Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

As a continuation of our previous work that turned toward the identification of antimycobacterial compounds with innovative structures, two series of pyrazole derivatives were synthesized by parallel solution-phase synthesis and were assayed as inhibitors of Mycobacterium tuberculosis (MTB), which is the causative agent of tuberculosis. One of these compounds showed high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazoles were also computationally investigated to analyze their fit properties to the pharmacophoric model for antitubercular compounds previously built by us and to refine structure–activity relationship analysis

Synthesis, biological evaluation, and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis: Part 2. Synthesis of rigid pyrazolones

Two series of novel rigid pyrazolone derivatives were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis. Two of these compounds showed a high activity against MTB (MIC = 4 μg/mL). The newly synthesized pyrazolones were also computationally investigated to analyze if their properties fit the pharmacophoric model for antitubercular compounds previously built by us. The results are in agreement with those reported by us previously for a class of pyrazole analogues and confirm the fundamental role of the p-chlorophenyl moiety at C4 in the antimycobacterial activity

Structure Prediction and Validation of the ERK8 Kinase Domain

Extracellular signal-regulated kinase 8 (ERK8) has been already implicated in cell transformation and in the protection of genomic integrity and, therefore, proposed as a novel potential therapeutic target for cancer. In the absence of a crystal structure, we developed a three-dimensional model for its kinase domain. To validate our model we applied a structure- based virtual screening protocol consisting of pharmacophore screening and molecular docking. Experimental characterization of the hit compounds confirmed that a high percentage of the identified scaffolds was able to inhibit ERK8. We also confirmed an ATP competitive mechanism of action for the two best-performing molecules. Ultimately, we identified an ERK8 drug-resistant \u27\u27gatekeeper\u27\u27 mutant that corroborated the predicted molecular binding mode, confirming the reliability of the generated structure. We expect that our model will be a valuable tool for the development of specific ERK8 kinase inhibitors

Erratum: Lipase-catalyzed regioselective acylation of resorcin[4]arenes (Journal of Molecular Catalysis B: Enzymatic (2002) 16 (24-247) PII: S1381117701000686)

10Immobilized lipase from Mucor miehei (RML) catalyzed the regioselective acylation of the C-2 side-chain of the C-alkyl resorcin[4]arene tetra-alcohol 1 in the 1,2-alternate form in organic solvents using vinyl acetate as acylating reagent. The influence of reaction parameters and solvent choice were also studied. Docking simulations allowed the determination of the binding geometry of 1, revealing the importance of Trp88 residue in stabilizing the Michaelis–Menten complex between enzyme and substrate.reservedmixedBotta, Bruno; Zappia, Giovanni; Tafi, Andrea; Botta, Maurizio; Manetti, Fabrizio; Cernia, Enrico; Milana, Giuliana; Palocci, Cleofe; Soro, Simonetta; Delle Monache, GiulianoBotta, Bruno; Zappia, Giovanni; Tafi, Andrea; Botta, Maurizio; Manetti, Fabrizio; Cernia, Enrico; Milana, Giuliana; Palocci, Cleofe; Soro, Simonetta; Delle Monache, Giulian

The GIS database of WOODnat project for the inventory and monitoring of walnut plantations in Italy and Spain

Within the activity of the H2020 ‘WOODnat’ project (“Second generation of planted hardwood forests in the European Union”) the growth parameters, yield and sanitary conditions of the most important walnut (Juglans spp.) plantations, established in Italy in the 1990s and in Spain starting from 1996, were recorded. One of the objectives of the project was to evaluate tree growth and stem quality to derive insight on the main environmental factors affecting the production of this valuable specie. An inventory of walnut plantations in the area of interest was necessary due to the relevance of this tree species in the EU timber market. In this paper the final dataset is presented and available with DOI: 10.5281/zenodo.3769940. The database is finalized to narrow the knowledge gap between growers and processing industry with the aim to relaunching the market for this valuable species. Data were collected in the spring 2017 and winter 2017-2018 on 27 stands established in Northern Italy (Piemonte and Lombardia), on 51 stands in Central Italy (Toscana and Marche) and on 17 stands in Spain for a total of 95 plantations. In each plantation, general information was collected such as the planting layout, spacing, age, environment conditions as well as tree-level dendrometric data and phytosanitary information. The sampled stands have been georeferenced in WGS84 reference system (EPSG 4326). These data can be exploited to assess potential wood volume obtainable and quality of raw material, and to identify the weaknesses and errors, strengths and opportunities of the experiences conducted to plan future plantings with greater awareness

Next generation of antiretroviral agents targeting the RNA binding site of the HIV-1 cellular cofactor DDX3: an innovative therapeutic approach

Introduction: Efficacy of currently approved anti-HIV drugs is hampered by mutations of the viral enzymes, leading invariably to drug resistance and chemotherapy failure. Recent data suggest that cellular co-factors also represent useful targets for anti-HIV therapy. We have recently provided evidence for the possibility to block HIV-1 replication by targeting its cellular cofactor DDX3. Material and methods: Molecular modeling and in silico technologies were applied to rationally design small molecules specifically targeting the RNA binding site of human DDX3. Biochemical studies of mutated DDX3 enzymes were also used to identify additional potential drug binding sites. Results Optimization of compounds identified by application of a high-throughput docking approach afforded a promising lead compound which proved to inhibit both the helicase and ATPase activity of DDX3 and to reduce the viral load of peripheral blood mononuclear cells (PBMC) infected with HIV-1. A novel interaction site has been also identified in DDX3, which, when blocked, can reduce viral replication, representing an additional target for small molecules inhibitors. Conclusions: We have identified the first inhibitors of HIV-1 replication targeting the RNA binding site of the cellular cofactor human DDX3. These compounds may offer superior selectivity over the ATP-competitive inhibitors previously developed. In addition, a novel RNA interacting motif specific to DDX3 has been identified, opening new venues for HIV-1 drug development

Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe

Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds. Here, we show that the two acylguanidine analogs, compound (1) and its novel fluoride derivative (2), strongly reduce growth and self-renewal of melanoma cells, inhibiting the level of the HH signaling target GLI1 in a dose-dependent manner. Both compounds induce apoptosis and DNA damage through the ATR/CHK1 axis. Mechanistically, they prevent G2 to M cell cycle transition, and induce signs of mitotic aberrations ultimately leading to mitotic catastrophe. In a melanoma xenograft mouse model, systemic treatment with 1 produced a remarkable inhibition of tumor growth without body weight loss in mice. Our data highlight a novel route for cell death induction by SMO inhibitors and support their use in therapeutic approaches for melanoma and, possibly, other types of cancer with active HH signaling

Adoption of new silvicultural methods in Mediterranean forests: the influence of educational background and sociodemographic factors on marker decisions

Producción Científica- Key message The adoption of new silvicultural methods and approaches requires an understanding of the differences between those and “old” or “conventional” approaches, along with extensive training to break previous knowledge bias. - Context Forestry is in transition towards ecosystem-based management, and new silvicultural approaches are appearing worldwide. However, the adoption of an alternative silvicultural approach is difficult in practice. - Aims We analyzed the effect of forestry background and demographic variables (gender and age) of 24 raters on the application of the systemic approach (SA) and the conventional approach (CA) in the Northern Apennines (Italy) and compared this with tree marking performed by experts. - Methods Data were analyzed as raters’ departures from experts’ selections at the stand and the individual tree level. The probability of tree selection was also calculated. - Results At the stand level, raters with forestry background performed the SA as if they were marking for crown thinning, whereas the CA was less intense than experts’ crown thinning. Non-foresters differentiated poorly between the SA and the CA. At the individual tree level, background and gender affected tree selection. - Conclusion The adoption of the SA as a silvicultural system may be conditioned by previous knowledge. The difference between SA and CA remains unclear when it comes to non-foresters. Gender was a more important variable than age in selecting which trees would be harvested

Discovery of non-nucleoside inhibitors of HIV-1 reverse transcriptase competing with the nucleotide substrate

How odd! A new class of non-nucleoside reverse transcriptase inhibitors with a 6-vinylpyrimidine scaffold (1) has been found to inhibit HIV-1 reverse transcriptase (RT) by competition with the nucleotide substrate after binding to the non-nucleoside inhibitor binding pocket of the enzyme. Molecular modeling studies have been performed to elucidate their peculiar behavior

The walnut plantations (Juglans spp.) in Italy and Spain: main factors affecting growth

Walnut tree species (Juglans spp.) are commonly used for high-quality wood production in plantation forestry. In this paper, the most relevant walnut plantations in Italy and Spain have been reviewed and analysed under a geographic and technician management point of view. Between 2016 and 2019 a total of 96 plantations (15 - 25 years old) were visited distributed in the North-western part of the Mediterranean basin. A statistical analysis (linear model no interaction and PCA) was then performed to evaluate the relative importance of some environmental and management variables for walnut trees in analysed plantations. Results highlighted a variable situation with many different adopted planting schemes across the regions as well as a not standardised spatial layout and management type (thinning). Lower densities and smaller trees were adopted in Italy with about 200 trees ha-1 versus 330 trees ha-1 in Spain. In addition to the age of the plantation as one of the most influencing parameters also the plantation density and the average crown diameter were highly statistically significant. Overall, the interesting potentiality of walnut for timber production with active management in suitable areas was detected as the focal point for a successful timber production from walnut trees