In the search for polypharmacological quaternary ammonium compound disinfectants, we sought to investigate the quaternization of the ianthelliformisamine C scaffold. We synthesized a small library of quaternary ammonium compounds, finding that the tetramethyl derivative had the best activity. We investigated the mechanism of action of the natural product and methylated derivative, finding that both permeabilized the membrane.

Abstract

In the search for novel quaternary ammonium compound (QAC) disinfectants that can evade bacterial resistance, we turned to natural products as a source of inspiration. Herein we used natural product ianthelliformisamine C as a scaffold to design a small library of QACs. We first synthesized ianthelliformisamine C via an amide coupling that allowed for facile purification without the need for protecting groups. We then alkylated and quaternized the internal amines to yield four novel QACs, but all but one demonstrated no antibacterial activity against the tested strains. Using a combination of membrane depolarization and permeabilization assays, we were able to demonstrate that ianthelliformisamine C and the active QAC analog enact cell death via membrane permeabilization, contrary to prior reports on ianthelliformisamine C's mechanism of action.

Aberrant expression or dysfunction of Cyclin-dependent kinase 7(CDK7) and Histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy.

The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including i.a. emesis, pain or cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5-group, and so we designed, synthesized and tested for NK1R affinity ten novel SF5-containing compounds. All the novel analogues exhibit detectable NK1R binding, with the best of them, compound 5a, binding only slightly worse (IC50 = 34.3 nM) than the approved NK1R-targeting drug, aprepitant (IC50 = 27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF5 group in our compounds occupies a position similar to that of one of CF3 groups of aprepitant as found in the crystal structure. Additionally, we checked on whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF5-group in the design of NK1R ligands.

Photodynamic therapy (PDT) efficiently induces apoptosis through visible-light irradiation of photosensitizers　(PSs) within tumors and microbial cells. Porphyrin analogues serve as widely utilized photosensitizing agents with their theranostic abilities being governed by molecular structures and central metal ions. However, these macrocyclic compounds tend to agglutinate and form stacks in aqueous environments, resulting in a loss of photochemical activity. To overcome this limitation, encapsulation within liposomes and polymer micelles enables the dispersion of porphyrins as monomolecular entities in aqueous solutions, preventing undesirable deactivation. Recently, the use reconstituted hemoproteins containing various metal-porphyrins and protein cages incorporating porphyrins have garnered significant interest as a new generation of biocompatible PSs. In this concept paper, we provide a comprehensive review of recent developments and trends of protein–porphyrin complex PSs for applications in anticancer and antimicrobial PDTs.

The 17^th EFMC Short Course on Medicinal Chemistry this year focused on Small Molecule Protein Degraders, and the opportunities and challenges that they present as a novel modality of drug design and development. This conference report summarizes the successful event, the lectures delivered, and the topics discussed.

Abstract

The 17^th EFMC Short Course on Medicinal Chemistry took place April 23–26, 2023 in Oegstgeest, near Leiden in the Netherlands. It covered for the first time the exciting topic of Targeted Protein Degradation (full title: Small Molecule Protein Degraders: A New Opportunity for Drug Design and Development). The course was oversubscribed, with 35 attendees and 6 instructors mainly from Europe but also from the US and South Africa, and representing both industry and academia. This report summarizes the successful event, key lectures given and topics discussed.

Converting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as photoswitchable tethered ligands (PTLs), offers additional advantages. These include localization of the PTLs to the receptor binding pocket. Covalent localization increases local ligand concentration, improves site selectivity and may improve the biological differences between the respective isomers. This work describes chemical, photophysical and biochemical characterizations of a variety of PTLs designed to target the µ-opioid receptor (µOR). These PTLs were modeled on fentanyl, with the lead disulfide-containing agonist found to covalently interact with this medically-relevant receptor.

The serious adverse effects caused by non-selective and selective cyclooxygenase-2 (COX-2) inhibitors remain significant concerns for current anti-inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to in silico analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound 6m, exhibiting potent balanced inhibition, was selected for subsequent in vitro anti-inflammatory assays. Treatment with 6m effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, as well as decreased production of prostaglandin E2 (PGE2), nitric oxide (NO), and reactive oxygen species (ROS). However, 6m has no effect on the MAPK signaling pathway. Therefore, due to its potent in vitro anti-inflammatory activity coupled with lack of cytotoxicity, 6m represents a promising candidate for further development as a new lead compound targeting inflammation.

Due to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram-negative pathogens, such as Pseudomonas aeruginosa, is especially challenging due their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, primary amines, imidazolines and imidazoles, promote antibiotic and adjuvant activity in Gram-negative bacteria, but few of these have been targeted towards Pseudomonas aeruginosa specifically despite this pathogen being deemed a critical threat by the United States Centers for Disease Control and Prevention. Herein, we examined a small series of known and unknown nitrogenous dimers, with guanidine, amidine, dimethyl amine, and pyridine functionality, for antibacterial activity against multidrug resistant Pseudomonas aeruginosa. We found that two, with bisbenzguanidine and bisbenzamidine functionality, are potent against clinical isolates of multidrug resistant and biofilm forming Pseudomonas aeruginosa.

Coumarin scaffold has proven to be promising in the development of bioactive agents, such as xanthine oxidase (XO) inhibitors. Novel hydroxylated 3-arylcoumarins were designed, synthesized, and evaluated for their XO inhibition and antioxidant properties. 3-(3’-Bromophenyl)-5,7-dihydroxycoumarin (compound 11) proved to be the most potent XO inhibitor, with an IC50 of 91 nM, being 162 times better than allopurinol, one of the reference controls. Kinetic analysis of compound 11 and compound 5 [3-(4’-bromothien-2’-yl)-5,7-dihydroxycoumarin], the second-best compound within the series (IC50 of 280 nM), has been performed, and both compounds showed a mixed-type inhibition. Both compounds present good antioxidant activity (ability to scavenge ABTS radical) and are able to reduce reactive species oxygen (ROS) levels in H2O2-treated cells. In addition, they proved to be non-cytotoxic in a Caco-2 cells viability assay. Molecular docking studies have been carried out to correlate the compounds’ theoretical and experimental binding affinity to the XO binding pocket.

Strategic modification of the guanidine tail and central hydroxamate bond in the antibacterial natural product pseudouridimycin (PUM) dramatically enhances its chemical stability. Three hydroxamate-modified analogues retain much of the antibacterial activity of PUM despite reduced RNAP-inhibitory activity. Stabilization of the hydroxamate C−N bond in PUM represents a viable strategy toward clinically relevant analogues.

Abstract

Pseudouridimycin (PUM) is a microbially produced C-nucleoside dipeptide that selectively targets the nucleotide addition site of bacterial RNA polymerase (RNAP) and that has a lower rate of spontaneous resistance emergence relative to current drugs that target RNAP. Despite its promising biological profile, PUM undergoes relatively rapid decomposition in buffered aqueous solutions. Here, we describe the synthesis, RNAP-inhibitory activity, and antibacterial activity of chemically stabilized analogues of PUM. These analogues feature targeted modifications that mitigate guanidine-mediated hydroxamate bond scission. A subset of analogues in which the central hydroxamate is replaced with amide or hydrazide isosteres retain the antibacterial activity of the natural product.