27 research outputs found
Novel Solution- and Solid-Phase Strategies for the Parallel and Combinatorial Synthesis of Small-Molecular-Weight Compound Libraries
In this account dedicated to '100 years Roche' in CHIMIA, we present some of our strategies towards the synthesis of interesting novel amino-acid-derived building blocks; multigeneration synthesis of thiazole libraries in solution; a novel solid-phase approach towards highly substituted pyrimidines using a novel safety-catch linker principle and a multidirectional cleavage procedure; a versatile solid-phase synthesis of quinazolones taking advantage of the Staudinger phosphorylimine chemistry combined with a novel cyclization and cleavage strategy, and finally a novel solid-phase diketopiperazine synthesis combining the Ugi four-component reaction with a final ring-forming cleavage step
Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB
With
the emergence of multidrug-resistant strains of <i>Mycobacterium
tuberculosis</i> there is a pressing need for new oral drugs
with novel mechanisms of action. Herein, we describe the identification
of a novel morpholino–thiophenes (MOT) series following phenotypic
screening of the Eli Lilly corporate library against <i>M. tuberculosis</i> strain H37Rv. The design, synthesis, and structure–activity
relationships of a range of analogues around the confirmed actives
are described. Optimized leads with potent whole cell activity against
H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine
model of infection are described. Mode-of-action studies suggest that
the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome <i>c</i> oxidoreductase, part of the bc1-aa3-type cytochrome <i>c</i> oxidase complex that is responsible for driving oxygen-dependent
respiration
A high-throughput screen against pantothenate synthetase (PanC) identifies 3-biphenyl-4-cyanopyrrole-2-carboxylic acids as a new class of inhibitor with activity against Mycobacterium tuberculosis
The enzyme pantothenate synthetase, PanC, is an attractive drug target in Mycobacterium tuberculosis . It is essential for the in vitro growth of M. tuberculosis and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identify inhibitors of PanC, optimized it for high-throughput screening, and tested a large and diverse library of compounds for activity. Two compounds belonging to the same chemical class of 3-biphenyl-4- cyanopyrrole-2-carboxylic acids had activity against the purified recombinant protein, and also inhibited growth of live M. tuberculosis in manner consistent with PanC inhibition. Thus we have identified a new class of PanC inhibitors with whole cell activity that can be further developed
Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth
Novel Solution- and Solid-Phase Syntheses of Heterocyclic Systems
Heterocyclic compounds are an attractive source of screening library structures because they possess varied structural diversity and can exhibit potent biological activity. In this context, we present some of our new and versatile approaches to rapid and efficient syntheses of pharmacologically
relevant core structures. These include: combination of both solution- and solid-phase processes in the synthesis of pyrazolo[1,5-a]-[1,3,5]-triazin-4-ones and pyrazolo[1,5-a]-[1,3,5]-triazines; parallel, multi-generation synthesis of highly functionalized heterocyclic compounds
in solution; a multi-step synthesis of 2,5-diketopiperazine on solid support taking advantage of a bicyclic ?-lactam scaffold, and a combined solid- and solution-phase synthesis of a new class of 2,4-diaminothiazoles
Novel Solution- and Solid-Phase Syntheses of Heterocyclic Systems
Heterocyclic compounds are an attractive source of screening library structures because they possess varied structural diversity and can exhibit potent biological activity. In this context, we present some of our new and versatile approaches to rapid and efficient syntheses of pharmacologically
relevant core structures. These include: combination of both solution- and solid-phase processes in the synthesis of pyrazolo[1,5-a]-[1,3,5]-triazin-4-ones and pyrazolo[1,5-a]-[1,3,5]-triazines; parallel, multi-generation synthesis of highly functionalized heterocyclic compounds
in solution; a multi-step synthesis of 2,5-diketopiperazine on solid support taking advantage of a bicyclic ?-lactam scaffold, and a combined solid- and solution-phase synthesis of a new class of 2,4-diaminothiazoles
Prediction of drug penetration in tuberculosis lesions
The
penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous
and drug-specific, but the factors underlying such differential partitioning
are unknown. We hypothesized that drug binding to macromolecules in
necrotic foci (or caseum) prevents passive drug diffusion through
avascular caseum, a critical site of infection. Using a caseum binding
assay and MALDI mass spectrometry imaging of tuberculosis drugs, we
showed that binding to caseum inversely correlates with passive diffusion
into the necrotic core. We developed a high-throughput assay relying
on rapid equilibrium dialysis and a caseum surrogate designed to mimic
the composition of native caseum. A set of 279 compounds was profiled
in this assay to generate a large data set and explore the physicochemical
drivers of free diffusion into caseum. Principle component analysis
and modeling of the data set delivered an in silico signature predictive
of caseum binding, combining 69 molecular descriptors. Among the major
positive drivers of binding were high lipophilicity and poor solubility.
Determinants of molecular shape such as the number of rings, particularly
aromatic rings, number of sp<sup>2</sup> carbon counts, and volume-to-surface
ratio negatively correlated with the free fraction, indicating that
low-molecular-weight nonflat compounds are more likely to exhibit
low caseum binding properties and diffuse effectively through caseum.
To provide simple guidance in the property-based design of new compounds,
a rule of thumb was derived whereby the sum of the hydrophobicity
(clogP) and aromatic ring
count is proportional to caseum binding. These tools can be used to
ensure desirable lesion partitioning and guide the selection of optimal
regimens against tuberculosis
In Vitro Evaluation of Novel Nitazoxanide Derivatives against Mycobacterium tuberculosis
Synthesis and Evaluation of the 2-Aminothiazoles as Anti-Tubercular Agents.
The 2-aminothiazole series has anti-bacterial activity against the important global pathogen Mycobacterium tuberculosis. We explored the nature of the activity by designing and synthesizing a large number of analogs and testing these for activity against M. tuberculosis, as well as eukaryotic cells. We determined that the C-2 position of the thiazole can accommodate a range of lipophilic substitutions, while both the C-4 position and the thiazole core are sensitive to change. The series has good activity against M. tuberculosis growth with sub-micromolar minimum inhibitory concentrations being achieved. A representative analog was selective for mycobacterial species over other bacteria and was rapidly bactericidal against replicating M. tuberculosis. The mode of action does not appear to involve iron chelation. We conclude that this series has potential for further development as novel anti-tubercular agents