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Visceral leishmaniasis (VL) is among the most neglected tropical diseases in the world. Drug cell permeability is essential for killing the intracellular residing parasites responsible for VL, making cell-permeating peptides a logical choice to address VL. Unfortunately, the limited biological stability of peptides restricts their usage. Sequence-specific oligo-N-substituted glycines ('peptoids') are a class of peptide mimics that offers an excellent alternative to peptides in terms of ease of synthesis and good biostability. We tested peptoids against the parasite Leishmania donovani in both forms, that is, intracellular amastigotes and promastigotes. N-alkyl hydrophobic chain addition (lipidation) and bromination of oligopeptoids yielded compounds with good antileishmanial activity against both forms, showing the promise of these antiparasitic peptoids as potential drug candidates to treat VL.

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

Mono- and binuclear Cu(I) complexes were isolated employing 2,1,3-benzoselenadiazole (BSeD) as the N-donor ligand, and triphenylphosphine or bis[(2-diphenylphosphino)phenyl] ether (DPEphos) as P-donors. Then, 77Se NMR was measured for the free ligand and the corresponding Cu(I) derivatives, and the related signal was downshifted by 12.86 ppm in the case of [Cu(BSeD)(PPh3)2(ClO4)], and around 15 ppm for the binuclear species. The structure of [Cu(BSeD)(PPh3)2(ClO4)] and [Cu2(μ2-BSeD)(DPEphos)2(ClO4)2] was confirmed by single-crystal X-ray diffraction. The geometry of the Cu(I) complexes was optimized through DFT calculations, and the nature of the Cu···O interaction was investigated through AIM analysis. The three Cu(I) complexes were characterized by intense absorption under 400 nm and, after being excited with blue irradiation, [Cu(BSeD)(PPh3)2(ClO4)] and [Cu2(μ2-BSeD)(PPh3)4(ClO4)2] exhibited weak red emissions centered at 700 nm. The lifetimes comprised between 121 and 159 μs support the involvement of triplet excited states in the emission process. The photoluminescent properties of [Cu(BSeD)(PPh3)2(ClO4)] were supported by TDDFT computations, and the emission was predicted at 710 nm and ascribed to a metal-to-ligand charge transfer (3MLCT) process, in agreement with the experimental data. [ABSTRACT FROM AUTHOR]

In this report, a new series of mono‐, di‐, tri‐, and tetra‐cationic pyridinium and vinyl pyridinium‐modified [2.2]paracyclophanes as useful molecular tectons for supramolecular systems are described. Regioselective functionalization at specific positions, followed by resolution step and successive transformations through Pd‐catalyzed Suzuki‐Miyaura and Mizoroki‐Heck cross‐coupling chemistry furnish a series of modular PCP scaffolds. In our proof‐of‐concept study, on N‐methylation, the PCPs bearing (cationic) pyridyl functionalities were demonstrated as useful molecular receptors in host‐guest supramolecular assays. The PCPs on grafting with light‐responsive azobenzene (−N=N−) functional core as side‐groups impart photosensitivity that can be remotely transformed on irradiation, offering photo‐controlled smart molecular functions. Furthermore, the symmetrical PCPs bearing bi‐, and tetra‐pyridyl functionalities at the peripheries have enormous potential to serve as ditopic and tetratopic 3D molecular tectons for engineering non‐covalent supramolecular assemblies with new structural and functional attributes. [ABSTRACT FROM AUTHOR]

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression. [ABSTRACT FROM AUTHOR]

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects. [ABSTRACT FROM AUTHOR]