4 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 μM
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
Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting InhA in Mycobacterium tuberculosis
InhA
is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid.
Translating enzyme inhibition to bacterial cidality by targeting the
fatty acid substrate site of InhA remains a daunting challenge. The
recent disclosure of a methyl-thiazole series demonstrates that bacterial
cidality can be achieved with potent enzyme inhibition and appropriate
physicochemical properties. In this study, we report the molecular
mode of action of a lead methyl-thiazole, along with analogues with
improved CYP inhibition profile. We have identified a novel mechanism
of InhA inhibition characterized by a hitherto unreported “Y158-out”
inhibitor-bound conformation of the protein that accommodates a neutrally
charged “warhead”. An additional novel hydrophilic interaction
with protein residue M98 allows the incorporation of favorable physicochemical
properties for cellular activity. Notably, the methyl-thiazole prefers
the NADH-bound form of the enzyme with a <i>K</i><sub>d</sub> of ∼13.7 nM, as against the NAD<sup>+</sup>-bound form of
the enzyme
Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
Whole-cell high-throughput
screening of the AstraZeneca compound
library against the asexual blood stage of Plasmodium
falciparum (<i>Pf</i>) led to the identification
of amino imidazoles, a robust starting point for initiating a hit-to-lead
medicinal chemistry effort. Structure–activity relationship
studies followed by pharmacokinetics optimization resulted in the
identification of <b>23</b> as an attractive lead with good
oral bioavailability. Compound <b>23</b> was found to be efficacious
(ED<sub>90</sub> of 28.6 mg·kg<sup>–1</sup>) in the humanized P. falciparum mouse model of malaria (<i>Pf</i>/SCID model). Representative compounds displayed a moderate to fast
killing profile that is comparable to that of chloroquine. This series
demonstrates no cross-resistance against a panel of <i>Pf</i> strains with mutations to known antimalarial drugs, thereby suggesting
a novel mechanism of action for this chemical class