We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (K = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition.
Starting from the analysis of the hypothetical binding mode of our previous furan-based hit (I), we successfully achieved our objective to replace the nitro moiety, leading to the disclosure of a new lead exhibiting a strong activity against MbtI. Our best candidate 1 h displayed a Ki of 8.8 µM and its antimycobacterial activity (MIC99 = 250 µM) is conceivably related to mycobactin biosynthesis inhibition. These results support the hypothesis that 5-phenylfuran-2-carboxylic derivatives are a promising class of MbtI inhibitors.
The huge number of direct STAT3 inhibitors recently identified demonstrates a strong interest in the investigation of this target, although it represents a challenging task considering that no drug targeting this enzyme is currently available for anticancer therapy. Notably, many studies on the available inhibitors evidenced that some of them possess a dual mechanism of action.
Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 μM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), still remains an
urgent global health issue, mainly due to the emergence of multi-drug resistant strains. Therefore, there
is a pressing need to develop novel and more efficient drugs to control the disease. In this context, targeting
the pathogen virulence factors, and particularly signal mechanisms, seems to be a promising
approach. An important transmembrane signaling system in Mtb is represented by receptor-type Serine/
Threonine protein kinases (STPKs). Mtb has 11 different STPKs, two of them, PknA and PknB, are
essential. By contrast PknG and PknH are involved in Mtb virulence and adaptation, and are fundamental
for the pathogen growth in infection models. Therefore, STPKs represent a very interesting group of
pharmacological targets in M. tuberculosis. In this work, the principal inhibitors of the mycobacterial
STPKs will be presented and discussed. In particular, medicinal chemistry efforts have been focused on
discovering new antimycobacterial compounds, targeting three of these kinases, namely PknA, PknB
and PknG. Generally, the inhibitory effect on these enzymes do not correlate with a significant antimycobacterial
action in whole-cell assays. However, compounds with activity in the low micromolar range
have been obtained, demonstrating that targeting Mtb STPKs could be a new promising strategy for the
development of drugs to treat TB infections.
The
Mg
2+
-dependent
Mycobacterium tuberculosis
salicylate synthase (MbtI) is a key enzyme involved in the biosynthesis
of siderophores. Because iron is essential for the survival and pathogenicity
of the microorganism, this protein constitutes an attractive target
for antitubercular therapy, also considering the absence of homologous
enzymes in mammals. An extension of the structure–activity
relationships of our furan-based candidates allowed us to disclose
the most potent competitive inhibitor known to date (
10
,
K
i
= 4 μM), which also proved
effective on mycobacterial cultures. By structural studies, we characterized
its unexpected Mg
2+
-independent binding mode. We also investigated
the role of the Mg
2+
cofactor in catalysis, analyzing the
first crystal structure of the MbtI–Mg
2+
–salicylate
ternary complex. Overall, these results pave the way for the development
of novel antituberculars through the rational design of improved MbtI
inhibitors.
CDC25 phosphatases play a critical role in the regulation of the cell cycle and thus represent attractive cancer therapeutic targets. We previously discovered the 4-(2carboxybenzoyl)phthalic acid (NSC28620) as a new CDC25 inhibitor endowed with promising anticancer activity in breast, prostate, and leukemia cells. Herein, we report a structure-based optimization of NSC28620, leading to the identification of a series of novel naphthylphenylketone and naphthylphenylamine derivatives as CDC25B inhibitors. Compounds 7j, 7i, 6e, 7f, and 3 showed higher inhibitory activity than the initial lead, with K i values in the low micromolar range. Kinetic analysis, intrinsic fluorescence studies, and induced fit docking simulations provided a mechanistic understanding of the activity of these derivatives. All compounds were tested in the highly aggressive human melanoma cell lines A2058 and A375. Compound 4a potently inhibited cell proliferation and colony formation, causing an increase of the G2/M phase and a reduction of the G0/G1 phase of the cell cycle in both cell lines.
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