Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2-pyrrol-2-yl)phosphonates as Imidazoline Receptor Ligands with Anti-Alzheimer and Analgesic Properties.

Imidazoline receptors (I-IRs) are altered in Alzheimer's disease (AD) patients and are associated with analgesia. I-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2-pyrrol-2-yl)phosphonates endowed with relevant affinities for I-IRs in human brain tissues.

Fungerps: discovery of the glucan synthase inhibitor enfumafungin and development of a new class of antifungal triterpene glycosides.

Covering: up to 2024Fungal pathogens are a major threat to public health, with emerging resistance to all three classes of antifungals that are currently available and increased incidence of invasive fungal infections among hospitalized patients. Ibrexafungerp is a semi-synthetic analog of enfumafungin and the first antifungal agent approved in more than 20 years since the launch of caspofungin, the first of echinocandins. This new drug approval was made possible after a long arduous journey lasting 25 years by dedicated and talented medicinal chemists from two companies that undertook tedious atom-by-atom chemical modification of the natural product enfumafungin, a glycosylated fernane-type triterpenoid isolated from the fungus .

Genome-Led Discovery of the Antibacterial Cyclic Lipopeptide Kutzneridine A and Its Silent Biosynthetic Gene Cluster from Species.

Genome analysis of sp. CA-103260 revealed a putative lipopeptide-encoding biosynthetic gene cluster (BGC) that was cloned into a bacterial artificial chromosome (BAC) and heterologously expressed in M1152. As a result, a novel cyclic lipo-tetrapeptide containing two diaminopropionic acid residues and an exotic ,-acetonide ring, kutzneridine A (), was isolated and structurally characterized.

Identification of novel small molecule-based strategies of COL7A1 upregulation and readthrough activity for the treatment of recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease caused by loss of function mutations in the gene coding for collagen VII (C7) due to deficient or absent C7 expression. This disrupts structural and functional skin architecture, leading to blistering, chronic wounds, inflammation, important systemic symptoms affecting the mouth, gastrointestinal tract, cornea, and kidney function, and an increased skin cancer risk. RDEB patients have an extremely poor quality of life and often die at an early age.

Repurposing the Open Global Health Library for the discovery of novel Mpro destabilizers with scope as broad-spectrum antivirals.

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find new candidates that target viral proteins with a clear and phenotype.

Escuzarmycins A-D, Potent Biofungicides to Control Blotch.

A study targeting novel antifungal metabolites identified potent antifungal activity against key plant pathogens in acetone extracts of sp. strain CA-296093. Feature-based molecular networking revealed the presence in this extract of antimycin-related compounds, leading to the isolation of four new compounds: escuzarmycins A-D (-).

Onychocolone A produced by the fungus Onychocola sp. targets cancer stem cells and stops pancreatic cancer progression by inhibiting MEK2-dependent cell signaling.

Pancreatic cancer (PC) shows a high fatality rate that can only be faced with a combination of surgery and chemotherapy or palliative treatment in the case of advanced patients. Besides, PC tumors are enriched with subpopulations of cancer stem cells (CSCs) that are resistant to the existing chemotherapeutic agents, which raises an important need for the identification of new drugs. To fill this gap, we have tested the anti-tumoral activity of microbial extracts, which chemical diversity offers a broad spectrum of potential new bioactive compounds.

Discovery of bioactive natural products of microbial origin as inhibitors of the PD-1/PD-L1 protein-protein interaction.

The PD-1/PD-L1 protein-protein interaction (PPI) controls an adaptive immune resistance mechanism exerted by tumor cells to evade immune responses. The large-molecule nature of current commercial monoclonal antibodies against this PPI hampers their effectiveness by limiting tumor penetration and inducing severe immune-related side effects. Synthetic small-molecule inhibitors may overcome such limitations and have demonstrated promising clinical translation, but their design is challenging.

Dilarmycins A-C, Calcium-Dependent Lipopeptide Antibiotics with a Non-canonical Ca-Binding Motif.

Genome analysis of strain sp. CA-278952 revealed a biosynthetic gene cluster encoding a putative lipopeptide with a sequence containing an Asp-Gly-Glu-Ala motif. We envisioned that this motif could mimic the canonical Asp-X-Asp-Gly sequence found in previously reported calcium-dependent lipopeptide antibiotics.

Naphthoquinone Derivatives from CF-097565 Display Anti-Tumour Activity in 3D Cultures of Breast Cancer Cells.

Cancer is one of the leading causes of death worldwide, with breast cancer being the second cause of cancer-related mortality among women. Natural Products (NPs) are one of the main sources for drug discovery. During a screening campaign focused on the identification of extracts from Fundación MEDINA's library inhibiting the proliferation of cancer cell lines, a significant bioactivity was observed in extracts from cultures of the fungus CF-097565.

Madurastatins with Imidazolidinone Rings: Natural Products or Side-Reaction Products from Extraction Solvents?

Madurastatins are a group of pentapeptides containing an oxazoline moiety, and, in a few cases, an imidazolidinone ring as an additional structural feature. In our search for new potential antiparasitic metabolites from natural sources, we studied the acetone extracts from a culture of sp. CA-135719.

Evaluation of pro-regenerative and anti-inflammatory effects of isolecanoric acid in the muscle: Potential treatment of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a devastating degenerative disease of skeletal muscles caused by loss of dystrophin, a key protein that maintains muscle integrity, which leads to progressive muscle degeneration aggravated by chronic inflammation, muscle stem cells' (MuSCs) reduced regenerative capacity and replacement of muscle with fibroadipose tissue. Previous research has shown that pharmacological GSK-3β inhibition favors myogenic differentiation and plays an important role in modulating inflammatory processes. Isolecanoric acid (ILA) is a natural product isolated from a fungal culture displaying GSK-3β inhibitory properties.

Establishment of a screening platform based on human coronavirus OC43 for the identification of microbial natural products with antiviral activity.

The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production.

Acoustic droplet ejection facilitates cell-based high-throughput screenings using natural products.

Natural Products (NPs) are one of the main sources for drug discovery. Many clinical drugs are NPs or NP-inspired compounds, and recently discovered New Chemical Entities (NCEs) of NPs are emerging as promising new drugs. High-Throughput Screening (HTS) of large sample sets or libraries has grown to be vital for the drug discovery field.

Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer's Disease.

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer's disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I receptors (I-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature.

Xerophytic Lichens from Gypsiferous Outcrops of Arid Areas of Andalusia as a Source of Anti-Phytopathogenic Depsides.

In a survey to evaluate the potential of lichens associated with gypsum areas as sources of new antifungal metabolites, six species of lichens were collected in the gypsum outcrops of the Sorbas Desert ( and ) and the Tabernas Desert (, , and ) in southern Spain. Raw lichen acetone extracts were tested against a panel of seven phytopathogenic fungi, including , , f.sp TR4, , , and .

Development and Validation of a HTS Platform for the Discovery of New Antifungal Agents against Four Relevant Fungal Phytopathogens.

Fungal phytopathogens are the major agents responsible for causing severe damage to and losses in agricultural crops worldwide. , , , and are included in the top ten fungal phytopathogens that impose important plant diseases on a broad range of crops. Microbial natural products can be an attractive alternative for the biological control of phytopathogens.

Strasseriolides display in vitro and in vivo activity against trypanosomal parasites and cause morphological and size defects in Trypanosoma cruzi.

Neglected diseases caused by kinetoplastid parasites are a health burden in tropical and subtropical countries. The need to create safe and effective medicines to improve treatment remains a priority. Microbial natural products are a source of chemical diversity that provides a valuable approach for identifying new drug candidates.

New Phocoenamicin and Maklamicin Analogues from Cultures of Three Marine-Derived Strains.

Antimicrobial resistance can be considered a hidden global pandemic and research must be reinforced for the discovery of new antibiotics. The spirotetronate class of polyketides, with more than 100 bioactive compounds described to date, has recently grown with the discovery of phocoenamicins, compounds displaying different antibiotic activities. Three marine strains (CA-214671, CA-214658 and CA-218877), identified as phocoenamicins producers, were chosen to scale up their production and LC/HRMS analyses proved that EtOAc extracts from their culture broths produce several structurally related compounds not disclosed before.

Crossiellidines A-F, Unprecedented Pyrazine-Alkylguanidine Metabolites with Broad-Spectrum Antibacterial Activity from sp.

Crosiellidines are intriguing pyrazine-alkylguanidine metabolites isolated from the minor actinomycete genus . Their structures present an unprecedented 2-methoxy-3,5,6-trialkyl pyrazine scaffold and uncommon guanidine prenylations, including an exotic -prenylated -hydroxyguanidine moiety. The novel substitution pattern of the 2-methoxypyrazine core inaugurates a new class of naturally occurring pyrazine compounds, the biosynthetic implications of which are discussed herein.

Dual targeting of the class V lanthipeptide antibiotic cacaoidin.

Antibiotic resistance is reaching alarming levels, demanding for the discovery and development of antibiotics with novel chemistry and mechanisms of action. The recently discovered antibiotic cacaoidin combines the characteristic lanthionine residue of lanthipeptides and the linaridin-specific N-terminal dimethylation in an unprecedented N-dimethyl lanthionine ring, being therefore designated as the first class V lanthipeptide (lanthidin). Further notable features include the high D-amino acid content and a unique disaccharide substitution attached to the tyrosine residue.

Identification and heterologous expression of the globomycin biosynthetic gene cluster.

Globomycin is a cyclic lipodepsipeptide originally isolated from several species which displays strong and selective antibacterial activity against Gram-negative pathogens. Its mode of action is based on the competitive inhibition of the lipoprotein signal peptidase II (LspA), which is absent in eukaryotes and considered an attractive target for the development of new antibiotics. Despite its interesting biological properties, the gene cluster encoding its biosynthesis has not yet been identified.

Antiparasitic Meroterpenoids Isolated from CF-080171.

is a fungal genus from which a wide range of diverse biologically active compounds have been isolated. A CF-080171 extract was identified to exhibit potent activity against 3D7 and Tulahuen whole parasites in a high-throughput screening (HTS) campaign of microbial extracts from the Fundación MEDINA's collection. Bioassay-guided isolation of the active metabolites from this extract afforded eight new meroterpenoids of varying potencies, namely, memnobotrins C-E (-), a glycosylated isobenzofuranone (), a tricyclic isobenzofuranone (), a tetracyclic benzopyrane (), a tetracyclic isobenzofuranone (), and a pentacyclic isobenzofuranone ().