors of <i>Mycobacterium tuberculosis</i>
A whole cell based screening effort
on a focused library from corporate
collection resulted in the identification of biarylmethoxy nicotinamides
as novel inhibitors of <i>M. tuberculosis</i> (Mtu) H37Rv.
The series exhibited tangible structure–activity relationships,
and during hit to lead exploration, a cellular potency of 100 nM was
achieved, which is an improvement of >200-fold from the starting
point.
The series is very specific to Mtu and noncytotoxic up to 250 ÎĽM
as measured in the mammalian cell line THP-1 based cytotoxicity assay.
This compound class retains its potency on several drug sensitive
and single drug resistant clinical isolates, which indicate that the
compounds could be acting through a novel mode of action
Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious <i>in Vivo</i>
We report 1,4-azaindoles as a new
inhibitor class that kills Mycobacterium tuberculosis <i>in vitro</i> and demonstrates efficacy in mouse tuberculosis
models. The series emerged from scaffold morphing efforts and was
demonstrated to noncovalently inhibit decaprenylphosphoryl-β-d-ribose2′-epimerase (DprE1). With “drug-like”
properties and no expectation of pre-existing resistance in the clinic,
this chemical class has the potential to be developed as a therapy
for drug-sensitive and drug-resistant tuberculosis