5 research outputs found
2‑Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against <i>Mycobacterium tuberculosis</i>
A cellular activity-based screen
on <i>Mycobacterium tuberculosis</i> (Mtb) H37Rv using a
focused library from the AstraZeneca corporate
collection led to the identification of 2-phenylindoles and arylsulphonamides,
novel antimycobacterial scaffolds. Both the series were bactericidal <i>in vitro</i> and in an intracellular macrophage infection model,
active against drug sensitive and drug resistant Mtb clinical isolates,
and specific to mycobacteria. The scaffolds showed promising structure–activity
relationships; compounds with submicromolar cellular potency were
identified during the hit to lead exploration. Furthermore, compounds
from both scaffolds were tested for inhibition of known target enzymes
or pathways of antimycobacterial drugs including InhA, RNA polymerase,
DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation.
Compounds did not inhibit any of the targets suggesting the potential
of a possible novel mode of action(s). Hence, both scaffolds provide
the opportunity to be developed further as leads and tool compounds
to uncover novel mechanisms for tuberculosis drug discovery
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
Structure Guided Lead Generation for <i>M. tuberculosis</i> Thymidylate Kinase (Mtb TMK): Discovery of 3‑Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors
<i>M. tuberculosis</i> thymidylate
kinase (Mtb TMK) has
been shown in vitro to be an essential
enzyme in DNA synthesis. In order to identify novel leads for Mtb
TMK, we performed a high throughput biochemical screen and an NMR
based fragment screen through which we discovered two novel classes
of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively.
We describe three cyanopyridone subseries that arose during our hit
to lead campaign, along with cocrystal structures of representatives
with Mtb TMK. Structure aided optimization of the cyanopyridones led
to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead
generation, augmented by crystal structures and the SAR from the cyanopyridones,
enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment
hit from 500 μM to 200 nM while simultaneously improving the
ligand efficiency. Cyanopyridone derivatives containing sulfoxides
and sulfones showed cellular activity against <i>M. tuberculosis</i>. To the best of our knowledge, these compounds are the first reports
of non-thymidine-like inhibitors of Mtb TMK
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
4‑Aminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity
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 noncovalent, reversible inhibitors
of DprE1 with slow on rates and long residence times of ∼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 (IC<sub>50</sub> < 10 nM) along with potent cellular activity (MIC = 60
nM) against Mtb