A5108786114- Biochemical and Molecular Research
- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Synthesis and Biological Evaluation
- Cancer therapeutics and mechanisms
- Synthesis and biological activity
- Tuberculosis Research and Epidemiology
- Nanoplatforms for cancer theranostics
- Pneumocystis jirovecii pneumonia detection and treatment
- Photodynamic Therapy Research Studies
- bioluminescence and chemiluminescence research
- Spaceflight effects on biology
- Bioactive Compounds and Antitumor Agents
- Synthesis and Characterization of Heterocyclic Compounds
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Carbon Dioxide Capture Technologies
- Enzyme function and inhibition
- Gear and Bearing Dynamics Analysis
- Chromium effects and bioremediation
- Electromagnetic Fields and Biological Effects
- Tribology and Lubrication Engineering
- Luminescence Properties of Advanced Materials
- Thermodynamic and Exergetic Analyses of Power and Cooling Systems
- Spacecraft and Cryogenic Technologies
- Environmental remediation with nanomaterials
University of Siena
2015-2025
SK Life Science (United States)
2015
Harvard University
2015
Massachusetts General Hospital
2014
Ospedale Santa Maria alle Scotte
2012
General Electric (Italy)
2011
ABSTRACT The inexorable increase of antibiotic resistance occurring in different bacterial species is increasing the interest developing new antimicrobial treatments that will be equally effective against multidrug-resistant strains and not themselves induce resistance. One these alternatives may photodynamic inactivation (PDI), which uses a combination nontoxic dyes, called photosensitizers (PS), excited by harmless visible light to generate reactive oxygen (ROS) type 1 (radical) 2 (singlet...
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three analogues (1-3) of published chromen-4-one derivatives were synthesized biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1-TbPTR1 Leishmania major-LmPTR1) parasites infantum). A crystal structure TbPTR1 in complex with compound first structures LmPTR1-flavanone complexes (compounds 3) solved....
Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from library natural products, we combined target-based screening on pteridine reductase 1 with phenotypic Trypanosoma brucei for hit identification. Flavonols were identified as hits, and 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. below 10 μM. Four X-ray crystal structures docking studies explained the observed structure–activity relationships. Compound 2...
2-Amino-benzo[d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking crystallography guided design synthesis 42 benzothiazoles. The compounds were assessed Trypanosoma brucei Leishmania major PTR1 inhibition in vitro activity against T. amastigote infantum. We several 2-amino-benzo[d]thiazoles with enzymatic (TbPTR1 IC50 = 0.35 μM; LmPTR1 1.9 μM) low μM antiparasitic brucei. ten...
Pteridine reductase 1 (PTR1) is a key folate pathway enzyme of pathogenic trypanosomatids that reduces biopterin to dihydro- and tetrahydrobiopterin. It promising target for drug design against diseases such as sleeping sickness or leishmaniases. Amongst known PTR1 inhibitors, 2-aminobenzothiazole derivatives the pocket were previously found show good overall toxicity profiles some them display anti-parasite activity. On other hand, compounds containing 3,4-dichlorophenyl moiety,...
Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated potential previously identified class thiadiazole inhibitors Leishmania major PTR1 activity against Trypanosoma brucei (Tb). solved crystal structures several TbPTR1-inhibitor complexes to guide structure-based design new derivatives. Subsequent synthesis and enzyme- cell-based assays confirm new, mid-micromolar TbPTR1 with low toxicity. In particular, compound 4m,...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present systematic, multidisciplinary approach to development selective antiparasitic compounds. Computational fragment-based design novel pteridine derivatives along iterations crystallographic structure determination allowed for derivation structure–activity relationship multitarget inhibition. yielded showing apparent picomolar inhibition T. brucei reductase 1...
According to the World Health Organization, more than 1 billion people are at risk of or affected by neglected tropical diseases. Examples such diseases include trypanosomiasis, which causes sleeping sickness; leishmaniasis; and Chagas disease, all prevalent in Africa, South America, India. Our aim within New Medicines for Trypanosomatidic Infections project was use (1) synthetic natural product libraries, (2) screening, (3) a preclinical absorption, distribution, metabolism,...
Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, types leishmaniasis. Recently, meaningful progresses in treatment HAT, due to brucei (Tb), have been achieved by introduction fexinidazole combination therapy eflornithine–nifurtimox. Nevertheless, drug resistance issues exitance animal reservoirs, development new NTD treatments is still required. For this...
Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental cycloguanil as an inhibitor Trypanosoma brucei PTR1 (TbPTR1). A small library derivatives was developed, resulting 1 and 2a having IC50 values 692 186 nM, respectively, toward TbPTR1. Structural analysis revealed that increased potency due combined...
The growing concern for the role of man-made CO2 emissions with respect to global warming combined large increase in energy demand spurred by developing nations and a population that is foreseen over next 15 years have recently turned attention potential CO2-neutral supply solutions. Waste heat recovery cycles applied fossil fueled plants offer local zero-emission solution producing additional electric energy, thereby increasing overall plant efficiency considerable reduction emission per...
Osteoarthritis (OA) is the most frequent joint disease, characterized by degradation of extracellular matrix and alterations in chondrocyte metabolism. Some authors reported that electromagnetic fields (EMFs) can positively interfere with patients affected OA, even though nature interaction still debated. Human primary osteoarthritic chondrocytes isolated from femoral heads OA-patients undergoing to total hip replacement, were cultured vitro exposed 30 min/day for two weeks...
The protozoan parasite Trypanosoma brucei is the etiological agent of human African trypanosomiasis (HAT). HAT, together with other neglected tropical diseases, causes serious health and economic issues, especially in subtropical areas. classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by expression pteridine 1 (PTR1). combined inhibition PTR1 DHFR activities represents promising strategy for...
Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of novel core structure inspiring new treatments parasitic diseases targeting trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate (DHFR) enzymes. In total, 592 compounds tested through medium-throughput assays. A subset 14 successfully inhibited enzyme activity in low micromolar...
Folate enzymes, namely, dihydrofolate reductase (DHFR) and pteridine (PTR1) are acknowledged targets for the development of antiparasitic agents against Trypanosomiasis Leishmaniasis. Based on amino dihydrotriazine motif drug Cycloguanil (Cyc), a known inhibitor both folate we have identified two novel series inhibitors, 2-amino triazino benzimidazoles (1) 2-guanidino (2), as their open ring analogues. Enzymatic screening was carried out PTR1, DHFR, thymidylate synthase (TS). The crystal...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present systematic, multidisciplinary approach to development selective anti-parasitic compounds. Computational fragment-based design novel pteridine derivatives along iterations crystallographic structure determination allowed for derivation structure-activity relationship multitarget inhibition. yielded showing apparent picomolar inhibition T. brucei reductase 1...
The optimization of compounds with multiple targets in the drug discovery cycle is a difficult multidimensional problem. Here, we present systematic, multidisciplinary approach to development selective anti-parasitic compounds. Efficient microwave-assisted synthesis pteridines along iterations crystallographic structure determination were used validate computational docking predictions and support derivation structure-activity relationship for multitarget inhibition. This yielded showing...
The optimization of compounds with multiple targets in the drug discovery cycle is a difficult multidimensional problem. Here, we present systematic, multidisciplinary approach to development selective anti-parasitic compounds. Efficient microwave-assisted synthesis pteridines along iterations crystallographic structure determination were used validate computational docking predictions and support derivation structure-activity relationship for multitarget inhibition. This yielded showing...
The optimization of compounds with multiple targets in the drug discovery cycle is a difficult multidimensional problem. Here, we present systematic, multidisciplinary approach to development selective anti-parasitic compounds. Efficient microwave-assisted synthesis pteridines along iterations crystallographic structure determination were used validate computational docking predictions and support derivation structure-activity relationship for multitarget inhibition. This yielded showing...