There are currently no small molecules clinically approved as immune checkpoint modulators. Besides possessing oral bioavailability, cell-penetrating capabilities and enhanced tumor penetration compared to monoclonal antibodies (mAbs), small molecules are amenable to pharmacokinetic optimization, which allows adopting flexible dosage regimens that may avoid immune-related adverse events associated with mAbs. The interaction of inducible co-stimulator (ICOS) with its ligand (ICOS-L) plays key roles in T-cell differentiation and activation of T-cell to B-cell functions. This study represents the development and validation of a virtual screening strategy to identify small molecules that bind a novel druggable binding pocket in human ICOS. We used a lipophilic canyon in the apo-structure of ICOS and the ICOS/ICOS-L interface individually as templates for molecular dynamics simulation to generate 3D pharmacophores subsequently used for virtual screening campaigns. Our strategy was successful finding a first-in-class small molecule ICOS binder (5P, KD value = 108.08 ± 26.76 µM) and validating biophysical screening platforms for ICOS-targeted small molecules. We anticipate that future structural optimization of 5P will result in the discovery of high affinity chemical ligands for ICOS.

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N-acetyl moiety for a N-carbamoyl group led to analogues with sub- and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug-susceptible and drug-resistant M. tuberculosis isolates. The new N-carbamoyl azaaurones exhibited improved microsomal stability, compared to their N-acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10-8, a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.

This scientific study explores the binding mechanisms of saccharine derivatives with human carbonic anhydrase IX (hCA IX), an antitumor drug target, with the aim of facilitating the design of potent and selective inhibitors. Through the use of crystallographic analysis, we investigate the structures of hCA IX - saccharine derivative complexes, unveiling their unique binding modes that exhibit both similarities to sulfonamides and distinct orientations of the ligand tail. Our comprehensive structural insights provide information regarding the crucial interactions between the ligands and the protein, shedding light on interactions that dictate inhibitor binding and selectivity. Through a comparative analysis of the binding modes observed in hCA II and hCA IX, isoform-specific interactions are identified, offering promising strategies for the development of isoform-selective inhibitors that specifically target tumor-associated hCA IX. The findings of this study significantly deepen our understanding of the binding mechanisms of hCA inhibitors, laying a solid foundation for the rational design of more effective inhibitors.

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 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 demonstrated decreased antibacterial activity compared to the parent scaffold. The most active QAC was susceptible to resistance in MRSA. We confirmed that ianthelliformisamine C and an active QAC analog permeabilize both gram-positive and gram-negative bacterial membranes.

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.

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.

The 17th 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.