γ-Cyclodextrins as Supramolecular Reactors for the Three-component Aza-Darzens Reaction in Water.

In recent decades, many efforts have been devoted to studying reactions catalyzed in nanoconfined spaces. The most impressive aspect of catalysis in nanoconfined spaces is that the reactivity of the molecules can be smartly driven to disobey classical behavior. A green and efficient three-component aza-Darzens (TCAD) reaction using a catalytic amount of γ-cyclodextrins (CDs) in water has been developed to synthesize N-phenylaziridines. CDs effectively performed this reaction in an environmentally friendly setting, achieving good yields. The same reaction was then performed using polymeric γ-CD such as a γ-cyclodextrin polymer crosslinked (GCDPC) with epichlorohydrin, a sponge-like macroporous γ-cyclodextrin-based cryogel (GCDC), and a γ-cyclodextrin-based hydrogel (GCDH). The homogeneous and heterogeneous catalyst recovery was then studied, and it was proved to be easily recycled several times without relevant activity loss. Water, as a unique and eco-friendly reaction medium, has been utilized for the first time, to the best of our knowledge, in this reaction. The inclusion of the reagents in CDs has been studied and rationalized by NMR spectroscopy experiments and molecular modeling calculations. The credit of the presented protocol includes good yields and catalyst reusability and precludes the use of organic solvents.

TiO2/Loofah-Halloysite Bio-Hybrid Composites as Efficient Systems for VOCs Removal.

Volatile organic compounds (VOCs), recognized as hazardous air contaminants, prompt the exploration of sustainable air purification methods. Solar photocatalytic oxidation emerges as a promising solution, utilizing semiconductor photocatalysts like titanium dioxide (TiO2). However, the raw material crisis necessitates reduced TiO2 usage, leading to investigations into TiO2 modification techniques. The study introduces a novel approach by employing natural fibers, specifically loofah sponge, as a TiO2 support. This method aims to maintain photocatalytic activity while minimizing TiO2 content. The article explores using halloysite, a natural clay mineral, as a supportive material, enhancing mechanical strength and adsorption properties. The resulting TiO2/loofah-halloysite composites are evaluated for their efficacy in gas-phase photocatalytic oxidation of toluene and ethanol, chosen as representative VOCs. The conversion of toluene and ethanol on the composite was 88 % and 39 %, respectively, with high selectivity toward CO2. In addition to its high performance, the bio-composite was stable for several conversion cycles, keeping the conversion activity unchanged. The study contributes to developing green hybrid materials for VOC removal, showcasing potential applications across industries.

Tetrazine-trans-cyclooctene ligation: Unveiling the chemistry and applications within the human body.

Bioorthogonal reactions have revolutionized chemical biology by enabling selective chemical transformations within living organisms and cells. This review comprehensively explores bioorthogonal chemistry, emphasizing inverse-electron-demand Diels-Alder (IEDDA) reactions between tetrazines and strained dienophiles and their crucial role in chemical biology and various applications within the human body. This highly reactive and selective reaction finds diverse applications, including cleaving antibody-drug conjugates, prodrugs, proteins, peptide antigens, and enzyme substrates. The versatility extends to hydrogel chemistry, which is crucial for biomedical applications, yet it faces challenges in achieving precise cellularization. In situ activation of cytotoxic compounds from injectable biopolymer belongs to the click-activated protodrugs against cancer (CAPAC) platform, an innovative approach to tumor-targeted prodrug delivery and activation. The CAPAC platform, relying on click chemistry between trans-cyclooctene (TCO) and tetrazine-modified biopolymers, exhibits modularity across diverse tumor characteristics, presenting a promising approach in anticancer therapeutics. The review highlights the importance of bioorthogonal reactions in developing radiopharmaceuticals for positron emission tomography (PET) imaging and theranostics, offering a promising avenue for diverse therapeutic applications.

The synthesis and properties of mitochondrial targeted iron chelators.

Iron levels in mitochondria are critically important for the normal functioning of the organelle. Abnormal levels of iron and the associated formation of toxic oxygen radicals have been linked to a wide range of diseases and consequently it is important to be able to both monitor and control levels of the mitochondrial labile iron pool. To this end a series of iron chelators which are targeted to mitochondria have been designed. This overview describes the synthesis of some of these molecules and their application in monitoring mitochondrial labile iron pools and in selectively removing excess iron from mitochondria.

Optimization of 4-amino-pyridazin-3(2H)-one as a valid core scaffold for FABP4 inhibitors.

Current clinical research suggests that fatty acid-binding protein 4 inhibitors (FABP4is), which are of biological and therapeutic interest, may show potential in treating cancer and other illnesses. We sought to uncover new structures through the optimization of the previously reported 4-amino and 4-ureido pyridazinone-based series of FABP4is as part of a larger research effort to create more potent FABP4 inhibitors. This led to the identification of 14e as the most potent analog with IC50 = 1.57 µM, which is lower than the IC50 of the positive control. Advanced modeling investigations and in silico absorption, distribution, metabolism, and excretion - toxicity calculations suggested that 14e represents a potential candidate for in vivo studies such as FABP4i.

1,2-Dibenzoylhydrazine as a Multi-Inhibitor Compound: A Morphological and Docking Study.

In the framework of the multitarget inhibitor study, we report an in silico analysis of 1,2-dibenzoylhydrazine (DBH) with respect to three essential receptors such as the ecdysone receptor (EcR), urease, and HIV-integrase. Starting from a crystallographic structural study of accidentally harvested crystals of this compound, we performed docking studies to evaluate the inhibitory capacity of DBH toward three selected targets. A crystal morphology prediction was then performed. The results of our molecular modeling calculations indicate that DBH is an excellent candidate as a ligand to inhibit the activity of EcR receptors and urease. Docking studies also revealed the activity of DBH on the HIV integrase receptor, providing an excellent starting point for developing novel inhibitors using this molecule as a starting lead compound.

Computer-Assisted Design of Peptide-Based Radiotracers.

In medical imaging, techniques such as magnetic resonance imaging, contrast-enhanced computerized tomography, positron emission tomography (PET), and single-photon emission computed tomography (SPECT) are extensively available and routinely used for disease diagnosis. PET probes with peptide-based targeting are typically composed of small peptides especially developed to have high affinity and specificity for a range of cellular and tissue targets. These probes' key benefits include being less expensive than traditional antibody-based PET tracers and having an effective chemical modification process that allows them to be radiolabeled with almost any radionuclide, making them highly appealing for clinical usage. Currently, as with every pharmaceutical design, the use of in silico strategies is steadily growing in this field, even though it is not part of the standard toolkit used during radiopharmaceutical design. This review describes the recent applications of computational design approaches in the design of novel peptide-based radiopharmaceuticals.

Steered Molecular Dynamics Simulations Study on FABP4 Inhibitors.

Ordinary small molecule de novo drug design is time-consuming and expensive. Recently, computational tools were employed and proved their efficacy in accelerating the overall drug design process. Molecular dynamics (MD) simulations and a derivative of MD, steered molecular dynamics (SMD), turned out to be promising rational drug design tools. In this paper, we report the first application of SMD to evaluate the binding properties of small molecules toward FABP4, considering our recent interest in inhibiting fatty acid binding protein 4 (FABP4). FABP4 inhibitors (FABP4is) are small molecules of therapeutic interest, and ongoing clinical studies indicate that they are promising for treating cancer and other diseases such as metabolic syndrome and diabetes.

Recent progress in the imaging of c-Met aberrant cancers with positron emission tomography.

Tyrosine-protein kinase Met-also known as c-Met or HGFR-is a membrane receptor protein with associated tyrosine kinase activity physiologically stimulated by its natural ligand, the hepatocyte growth factor (HGF), and is involved in different ways in cancer progression and tumourigenesis. Targeting c-Met with pharmaceuticals has been preclinically proved to have significant benefits for cancer treatment. Recently, evaluating the protein status during and before c-Met targeted therapy has been shown of relevant importance by different studies, demonstrating that there is a correlation between the status (e.g., aberrant activation and overexpression) of the HGFR with therapy response and clinical prognosis. Currently, clinical imaging based on positron emission tomography (PET) appears as one of the most promising tools for the in vivo real-time scanning of irregular alterations of the tyrosine-protein kinase Met and for the diagnosis of c-Met related cancers. In this study, we review the recent progress in the imaging of c-Met aberrant cancers with PET. Particular attention is directed on the development of PET probes with a range of different sizes (HGF, antibodies, anticalines, peptides, and small molecules), and radiolabeled with different radionuclides. The goal of this review is to report all the preclinical imaging studies based on PET imaging reported until now for in vivo diagnosis of c-Met in oncology to support the design of novel and more effective PET probes for in vivo evaluation of c-Met.

Artificial Intelligence Technologies for COVID-19 De Novo Drug Design.

The recent covid crisis has provided important lessons for academia and industry regarding digital reorganization. Among the fascinating lessons from these times is the huge potential of data analytics and artificial intelligence. The crisis exponentially accelerated the adoption of analytics and artificial intelligence, and this momentum is predicted to continue into the 2020s and beyond. Drug development is a costly and time-consuming business, and only a minority of approved drugs generate returns exceeding the research and development costs. As a result, there is a huge drive to make drug discovery cheaper and faster. With modern algorithms and hardware, it is not too surprising that the new technologies of artificial intelligence and other computational simulation tools can help drug developers. In only two years of covid research, many novel molecules have been designed/identified using artificial intelligence methods with astonishing results in terms of time and effectiveness. This paper reviews the most significant research on artificial intelligence in de novo drug design for COVID-19 pharmaceutical research.

Targeting the SARS-CoV-2 HR1 with Small Molecules as Inhibitors of the Fusion Process.

The rapid and global propagation of the novel human coronavirus that causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of this virus. In this paper, we studied the spike protein S2 domain of SARS-CoV-2 as it is the most conserved component and controls the crucial fusion process of SARS-CoV-2 as a target for different databases of small organic compounds. Our in silico methodology, based on pharmacophore modeling, docking simulation and molecular dynamics simulations, was first validated with ADS-J1, a potent small-molecule HIV fusion inhibitor that has already proved effective in binding the HR1 domain and inhibiting the fusion core of SARS-CoV-1. It then focused on finding novel small molecules and new peptides as fusion inhibitors. Our methodology identified several small molecules and peptides as potential inhibitors of the fusion process. Among these, NF 023 hydrate (MolPort-006-822-583) is one of the best-scored compounds. Other compounds of interest are ZINC00097961973, Salvianolic acid, Thalassiolin A and marine_160925_88_2. Two interesting active peptides were also identified: AP00094 (Temporin A) and AVP1227 (GBVA5). The inhibition of the spike protein of SARS-CoV-2 is a valid target to inhibit the virus entry in human cells. The discussed compounds reported in this paper led to encouraging results for future in vitro tests against SARS-CoV-2.

An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022.

Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.

Novel Tyrosine Kinase Inhibitors to Target Chronic Myeloid Leukemia.

This paper reports on a novel series of tyrosine kinase inhibitors (TKIs) potentially useful for the treatment of chronic myeloid leukemia (CML). The newly designed and synthesized compounds are structurally related to nilotinib (NIL), a second-generation oral TKI, and to a series of imatinib (IM)-based TKIs, previously reported by our research group, these latter characterized by a hybrid structure between TKIs and heme oxygenase-1 (HO-1) inhibitors. The enzyme HO-1 was selected as an additional target since it is overexpressed in many cases of drug resistance, including CML. The new derivatives 1a-j correctly tackle the chimeric protein BCR-ABL. Therefore, the inhibition of TK was comparable to or higher than NIL and IM for many novel compounds, while most of the new analogs showed only moderate potency against HO-1. Molecular docking studies revealed insights into the binding mode with BCR-ABL and HO-1, providing a structural explanation for the differential activity. Cytotoxicity on K562 CML cells, both NIL-sensitive and -resistant, was evaluated. Notably, some new compounds strongly reduced the viability of K562 sensitive cells.

Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors.

Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10-50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.

Synthesis and in vitro evaluation of chlorogenic acid amides as potential hypoglycemic agents and their synergistic effect with acarbose.

Type 2 Diabetes mellitus is a chronic disease considered one of the most severe global health emergencies. Chlorogenic acid (1) has been shown to delay intestinal glucose absorption by inhibiting the activity of α-glucosidase (α-Glu) and α-amylase (α-Amy). In the present work, eleven chlorogenic acid amides have been synthesized and evaluated for their antioxidant properties (as DPPH and ORAC) and inhibition activity towards the two enzymes and, with the aim to obtain dual-action antidiabetic agents. The two most promising hypoglycemic compounds, bearing a tertiary amine function on an alkyl chain (8) and a benzothiazole scaffold (11), showed IC50 values lower than that of (1) (45.5 µM α-Glu; 105.2 µM α-Amy). Amides 8 and 11 were by far more potent α-Glu inhibitors than the antidiabetic drug acarbose (IC50 = 268.4 µM) and about twice less active toward α-Amy than acarbose (IC50 = 34.4 µM). Kinetics experiments on amides 8 and 11 indicated these compounds as mixed-type inhibitors of α-Glu with K'i values of 13.3 and 6.3 µM, respectively. The amylase inhibition occurred with a competitive mechanism in the presence of 8 (Ki = 79.7 µM) and with a mixed-type mechanism with 11 (Ki = 19.1 µM; K'i = 93.6 µM). Molecular docking analyses supported these results, highlighting the presence of additional binding sites in both enzymes. Fluorescence experiments confirmed the grater affinity of amides 8 and 11 towards the two enzymes respect to (1). Moreover, a significant enhancement in acarbose efficacy was observed when inhibition assays were performed adding acarbose and amide 11. The above outcomes pinpointed the benzothiazole-based amide 11 as a promising candidate for further studies on type 2 diabetes treatment, both alone or combined with acarbose.

Growing the molecular architecture of imidazole-like ligands in HO-1 complexes.

Up-regulation of HO-1 had been frequently reported in different cases and types of human malignancies. Since poor clinical outcomes are reported in these cases, this enzyme's inhibition is considered a valuable and proven anticancer approach. To identify novel HO-1 inhibitors suitable for drug development, we report a structure-guided fragment-based approach to identify new lead compounds. Different parts of the selected molecules were analyzed, and the different series of novel compounds were virtually evaluated. The growing experiments of the classical HO-1 inhibitors structure led us to different hit-compounds. A synthetic pathway for six selected molecules was designed, and the compounds were synthesized. The biological activity revealed that molecules 10 and 12 inhibit the HO-1 activity with an IC50 of 1.01 and 0.90 µM, respectively. This study suggested that our growing approach was successful, and these results are ongoing for further development.

Green Efficient One-Pot Synthesis and Separation of Nitrones in Water Assisted by a Self-Assembled Nanoreactor.

This article reports an alternative method for preparing nitrones using a tetrahedral capsule as a nanoreactor in water. Using the hydrophobic cavity of the capsule allowed us to reduce the reaction times and easily separate the nitrones from the reaction mixture, obtaining reaction yields equal or comparable to those obtained with the methods already reported. Furthermore, at the basis of this methodology, there is an eco-friendly approach carried out that can certainly be extended to other synthesis methods for the preparation of other substrates by exploiting various types of macrocyclic hosts, suitably designed and widely used in supramolecular chemistry.

Illuminating the Path to Target GPCR Structures and Functions.

G-Protein-coupled receptors (GPCRs) are ubiquitous within eukaryotes, responsible for a wide array of physiological and pathological processes. Indeed, the fact that they are the most drugged target in the human genome is indicative of their importance. Despite the clear interest in GPCRs, most information regarding their activity has been so far obtained by analyzing the response from a "bulk medium". As such, this Perspective summarizes some of the common methods for this indirect observation. Nonetheless, by inspecting approaches applying super-resolution imaging, we argue that imaging is perfectly situated to obtain more detailed structural and spatial information, assisting in the development of new GPCR-targeted drugs and clinical strategies. The benefits of direct optical visualization of GPCRs are analyzed in the context of potential future directions in the field.

Cucurbit[7]uril as a catalytic nanoreactor for one-pot synthesis of isoxazolidines in water.

The main objective of supramolecular chemistry is to mimic the macrosystems present in nature, a goal that fits perfectly with the green chemistry guidelines. The aim of our work is to use the hydrophobic cavity of cucurbit[7]uril (CB[7]) to mimic nature for performing different dehydration and cycloaddition reactions in water. The hydrophobic cavity of CB[7] made it possible to synthesize nitrones and isoxazolidines in a one-pot fashion using water as a reaction solvent. Substituted isoxazolidines were obtained from the cycloaddition of nitrones with various styrenes and cinnamates, under microwave irradiation, with a catalytic amount of CB[7], and a moderate increase in the formation of the trans adduct was observed, compared to the reaction being carried out in toluene. The mechanism of the reaction and the inclusion of reagents and products in the CB[7] cavity have been studied and rationalized by NMR spectroscopy, ESI-MS experiments, and molecular modeling calculations.

Identification of a potent heme oxygenase-2 (HO-2) inhibitor by targeting the secondary hydrophobic pocket of the HO-2 western region.

The enzymatic family of heme oxygenase (HO) is accountable for heme breakdown. Among the two isoforms characterized to date, HO-2 is poorly investigated due to the lack of potent HO-2 chemical modulators and the greater attentiveness towards HO-1 isoform. In the present paper, we report the rational design and synthesis of HO-2 inhibitors achieved by modulating the volume of known HO-1 inhibitors. The inhibition preference has been moved from HO-1 to HO-2 by merely increasing the volume of the substituent in the western region of the inhibitors. Docking studies demonstrated that new derivatives soak differently in the two binding pockets, probably due to the presence of a Tyr187 residue in HO-2. These findings could be useful for the design of new selective HO-2 compounds.