Emanuele Amata

Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery

Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors’ biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.

Development of a Sigma-2 Receptor affinity filter through a Monte Carlo based QSAR analysis

Abstract For the first time in sigma‐2 (&sgr;2) receptor field, a quantitative structure–activity relationship (QSAR) model has been built using pKi values of the whole set of known selective &sgr;2 receptor ligands (548 compounds), taken from the Sigma‐2 Receptor Selective Ligands Database (S2RSLDB) (http://www.researchdsf.unict.it/S2RSLDB/), through the Monte Carlo technique and employing the software CORAL. The model has been developed by using a large and structurally diverse set of compounds, allowing for a prediction of different populations of chemical compounds endpoint (&sgr;2 receptor pKi). The statistical quality reached, suggested that model for pKi determination is robust and possesses a satisfactory predictive potential. The statistical quality is high for both visible and invisible sets. The screening of the FDA approved drugs, external to our dataset, suggested that sixteen compounds might be repositioned as &sgr;2 receptor ligands (predicted pKi ≥ 8). A literature check showed that six of these compounds have already been tested for affinity at &sgr;2 receptor and, of these, two (Flunarizine and Terbinafine) have shown an experimental &sgr;2 receptor pKi > 7. This suggests that this QSAR model may be used as focusing screening filter in order to prospectively find or repurpose new drugs with high affinity for the &sgr;2 receptor, and overall allowing for an enhanced hit rate respect to a random screening. Graphical abstract Figure. No Caption available.

S2RSLDB: a comprehensive manually curated, internet-accessible database of the sigma-2 receptor selective ligands

AbstractBackground Sigma (σ) receptors are accepted as a particular receptor class consisting of two subtypes: sigma-1 (σ1) and sigma-2 (σ2). The two receptor subtypes have specific drug actions, pharmacological profiles and molecular characteristics. The σ2 receptor is overexpressed in several tumor cell lines, and its ligands are currently under investigation for their role in tumor diagnosis and treatment. The σ2 receptor structure has not been disclosed, and researchers rely on σ2 receptor radioligand binding assay to understand the receptor’s pharmacological behavior and design new lead compounds.Description Here we present the sigma-2 Receptor Selective Ligands Database (S2RSLDB) a manually curated database of the σ2 receptor selective ligands containing more than 650 compounds. The database is built with chemical structure information, radioligand binding affinity data, computed physicochemical properties, and experimental radioligand binding procedures. The S2RSLDB is freely available online without account login and having a powerful search engine the user may build complex queries, sort tabulated results, generate color coded 2D and 3D graphs and download the data for additional screening.ConclusionThe collection here reported is extremely useful for the development of new ligands endowed of σ2 receptor affinity, selectivity, and appropriate physicochemical properties. The database will be updated yearly and in the near future, an online submission form will be available to help with keeping the database widely spread in the research community and continually updated. The database is available at http://www.researchdsf.unict.it/S2RSLDB.Graphical abstract

Sigma-2 receptor ligands QSAR model dataset

The data have been obtained from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB) and refined according to the QSAR requirements. These data provide information about a set of 548 Sigma-2 (σ2) receptor ligands selective over Sigma-1 (σ1) receptor. The development of the QSAR model has been undertaken with the use of CORAL software using SMILES, molecular graphs and hybrid descriptors (SMILES and graph together). Data here reported include the regression for σ2 receptor pKi QSAR models. The QSAR model was also employed to predict the σ2 receptor pKi values of the FDA approved drugs that are herewith included.

Recent advances in drug discovery of phototherapeutic non-porphyrinic anticancer agents

In the search of novel strategies for the treatment of cancer, photodynamic therapy (PDT) has emerged as an effective, safe for repeated use, and non-invasive method. This technique involves the use of two major non-toxic components, a photosensitizer (PS) and a visible or near-infrared (NIR) light source, combined to induce cellular damage in an oxygen-dependent or -independent manner. Macrocyclic compounds, involving porphyrin and their derivatives, represent the major class of PS agents used in PDT. However, due to the drawbacks associated with these PS, like photosensitivity, dark toxicity, and low wavelength absorbance, new classes of PS appear to be needed. This review summarizes over the recent advances in drug discovery of non-porphyrinic PS suitable as anticancer therapeutics in PDT. The different compounds are grouped by chemical classes and discussed in terms of phototoxicity, together with the critical aspects of design and structure-activity relationship.

4-Nitro-2,1,3-benzoxadiazole derivatives as potential fluorescent sigma receptor probes

New fluorescent derivatives for σ receptors were designed and synthesized. To achieve this purpose, a 4-nitro-2,1,3-benzoxadiazole fluorescent tag was connected through a piperazine linker to a modified skeleton derived from selected σ receptor agonists or antagonists. Compounds 5g, 7b, 7e and 7g displayed high σ1 affinity and low σ1/σ2 selectivity (Kiσ1 ranging from 31.6 nM to 48.5 nM, Kiσ1/σ2 = 5–18), while compound 5d exhibited high σ2 affinity and selectivity (Kiσ2 = 56.8 nM, Kiσ1 > 5000 nM). Binding affinity studies revealed that compounds 5d, 5g, 7b, 7e and 7g showed no affinity towards several receptors including opioid, dopaminergic, serotonergic, adrenergic, muscarinic, histaminergic, N-methyl-D-aspartate (NMDA), NMDA receptor channel, or dopamine and serotonine transporters. The fluorescent properties, cellular uptake and confocal microscopy studies on 5d suggest a potential use of this probe to further clarify the molecular role of σ2 receptor subtypes in normal and cancer cells.

Heme Oxygenase Database (HemeOxDB) and QSAR Analysis of Isoform 1 Inhibitors

Due to increasing interest in the field of heme oxygenases (HOs), we built a ligand database called HemeOxDB that includes the entire set of known HO‐1 and HO‐2 inhibitors, resulting in more than 400 compounds. The HemeOxDB is available online at http://www.researchdsf.unict.it/hemeoxdb/, and having a robust search engine allows end users to build complex queries, sort tabulated results, and generate color‐coded two‐ and three‐dimensional graphs. This database will grow to be a tool for the design of potent and selective HO‐1 or HO‐2 inhibitors. We were also interested in virtually searching for alternative inhibitors, and, for the first time in the field of HOs, a quantitative structure–activity relationship (QSAR) model was built using half‐maximal inhibitory concentration (IC50) values of the whole set of known HO‐1 inhibitors, taken from the HemeOxDB and employing the Monte Carlo technique. The statistical quality suggested that the model is robust and possesses desirable predictive potential. The screening of US Food and Drug Administration (FDA)‐approved drugs, external to our dataset, suggested new predicted inhibitors, opening the way for replacing imidazole groups. The HemeOxDB and the QSAR model reported herein may help in prospectively identifying or repurposing new drugs with optimal structural attributes for HO enzyme inhibition.

Comprehensive data on a 2D-QSAR model for Heme Oxygenase isoform 1 inhibitors

The data have been obtained from the Heme Oxygenase Database (HemeOxDB) and refined according to the 2D-QSAR requirements. These data provide information about a set of more than 380 Heme Oxygenase-1 (HO-1) inhibitors. The development of the 2D-QSAR model has been undertaken with the use of CORAL software using SMILES, molecular graphs and hybrid descriptors (SMILES and graph together). The 2D-QSAR model regressions for HO-1 half maximal inhibitory concentration (IC50) expressed as pIC50 (pIC50=−LogIC50) are here included. The 2D-QSAR model was also employed to predict the HO-1 pIC50values of the FDA approved drugs that are herewith reported.

Heme oxygenase-1: A new druggable target in the management of chronic and acute myeloid leukemia

Heme oxygenase-1 (HO-1) is the enzyme catalyzing the rate-limiting oxidative degradation of cellular heme into free iron, carbon monoxide (CO), and biliverdin, which is then rapidly converted into bilirubin. By means of these catabolic end-products and by removal of pro-oxidant heme, HO-1 exerts antioxidant, antiapoptotic, and immune-modulating effects, leading to overall cytoprotective and beneficial functions in mammalian cells. Therefore, HO-1 is considered a survival molecule in various stress-related conditions. By contrast, growing evidence suggests that HO-1 is a survival-enhancing molecule also in various solid and blood cancers, such as various types of leukemia, promoting carcinogenesis, tumor progression, and chemo-resistance. Among leukemias, chronic myeloid leukemia (CML) is currently therapeutically well treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM) and its congeners; nevertheless, resistance to all kinds of current drugs persist in a number of patients. Moreover, treatment outcomes for acute myeloid leukemia (AML) remain unsatisfactory, despite progress in chemotherapy and hematopoietic stem cell transplantation. Therefore, identification of new eligible targets that may improve leukemias therapy is of general interest. Several recent papers prove that inhibition of HO-1 through HO-1 inhibitors as well as modulation of other pathways involving HO-1 by a number of different new or known molecules, are critical for leukemia treatment. This review summarizes the current understanding of the pro-tumorigenic role of HO-1 and its potential as a molecular target for the treatment of leukemias.

Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. A comprehensive systematic review

Small molecule inhibitors of adipocyte fatty acid binding protein 4 (FABP4) have attracted interest following the recent publications of beneficial pharmacological effects of these compounds. FABP4 is predominantly expressed in macrophages and adipose tissue where it regulates fatty acids (FAs) storage and lipolysis and is an important mediator of inflammation. In the past years, hundreds FABP4 inhibitors have been synthesized for effective atherosclerosis and diabetes treatments, including derivatives of niacin, quinoxaline, aryl-quinoline, bicyclic pyridine, urea, aromatic compounds and other novel heterocyclic compounds. This review provides an overview of the synthesized and discovered molecules as adipocyte fatty acid binding protein 4 inhibitors (FABP4is) since the synthesis of the putative FABP4i, BMS309403, highlighting the interactions of the different classes of inhibitors with the targets.