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This review describes the progress of the last decade on the synthesis of substituted benzofurans, which are useful scaffolds for the synthesis of numerous natural products and pharmaceuticals. In particular, new intramolecular and intermolecular C–C and/or C–O bond-forming processes, with transition-metal catalysis or metal-free are summarized. (1) Introduction. (2) Ring generation via intramolecular cyclization. (2.1) C7a–O bond formation: (route a). (2.2) O–C2 bond formation: (route b). (2.3) C2–C3 bond formation: (route c). (2.4) C3–C3a bond formation: (route d). (3) Ring generation via intermolecular cyclization. (3.1) C7a-O and C3–C3a bond formation (route a + d). (3.2) O–C2 and C2–C3 bond formation: (route b + c). (3.3) O–C2 and C3–C3a bond formation: (route b + d). (4) Benzannulation. (5) Conclusion.

A library of dihydropyrimidinones was synthesized via a “one-pot” three component Biginelli reaction using different aldehydes in combination with β-dicarbonyl compounds and urea. Selected 2-thiooxo and 2-imino analogs were also obtained with the Biginelli reaction from thiourea and guanidine hydrochloride, respectively. The products were screened in vitro for their β-secretase inhibitory activity. The majority of the compounds resulted to be active, with IC50 in the range 100 nM–50 μM.

The continuous emergence of SARS-CoV-2 variants caused the persistence of the COVID-19 epidemic and challenged the effectiveness of the existing vaccines. The viral proteases are the most attractive targets for developing antiviral drugs. In this scenario, our study explores the use of HIV-1 protease inhibitors against SARS-CoV-2. An in silico screening of a library of HIV-1 proteases identified four anti-HIV compounds able to interact with the 3CLpro of SARS-CoV-2. Thus, in vitro studies were designed to evaluate their potential antiviral effectiveness against SARS-CoV-2. We employed pseudovirus technology to simulate, in a highly safe manner, the adsorption of the alpha (α-SARS-CoV-2) and omicron (ο-SARS-CoV-2) variants of SARS-CoV-2 and study the inhibitory mechanism of the selected compounds for cell–virus interaction. The results reported a mild activity against the viral proteases 3CLpro and PLpro, but efficient inhibitory effects on the internalization of both variants mediated by cathepsin B/L. Our findings provide insights into the feasibility of using drugs exhibiting antiviral effects for other viruses against the viral and host SARS-CoV-2 proteases required for entry.

Background Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) are hematological malignancies with poor prognosis due to drug resistance, with no effective therapies. Drug resistance occurs from alterations in microenvironment and metabolism. Impaired mitochondrial metabolism underlies drug resistance in MM and CLL, and drugs targeting mitochondrial respiration show cytotoxicity and increase chemotherapy sensitivity. HIV protease inhibitors like nelfinavir show antitumor activity and resensitize drug-resistant cells to bortezomib and venetoclax. We evaluated effects of two HIV protease inhibitor precursors, BupM-NH2 and BnpM-NH2, on MM and CLL cells and their mechanism. Methods The cytotoxicity of the compounds was evaluated in MM (MM1S and RPMI-8226) and CLL (HG3) cell lines, peripheral blood mononuclear cells (PBMCs) and in patient-derived MM cells using MTS assays. Apoptosis was assessed by Annexin V staining and cell cycle analysis using flow cytometry. Western blotting was employed to assess protein expression to investigate the effects of the tested compounds on autophagy, endoplasmic reticulum stress, and respiratory chain function. Cellular metabolic activity was measured using Seahorse analyzer, whereas mitochondrial function and ROS generation were quantified via flow cytometry with MitoSOX and MitoTracker staining. Results BupM-NH2 and BnpM-NH2 at 50 µM decreased MM and CLL cell viability by 60% and 90%, while reducing PBMC viability by 40% and 50%. These compounds inhibited autophagy and mitochondrial respiration, reducing ATP production by 70% in MM, 30–60% in CLL, and 50% in PBMCs. BnpM-NH2 decreased the viability of cells from newly diagnosed multiple myeloma (NDMM) patients by 60% but showed a non-significant 15% reduction in relapsed/refractory multiple myeloma (RRMM) patients, whereas BupM-NH2 had no significant impact. Both compounds induced stress in respiratory chain and mitochondria that may help resensitize drug-resistant MM and CLL. Conclusions BupM-NH2, and particularly BnpM-NH2, showed enhanced cytotoxicity against MM, CLL, and NDMM cells compared to PBMCs by inducing apoptosis through autophagy and mitochondrial respiration inhibition. While the cytotoxic effect in RRMM is less pronounced and nonsignificant, BupM-NH2 and BnpM-NH2 induces stress in respiratory chain and mitochondria, which may re-sensitize resistant tumor cells to treatments. Therefore these compounds may hold promise as novel therapeutic agents for MM and CLL treatment.

Here, we report the synthesis, enzyme inhibition and structure–activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P’ and P’’ and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/ml BSA. Compounds 9a–c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compared.

Permethylated anigopreissin A (PAA), a fully protected form of the natural anigopreissin A, was found in our previous study to be active against several cancer cells, up to IC50 0.24 μM for HepG2 cells. Herein, a total of thirteen PAA analogues with variations in the number, position of substituents and unsaturation were synthesised starting from a common precursor, and their ability to induce cell growth inhibition was tested. By comparing the antiproliferative effect of the analogues with PAA and with the help of computational studies, we have gained valuable insights into both the biological activity and structure of this natural class of compounds. Indeed, we discovered the importance of the C-3 ring in modulating the biological activity of PAA, as well as the crucial role of the trans configuration of the styryl double bond and the significance of substitutions on the other parts of the molecule.

Background: Several pre-clinical and clinical reports suggest that HIV-1 protease inhibitors, in addition to the antiretroviral properties, possess pleiotropic pharmacological effects including anticancer action. Therefore, we investigated the pro-apoptotic activity in tumor cells of two molecules, RDD-19 and RDD-142, which are hydroxyethylamine derivatives’ precursors of darunavir and several HIV-1 protease inhibitors. Methods: Three hepatoma cell lines and one non-pathological cell line were treated with RDD-19 and RDD-142, and cell viability was assessed. The expression levels of several markers for ER stress, autophagy, cellular ubiquitination, and Akt activation were quantified in HepG2 cells treated with RDD-19 and RDD-142 to evaluate apoptotic and non-apoptotic cell death. Results: RDD-19 and RDD-142 showed a greater dose-dependent cytotoxicity towards the hepatic tumor cell line HepG2 compared to the non-pathological hepatic cell line IHH. Both molecules caused two types of cell death, a caspase-dependent apoptosis, which was ascertained by a series of biochemical and morphological assays, and a caspase-independent death that was characterized by the induction of ER stress and autophagy. The strong increase of ubiquitinated proteins inside the cells suggested that the target of these molecules could be the proteasome and in silico molecular docking analysis that was used to support the plausibility of this hypothesis. Furthermore, cells treated with the two compounds displayed decreased levels of p-AKT, which interferes with cell survival and proliferation. Conclusions: These findings demonstrate that two compounds, RDD-19 and RDD-142, have pleiotropic effects and that they may represent promising anticancer candidates.

Since the first cases of AIDS, reported in 1980, this disease has become chronic over the years, and researchers have been trying to keep it under control. Despite the development and spread of mutate viruses, HIV protease remains an important pharmacological target. In the development of new HIV protease inhibitors, heterocyclic fragments have proven to be of great importance, owing to their rigid core structure, which may fit better into the enzyme’s hydrophobic pockets, and the presence of a heteroatom, which may increase the number of H-bonding interactions at the active site. According to the concept of targeting the protein backbone, different aromatic or non-aromatic heterocyclic moieties have yielded inhibitors with sufficient activity against mutant viruses. This paper provides an overview of HIV protease inhibitors developed over the last fifteen years, with a focus on the presence of heterocycles in their structure, either in the core or on the side chains, which are crucial for their activity. The rationale behind the design of these new inhibitors, as well as the key synthetic steps involved in their preparation, is also described.

Liver cancer is one of the most common causes of cancer death worldwide. In recent years, substantial progress has been made in the development of systemic therapies, but there is still the need for new drugs and technologies that can increase the survival and quality of life of patients. The present investigation reports the development of a liposomal formulation of a carbamate molecule, reported as ANP0903, previously tested as an inhibitor of HIV-1 protease and now evaluated for its ability to induce cytotoxicity in hepatocellular carcinoma cell lines. PEGylated liposomes were prepared and characterized. Small, oligolamellar vesicles were produced, as demonstrated by light scattering results and TEM images. The physical stability of the vesicles in biological fluids was demonstrated in vitro, alongside the stability during storage. An enhanced cellular uptake was verified in HepG2 cells treated with liposomal ANP0903, resulting in a greater cytotoxicity. Several biological assays were performed to elucidate the molecular mechanisms explaining the proapoptotic effect of ANP0903. Our results allow us to hypothesize that the cytotoxic action in tumor cells is probably due to the inhibition of the proteasome, resulting in an increase in the amount of ubiquitinated proteins within the cells, which in turn triggers activation of autophagy and apoptosis processes, resulting in cell death. The proposed liposomal formulation represents a promising approach to deliver a novel antitumor agent to cancer cells and enhance its activity.

This minireview provides a brief outline of the peculiar aspects of the preparation of peptidomimetic and pseudopeptidic structures containing heterocycles. In particular novel tricyclic structures are investigated as potential drugs.