4 research outputs found
2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis:Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization
<i>Mycobacterium tuberculosis</i> (<i>MTb</i>) possesses
two nonproton pumping type II NADH dehydrogenase (NDH-2)
enzymes which are predicted to be jointly essential for respiratory
metabolism. Furthermore, the structure of a closely related bacterial
NDH-2 has been reported recently, allowing for the structure-based
design of small-molecule inhibitors. Herein, we disclose <i>MTb</i> whole-cell structure–activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the <i>ndh</i> encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in <i>MTb</i> was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by <i>ndhA</i> in <i>MTb</i>. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial <i>MTb</i> SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors
Structure–Activity Relationship Studies of Orally Active Antimalarial 3,5-Substituted 2‑Aminopyridines
In an effort to address potential cardiotoxicity liabilities
identified
with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine
derivatives were synthesized. Several compounds exhibited potent antiplasmodial
activity against both the multidrug resistant (K1) and sensitive (NF54)
strains in the low nanomolar range. Some compounds displayed a significant
reduction in potency in the hERG channel inhibition assay compared
to previously reported frontrunner analogues. Several of these new
analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further
evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial
and hERG activity was delineated
2,4-Diaminothienopyrimidines as Orally Active Antimalarial Agents
A novel
series of 2,4-diaminothienopyrimidines with potential as
antimalarials was identified from whole-cell high-throughput screening
of a SoftFocus ion channel library. Synthesis and structure–activity
relationship studies identified compounds with potent antiplasmodial
activity and low in vitro cytotoxicity. Several of these analogues
exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the
hERG potassium channel was identified as a liability for this series
3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential
A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines
has been identified from phenotypic whole cell high-throughput screening
of a commercially available SoftFocus kinase library. The compounds
were evaluated in vitro for their antiplasmodial activity against
K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible
strain) as well as for their cytotoxicity. Synthesis and structure–activity
studies identified a number of promising compounds with selective
antiplasmodial activity. One of these frontrunner compounds, <b>15</b>, was equipotent across the two strains (K1 = 25.0 nM, NF54
= 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine
IC<sub>50</sub> K1 = 194.0 nM). Compound <b>15</b> completely
cured <i>Plasmodium berghei</i>-infected mice with a single
oral dose of 30 mg/kg. Dose–response studies generated ED<sub>50</sub> and ED<sub>90</sub> values of 0.83 and 1.74 mg/kg for <b>15</b> in the standard four-dose Peters test. Pharmacokinetic
studies in the rat indicated that this compound has good oral bioavailability
(51% at 20 mg/kg) and a reasonable half-life (<i>t</i><sub>1/2</sub> ∼ 7–8 h)