Discovery of -substituted-2-oxoindolin benzoylhydrazines as c-MET/SMO modulators in EGFRi-resistant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide, poses a formidable challenge due to its heterogeneity and the emergence of resistance to targeted therapies. While initially effective, first- and third-generation EGFR-tyrosine kinase inhibitors (TKIs) often fail to control disease progression, leaving patients with limited treatment options. To address this unmet medical need, we explored the therapeutic potential of multitargeting agents that simultaneously inhibit two key signalling pathways, the mesenchymal-epithelial transition factor (c-MET) and the G protein-coupled receptor Smoothened (SMO), frequently dysregulated in NSCLC.

Discovering Dually Active Anti-cancer Compounds with a Hybrid AI-structure-based Approach.

Cancer's persistent growth often relies on its ability to maintain telomere length and tolerate the accumulation of DNA damage. This study explores a computational approach to identify compounds that can simultaneously target both G-quadruplex (G4) structures and poly(ADP-ribose) polymerase (PARP)1 enzyme, offering a potential multipronged attack on cancer cells. We employed a hybrid virtual screening (VS) protocol, combining the power of machine learning with traditional structure-based methods.

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1 expression.

Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1, we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression.

Surgical Conservative Management of a Retained Placenta after Angular Pregnancy, a Case Report and Literature Review.

Angular pregnancies are rare and difficult to diagnose. Evidence suggests they are associated with a higher risk of intrauterine growth restriction and abnormal third stage of labor due to a retained placenta. The lack of standardized AP diagnostic criteria impacts on their correct identification and makes the treatment of potential complications challenging.

Development of novel dipeptide nitriles as inhibitors of rhodesain of Trypanosoma brucei rhodesiense.

In this paper, we developed a new series of dipeptide nitriles that were demonstrated to be reversible rhodesain inhibitors at nanomolar level, with EC values against cultured T. b. brucei in the micromolar range.

Successful Vaginal Delivery after Induction of Labour in a Patient Treated for Non-Hodgkin's Lymphoma of the Cervix: A Case Report and Literature Review.

Objective: Primary non-Hodgkin's lymphomas of the cervix are rare; they represent about 1% of all cases. There are no available guidelines regarding the safest mode of delivery after treatment and resolution of a cervical lymphoma. .

Awareness of gestational diabetes mellitus foetal-maternal risks: an Italian cohort study on pregnant women.

Background: Gestational diabetes mellitus (GDM) incidence is increasing worldwide. It represents a major risk factor for adverse foetal-maternal outcomes. Awareness among women in regard to GDM-related risks (in particular foetus ones) has been proven to have an impact on compliance with recommendations.

FEPrepare: A Web-Based Tool for Automating the Setup of Relative Binding Free Energy Calculations.

Relative binding free energy calculations in drug design are becoming a useful tool in facilitating lead binding affinity optimization in a cost- and time-efficient manner. However, they have been limited by technical challenges such as the manual creation of large numbers of input files to set up, run, and analyze free energy simulations. In this Application Note, we describe FEPrepare, a novel web-based tool, which automates the setup procedure for relative binding FEP calculations for the dual-topology scheme of NAMD, one of the major MD engines, using OPLS-AA force field topology and parameter files.

Toxicological aspects of cannabinoid, pesticide and metal levels detected in light Cannabis inflorescences grown in Italy.

Recently, the cultivation of light Cannabis, with a total THC content less than 0.6%, has been encouraged due to its industrial and therapeutic potential. This has increased the consumption of hemp for both smoking purposes and food preparation.

PyRMD: A New Fully Automated AI-Powered Ligand-Based Virtual Screening Tool.

Artificial intelligence (AI) algorithms are dramatically redefining the current drug discovery landscape by boosting the efficiency of its various steps. Still, their implementation often requires a certain level of expertise in AI paradigms and coding. This often prevents the use of these powerful methodologies by non-expert users involved in the design of new biologically active compounds.

Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase.

Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids.

Inhibition studies on carbonic anhydrase isoforms I, II, IV and IX with N-arylsubstituted secondary sulfonamides featuring a bicyclic tetrahydroindazole scaffold.

Carbonic Anhydrases (CAs) are pharmaceutically relevant targets for the treatment of several disease conditions. The ubiquitous localization of these enzymes and the high homology shared by the different isoforms represent substantial impediments for the discovery of potential drugs devoid of off-target side effects. As a consequence, substantial efforts are still needed to allow for the full realization of the pharmacological potential of CA modulators.

Lead Discovery of SARS-CoV-2 Main Protease Inhibitors through Covalent Docking-Based Virtual Screening.

During almost all 2020, coronavirus disease 2019 (COVID-19) pandemic has constituted the major risk for the worldwide health and economy, propelling unprecedented efforts to discover drugs for its prevention and cure. At the end of the year, these efforts have culminated with the approval of vaccines by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) giving new hope for the future. On the other hand, clinical data underscore the urgent need for effective drugs to treat COVID-19 patients.

Structure-Activity Relationship Studies on Oxazolo[3,4-]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent Activity.

Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists have been discovered which, however, require further optimization of their pharmacological profile.

Nanopesticides: Physico-chemical characterization by a combination of advanced analytical techniques.

The recent application of manufactured nanomaterials (MNMs) in plant protection products (PPPs) enhances stability of the active substance (a.s.), minimizes application losses, reduces the quantities of a.

Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment.

In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure-activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range.

Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.

Starting from the reversible rhodesain inhibitors 1 a-c, which have K values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i.

Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis.

This paper describes an optimization strategy of the highly active vinyl ketone which was recognized as a strong inhibitor of rhodesain of , endowed with a value of 67 × 10 M min coupled with a high binding affinity ( = 38 pM). We now report a new structure-activity relationship study based on structural variations on the P3, P2, and P1' sites which led us to identify two potent lead compounds, i.e.

Novel 2-substituted-benzimidazole-6-sulfonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IX and XII and molecular docking studies.

Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes.

Anti-Irritant and Anti-Inflammatory Effects of DHA Encapsulated in Resveratrol-Based Solid Lipid Nanoparticles in Human Keratinocytes.

We recently found that the dietary long chain omega-3 polyunsaturated fatty acid (LC-ω-3 PUFA), docosahexaenoic acid (DHA), showed enhanced antineoplastic activity against colon cancer cells if encapsulated in resveratrol-based solid lipid nanoparticles (RV-SLNs). In the present study, we investigated whether the DHA enclosed in RV-SLNs (DHA-RV-SLNs) could have the potential of attenuating irritation and inflammation caused by environmental factors at the skin level. To this aim, we used two keratinocyte lines (HaCaT and NCTC 2544 cells) and exposed them to the cytotoxic action of the surfactant, sodium dodecyl sulfate (SDS), as an in vitro model of irritation, or to the pro-inflammatory activity of the cytokine TNF-α.

Identification of novel indole derivatives acting as inhibitors of the Keap1-Nrf2 interaction.

Nine indole derivatives () were tested as potential inhibitors of the Keap1-Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only - revealed to be remarkably more active than -butylhydroxyquinone (-BHQ), with standing out as the best performing compound.

Discovery of Pyrido[3',2':5,6]thiopyrano[4,3-]pyrimidine-Based Antiproliferative Multikinase Inhibitors.

Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (-) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds , , and revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives.