New Chromane-Based Derivatives as Inhibitors of Mycobacterium tuberculosis Salicylate Synthase (MbtI): Preliminary Biological Evaluation and Molecular Modeling Studies

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

The role of vascular endothelial growth factor and matrix metalloproteinases in canine lymphoma: in vivo and in vitro study

Background: Canine lymphoma represents the most frequent haematopoietic cancer and it shares some similarities with human non-Hodgkin lymphoma. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play a coordinated role during invasion and proliferation of malignant cells; however, little is known about their role in canine haematologic malignancies. The aim of this study was to investigate the mRNA and protein expression of VEGF and the most relevant MMPs in canine lymphoma. Lymph node aspirates from 26 B-cell and 21 T-cell lymphomas were collected. The protein expression levels of MMP-9, MMP-2 and VEGF-A were evaluated by immunocytochemistry, and the mRNA levels of MMP-2, MMP-9, MT1-MMP, TIMP-1, TIMP-2, RECK, VEGF-A and VEGF-164 were measured using quantitative RT-PCR.Results: MT1-MMP, TIMP-1 and RECK mRNA levels were significantly higher in T-cell lymphomas than in B-cell lymphomas. Higher mRNA and protein levels of MMP-9 and VEGF-A were observed in T-cell lymphomas than in B-cell lymphomas and healthy control lymph nodes. A positive correlation was found between MMP-9 and VEGF-A in T-cell lymphomas. Moreover, MMP-9, MT1-MMP, TIMP-1 and VEGF-A were expressed at the highest levels in high-grade T-cell lymphomas.Conclusions: This study provides new information on the expression of different MMPs and VEGF in canine lymphoma, suggesting a possible correlation between different MMPs and VEGF, immunophenotype and prognosis

Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents

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 (Ki = 5.3 μM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 μM), which is conceivably related to mycobactin biosynthesis inhibition

Crystal structure of 3-(3-oxo-2,3,4,4a,5,6-hexahydrobenzo[h]cinnolin-2-yl)propionic acid

The asymmetric unit of the title compound, C15H16N2O3, contains two independent molecules, which present a different conformation of the carboxylic acid side chain [C—C—C—OH torsion angles = 65.3 (7) and −170.1 (5)°]. In both molecules, the dihydropyridazinone ring adopts a geometry intermediate between a twisted-boat and a half-chair conformation, while the central six-membered ring is almost in a half-boat conformation. In the crystal, molecules are linked by O—H...Ok (k = ketone) hydrogen bonds, generating [01-1] chains. Aromatic π–π stacking contacts between the benzene and the dihydropyridazinone rings [centroid–centroid distance [3.879 (9) Å] are also observed

Insights on the Modulation of SIRT5 Activity: A Challenging Balance

SIRT5 is a member of the Sirtuin family, a class of deacetylating enzymes consisting of seven isoforms, involved in the regulation of several processes, including gene expression, metabolism, stress response, and aging. Considering that the anomalous activity of SIRT5 is linked to many pathological conditions, we present herein an overview of the most interesting modulators, with the aim of contributing to further development in this field

Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach

Signal transducer and activator of transcription 3 (STAT3) plays an essential role in cell growth regulation and survival. An aberrant STAT3 activation and/or expression is implied in various solid and blood tumors as well as in other pathologies like rheumatoid arthritis and pulmonary fibrosis, thus making the search for STAT3 inhibitors a growing field of study. With the aim of identifying new inhibitors of STAT3 dimerization, we screened a database including more than 1 320 000 commercially available compounds using a receptor-based pharmacophore model comprising the key protein-protein interactions identified in the STAT3 dimer and refining the search through docking and molecular dynamic simulations studies. STAT3 binding assays revealed a significant STAT3 inhibitory activity and selectivity versus Grb2 for one of the four top-scored compounds, thus verifying the reliability of the virtual screening workflow. Moreover, such compound could already be considered as a lead for the development of new and more potent STAT3 dimerization inhibitors