With an optimized S1’-S2’ ligand, the E-64c-hydrazide derived compound efficiently inhibits the cysteine protease cathepsin C and thus suppresses the proteolytic activation of neutrophil elastase in the neutrophil precursor cell line U937.

Abstract

The zymogens of the neutrophil serine proteases elastase, proteinase 3, and cathepsin G are converted proteolytically into their pro-inflammatory active forms by the action of cathepsin C. The inhibition of this cysteine protease therefore is an interesting therapeutic approach for the treatment of inflammatory disorders with a high neutrophil burden such as COPD. Based on E-64c-hydrazide as lead structure, we have recently developed a covalently acting cathepsin C inhibitor using a n-butyl residue attached at the amine nitrogen of the hydrazide moiety to efficiently address the deep hydrophobic S2 pocket. To further optimize the affinity and selectivity profile of this inhibitor, the S1’-S2’ area was now investigated by a combinatorial approach, showing that Nle-tryptamide is a ligand superior to the initially used Leu-isoamylamide. Using the neutrophil precursor line U937 as a cell culture model, this optimized inhibitor blocks the intracellular cathepsin C activity and thereby suppresses the activation of neutrophil elastase.

The compounds 8-fluoro-7-methyl-5-(pyridin-2-yl)tetrazolo[1,5-c]pyrimidine and 5-(pyridin-2-yl)-8,9-dihydro-7H-cyclopenta[e]tetrazolo[1,5-c]pyrimidine belong to a novel class of antifungals. Both compounds with tetrazole backbone exhibit inhibitory activity that is equivalent or superior to those of conventional drugs on a weight-per-volume basis, with IC₅₀ equalling 0.05 μM (0.012 μg mL⁻¹) against each Cryptococcus species. Thus, tetrazole-backbone-containing compounds may be novel antifungal drugs with distinct mechanisms against cryptococcosis.antifungal agentsCandidaCryptococcushigh-throughput screeningtetrazoles

Abstract

Cryptococcosis has become a major health problem worldwide and caused morbidity and mortality in immunocompromised patients, especially those infected with human immunodeficiency virus (HIV). Despite the global distribution of cryptococcosis, the number and types of the available antifungals are limited, and the treatment outcomes in HIV patients are generally poor. In this study, we screened a compound library and identified one tetrazole derivative as an efficient inhibitor of Cryptococcus neoformans and Cryptococcus gattii. We further designed and synthesized a series of tetrazole derivatives and determined their structure-activity relationship, demonstrating that tetrazole backbone-containing compounds could be developed as novel antifungal drugs with distinct mechanisms against Cryptococcus spp. Our findings provide a starting point for novel target identification and structural optimization to develop a distinct class of therapeutics for patients with cryptococcosis.

Antibiotics with novel and polypharmacological mechanisms of action are urgently needed. To this end, the total synthesis of mindapyrroles A and B was completed via a Friedel-Crafts alkylation. The antibacterial activity of these compounds was investigated against a panel of gram-positive and gram-negative pathogens, and their mechanism of action was determined to be different from their monomer pyoluteorin.

Abstract

In the search for antibacterial compounds that can overcome drug resistant species, molecules that enact novel or polypharmacological mechanisms of action (MoA) are needed. As a preliminary foray into molecules of this background, the total synthesis of mindapyrroles A and B was undertaken leveraging a biomimetic approach. Following their synthesis, they and their monomer pyoluteorin were tested against a range of pathogenic bacteria in minimum inhibitory concentration assays to confirm their activity. These molecules were then tested for their ability to disrupt membrane potential in S. aureus. Our findings indicate that pyoluteorin acts as a protonophore but the mindapyrroles do not. This work encapsulates the first total synthesis of mindapyrrole B and the second total synthesis of mindapyrrole A in 11 % and 30 % overall yields, respectively. It also provides insights into the antibacterial properties and different MoAs between the monomer and dimers.

High-contrast and fast-removable fluorinated agents C₁₀F₁₈H₄O₂ and C₁₁F₁₈H₆ for the ¹⁹F MRI method were designed. The synthesis of these compounds is not complicated. The emulsions with these substances were developed, and in vivo MRI studies in laboratory rats were carried out. The substances are non-toxic, and they are excreted from the living organism in ~30 days.

Abstract

¹⁹F MRI is a unique technique for tracking and quantifying the indicator (¹⁹F-MRI label) in vivo without the use of ionizing radiation. Here we report new ¹⁹F-MRI labels, which are compounds with perfluoro-tert-butyl groups: 1,2-bis(perfluoro-tert-butoxy)ethane (C₁₀F₁₈H₄O₂) and 1,3-bis(perfluoro-tert-butyl)propane (C₁₁F₁₈H₆). Both substances contain 18 equivalent ¹⁹F atoms, constituting 68.67 % and 71.25 % of the molecule, respectively. The emulsions with ¹⁹F molecules were prepared and used in ¹⁹F MRI studies in laboratory rats in vivo. The substances demonstrated high contrast properties, good biological inertness and the ability to be rapidly eliminated from the body. We showed that at a dose of 0.34 mg/g of body weight in rats, the time for complete elimination of C₁₀F₁₈H₄O₂ and C₁₁F₁₈H₆ is ∼30 days. The results turned out to be promising for the use of the presented compounds in ¹⁹F MRI applications, especially since they are quite easy to synthesize.

Novel benzo[b]thienyl and 2-bithienyl amidino-substituted benzothiazoles and benzimidazoles were shown to have antitumor and antitrypanosomal activities in vitro. Benzothiazoles were found to be more active than benzimidazole analogs as both antiproliferative and antitrypanosomal agents. Benzothiazoles were selective against lung carcinoma cells, and the benzimidazoles were selective against cervical carcinoma cells. The benzimidazoles target DNA, the benzothiazoles have a different cellular target.

Abstract

Novel benzo[b]thienyl- and 2,2′-bithienyl-derived benzothiazoles and benzimidazoles were synthesized to study their antiproliferative and antitrypanosomal activities in vitro. Specifically, we assessed the impact that amidine group substitutions and the type of thiophene backbone have on biological activity. In general, the benzothiazole derivatives were more active than their benzimidazole analogs as both antiproliferative and antitrypanosomal agents. The 2,2′-bithienyl-substituted benzothiazoles with unsubstituted and 2-imidazolinyl amidine showed the most potent antitrypanosomal activity, and the greatest selectivity was observed for the benzimidazole derivatives bearing isopropyl, unsubstituted and 2-imidazolinyl amidine. The 2,2′-bithiophene derivatives showed most selective antiproliferative activity. Whereas the all 2,2′-bithienyl-substituted benzothiazoles were selectively active against lung carcinoma, the benzimidazoles were selective against cervical carcinoma cells. The compounds with an unsubstituted amidine group also produced strong antiproliferative effects. The more pronounced antiproliferative activity of the benzothiazole derivatives was attributed to different cytotoxicity mechanisms. Cell cycle analysis, and DNA binding experiments provide evidence that the benzimidazoles target DNA, whereas the benzothiazoles have a different cellular target because they are localized in the cytoplasm and do not interact with DNA.

Over the past two decades, lysyl oxidases have been recognised as key enzymes in tumour invasion and metastasis, which has spurred efforts to develop inhibitors and molecular probes for therapeutic and imaging purposes, respectively. This review summarises the structural and functional aspects of these unique enzymes in relation to tumour progression and highlights recent developments in inhibitors and imaging probes.

Abstract

The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure-activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.

The Front Cover illustrates pulmonary fungal infection caused by Cryptococcus species. Pathogenic fungi are eukaryotes and structurally similar to human cells, thus making it challenging to develop target-specific antifungal agents. The emergence of drug-resistant fungi has also created a need for novel classes of antifungal therapeutics. Tetrazole-backbone-containing compounds may be novel antifungal drugs with distinct mechanisms against cryptococcosis. Cover design by Nana Nakada and Taiga Miyazaki with special technical support from Rie Matsuura. More information can be found in the Research Article by Nana Nakada, Taiga Miyazaki et al..

In this review, we shed light on how the shapes of the glyco-nanostructures govern cell-specific homing and immune responses. We examine recent advances in glyco-nanostructures of various shapes that modulate carbohydrate–protein interactions. We specifically emphasize glyco-nanostructures constructed from small-molecule amphiphilic carbohydrates, block copolymers, metal-based nanoparticles, and carbon-based materials, highlighting their potential applications in glycobiology.

Abstract

Carbohydrate–protein interactions (CPIs) play a crucial role in the regulation of various physiological and pathological processes within living systems. However, these interactions are typically weak, prompting the development of multivalent probes, including nanoparticles and polymer scaffolds, to enhance the avidity of CPIs. Additionally, the morphologies of glyco-nanostructures can significantly impact protein binding, bacterial adhesion, cellular internalization, and immune responses. In this review, we have examined the advancements in glyco-nanostructures of different shapes that modulate CPIs. We specifically emphasize glyco-nanostructures constructed from small-molecule amphiphilic carbohydrates, block copolymers, metal-based nanoparticles, and carbon-based materials, highlighting their potential applications in glycobiology.