A5052388366- Peptidase Inhibition and Analysis
- Histone Deacetylase Inhibitors Research
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Trypanosoma species research and implications
- HIV/AIDS drug development and treatment
- Research on Leishmaniasis Studies
- Synthesis of heterocyclic compounds
- Click Chemistry and Applications
- Neuroscience and Neuropharmacology Research
- Synthesis and Biological Evaluation
- Protein Degradation and Inhibitors
- Synthesis and pharmacology of benzodiazepine derivatives
- Malaria Research and Control
- Receptor Mechanisms and Signaling
- Biochemical and Molecular Research
- Bioactive Compounds and Antitumor Agents
- Pneumocystis jirovecii pneumonia detection and treatment
- Synthesis and Catalytic Reactions
- Synthesis and biological activity
- Cannabis and Cannabinoid Research
- HIV Research and Treatment
- Computational Drug Discovery Methods
- Synthetic Organic Chemistry Methods
- Cancer Mechanisms and Therapy
Wellcome Centre for Anti-Infectives Research
2020-2023
University of Dundee
2020-2023
University of Siena
2016-2021
University of Perugia
2018
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed our immunohistochemistry studies on HDAC6 overexpression in tissues. We herein developed series of novel hHDAC6 inhibitors, having low inhibitory potency over hHDAC1 and hHDAC8, as potential pharmacological tools for treatment. Their was combined vitro vivo toxicity. Structural analysis 6h structure–activity...
The development of a novel comprehensive approach for the prediction hERG activity is herein presented. Software Phase has been used to derive 3D-QSAR model, employing as alignment rule common pharmacophore built on subset 22 highly active compounds (threshold Ki: 50 nM) against K+ channel. Five features comprised pharmacophore: two aromatic rings (R1 and R2), one hydrogen-bond acceptor (A), hydrophobic site (H), positive ionizable function (P). sequential model developed with set 421...
Tuberculosis (TB) is one of the top 10 causes death worldwide. This scenario further complicated by insurgence multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification appropriate drugs with multi-target affinity profiles considered to be a widely accepted strategy overcome rapid development resistance. aim this study was discover Food Drug Administration (FDA)-approved possessing antimycobacterial activity, potentially coupled an effective profile. An integrated...
New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field urgently required. Despite concerted efforts over last several years, number of new chemical entities suitable clinical development treatment Leishmania remains low. Here, we describe discovery preclinical DNDI-6174, an inhibitor cytochrome bc 1 complex activity originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required...
We describe herein the development and experimental validation of a computational protocol for optimizing series 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from previously developed micromolar IN), we performed an in-depth investigation based on in silico structure-based combinatorial library designing approach. This method allowed us to combine design side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies Molecular Dynamics (MD)...
Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report development a series spiroindoline-based HDAC6 isoform-selective based on X-ray crystal studies hit 6a. We identified compound 6j most potent selective hHDAC6 inhibitor series. Biological investigation compounds 6b, 6h, demonstrated their antiproliferative activity against several cancer cell lines. Western blotting indicated that...
Insight into the mechanism of action oleuropein aglycone as a potent anti-amyloidogenic agent.
Schistosomiasis (also known as bilharzia) is a neglected tropical disease caused by platyhelminths of the genus Schistosoma. The endemic in and subtropical areas world where water infested intermediate parasite host, snail. More than 800 million people live more 200 are infected require treatment. Praziquantel (PZQ) drug choice for schistosomiasis treatment transmission control being safe very effective against adult worms all clinically relevant Schistosoma species. Unfortunately, it...
Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards specific isoform, limiting their clinical applicability. Among isoforms, HDAC1 represents crucial target for designing selective HDACIs, being aberrantly expressed several malignancies. Accordingly, development predictive...
Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking catabolism would elicit effects, devoid psychotropic effects. We herein report discovery selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors promising efficacy, starting from a further investigation our prototypical inhibitor 2a....
Phenotypic screening identified a benzothiophene compound with activity against Leishmania donovani, the causative agent of visceral leishmaniasis. Using multiple orthogonal approaches, oxidosqualene cyclase (OSC), key enzyme sterol biosynthesis, was as target this racemic and its enantiomers. Whole genome sequencing genome-wide overexpression library confirmed that OSC gene amplification is associated resistance to 1. Introduction an ectopic copy into wild-type cells reduced susceptibility...
Despite the progress in discovery of antiretroviral compounds for treating HIV-1 infection by targeting HIV integrase (IN), a promising and well-known drug target against HIV-1, there is growing need to increase armamentarium HIV, avoiding resistance issue.To develop novel IN inhibitors, series 3-hydroxy-pyrane-4-one (HP) 3- hydroxy-pyridine-4-one (HPO) derivatives have been rationally designed synthesized.To provide significant characterization compounds, in-depth computational analysis was...
Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, against the whole parasite in vitro. In this study, we tested cinnamides that synthesized to target human arginase. The compound caffeic phenethyl amide (CAPA), a weak inhibitor of (IC50 = 60.3 ± 7.8 μM) was found have 9-fold more potency L-ARG 6.9 0.7 μM). other did not inhibit characterized L-ARG, showing an IC50 between 1.3–17.8 μM, where most active 15 1.3 0.1 All...
Starting from 1–4 and 7 structural templates, analogues based on bioisosteric replacements (5a–c vs 1, 2 6 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, GluK3 receptors discovered. The requirements interaction elucidated by determining X-ray structures of GluK3-LBD with 5c computational studies. Antinociceptive potential was demonstrated GluK1 partial agonist 3 antagonist (2 mg/kg ip).