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Stroke is the second highest cause of death and leading cause of disability with the high economic burden worldwide. The incidence of stroke is increasing faster and more prevalent for the global population over age 65. Ischemic stroke (IS) has a higher incidence than hemorrhagic stroke, accounting over 80% of the total incidence of stroke. The incidence rate of ischemic stroke is increasing in all age groups and both sexes. In the modern era, hypertension, high blood pressure and lifestyle are considered as the causes of the disease. Compared to severity, the treatment options for stroke is still limited, mainly thromolytic and thrombectomy therapy. In the past decade, a number of therapeutic agents have been studied for neuroprotection in the acute ischemic stroke to protect the brain from ischemic injury. Several study methods focus to improve neurons functions around the ischemic core and protect from the shock. Many signaling pathways including NF-kB, NrF, Nrf2-Keap1, PI3K/AKT, JAK/STAT signaling pathways are strongly associated for the indication. Controlling the signaling pathways by small molecules potentially improve the neuronal functions. In this article, we review the recent advancement of the drug discovery, controlling signaling pathways by small molecules, and kinase inhibitors in this direction.

The Gram-negative, pathogenic bacteria Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) have been identified as a particular threat due to rising multidrug resistance, and antibiotics with novel mechanisms of action are needed. Bacterial bioenergetics is a promising but underdeveloped drug target since the complexes of oxidative phosphorylation are critical to cell survival in these organisms. Building from our previous work using quinoline derivatives to inhibit the ATP synthase of PA, we report a new set of 14 quinoline derivatives that demonstrates potent inhibition of the AB ATP synthase, with the best inhibitor having an IC50 of 230 ng/mL in vitro, expands the quinoline structure-activity relationship against the PA enzyme, and establishes molecular strategies for achieving selectivity between PA and AB. Furthermore, several compounds demonstrated potent antibacterial activity against multidrug resistant strains of AB and PA indicating ATP synthase as a promising new area for broad spectrum antibiotic development in AB.

The severe adverse effects associated with imbalanced cyclooxygenase-2 (COX-2) inhibition continue to pose significant challenges in the development of contemporary anti-inflammatory drugs. In recent years, the approach to COX-2 inhibitor drug development has shifted from a focus on highly selective inhibition of COX-2 to a strategy that emphasizes more moderate selectivity. The amino acid sequence and structural similarities between inducible COX-2 and constitutive cyclooxygenase-1 (COX-1) isoforms present both substantial opportunities and challenges for the design of next generation of balanced COX-2 inhibitors. As part of our ongoing research into the discovering novel and safer COX-2 inhibitors, we reported herein a highly potent and balanced COX-2 inhibitor 21d (IC50 value = 1.35 µM, selectivity profile (IC50 (COX-1)/IC50 (COX-2) = 22.34)). In vivo assays demonstrated that 21d significantly alleviated histological damage and provided robust protection against dextran sulfate sodium (DSS)-induced acute colitis.

In this Guest Editorial for the MedChem Musings series, Mike, Former Senior Research Director at GSK, reflects on a career doing "STUFF": Science, Technology, Useful Functions and Fun. Mike summarises some of the many things he has been involved in throughout his 45 year-career in drug discovery, from which future generations of researchers can hopefully find practical advice and inspiration.

New strategies are needed to prevent and control upcoming outbreaks of SARS-CoV-2 infections, independent of vaccination. SARS-CoV-2 binds to the human ACE-2 receptor through the receptor binding domain (RBD) of the spike (S) protein, allowing the virus to enter human cells and begin replication. When peptides corresponding to four regions of RBD containing previously reported ACE-2 interaction sites were explored, the sequence 392 to 421, peptide p392wt, bound strongly to ACE-2 and inhibited wild-type RBD binding to ACE-2. Interestingly, p392 peptides corresponding to mutated sequences from different SARS-CoV-2 VOCs, including the current VOC BA.5 and KP.3, bound less strongly to ACE-2, but showed partially better inhibition of the ACE-2 interaction of all tested RBDs. When studied in a SARS-CoV-2 pseudovirus assay, the p392 peptides showed a good inhibition rate of 98.8±8.1 % at a peptide concentration of ~244 μmol/L, while none of the p392 peptides inhibited antibody binding to the RBD, suggesting that peptide treatment is sufficient in the presence of anti-RBD antibodies. Interestingly these peptides were active in the presence of diluted human serum and non-toxic to human cell lines.

Chimera-type galectin-3 (Gal-3) is a β-galactoside-binding protein containing a single conserved carbohydrate-recognition domain, crucial in fibrosis and carcinogenesis. Selenium-based Gal-3 inhibitors have emerged as promising therapeutic agents, particularly for treating neoplastic diseases. Among them, a seleno-digalactoside (SeDG) substituted with a benzyl group at position 3 of both saccharide residues (benzyl 3,3'-seleno-digalactoside, SeDG-Bn), attracted considerable attention for its selectivity and potent inhibitory efficacy against Gal-3. NMR spectroscopy and molecular dynamics simulations were combined to investigate the binding of SeDG-Bn to Gal-3 at the molecular level. This approach revealed the recognized epitope, the binding mode within Gal-3 binding pocket, and enabled the generation of a 3D model of the complex. Our findings show that the presence of a single benzyl group establishes hydrophobic contacts with amino acids in Gal-3 b-sheets S2 and S3, crucially enhancing the binding affinity compared to unmodified SeDG. The digalactose backbone orientation in Gal-3 binding site is partially modified by the benzoyl group with respect to complexes with lactosamine and SeDG. These results provide valuable insights into the design of more potent and selective inhibitors for Gal-3, potentially contributing to new therapeutic strategies for conditions such as cancer and fibrosis.

Oxindole-based natural indoles analogues retain the rigidity and size of the original indole ring system whilst introducing more 3-dimensionality and potential increased water solubility. We report the first preparation of a diverse series of new melatonin analogues 4, 6, 11, 12 based on 3-hydroxy-2-oxindoles (11) and hydroxy-free 2-oxindoles (4, 6, 12) and evaluated their ability to reduce intraocular pressure as well as their neuroprotective and antioxidant properties. Reductive amination was used to obtain new 5-(benzylamino)-substituted (indolin-3-yl)acetonitriles 11 and (indolin-3-yl)acetic acids 12 with high yields. Compounds 4 a, c, 6 a and 11 a, d, h, j-l demonstrated IOP reduction effect in range 15-27 % similar to the effect of reference compounds melatonin and timolol (12 % and 18 % reduction, respectively). 5-(Benzylamino)-substituted 3-hydroxy-2-oxindoles 11, unlike compounds 4, 6, inhibited lipid peroxidation in range 2.075-13.012 μM. Inhibition of NQO2 associated with antioxidant properties of melatonin was also evaluated for synthesized compounds and it was found that compound 11 h showed the best NQO2 inhibitory activity with an IC₅₀=39 μM (vs. melatonin IC₅₀=64 μM). All synthesized compounds 4, 6, 11, 12 at a concentration of 30 μM do not possess the mitochondrial toxicity. Moreover, no disruption of tubulin polymerization was observed even in the presence of 100 μM of the compounds. Thus, 3-hydroxy-2-oxindole derivatives 11 can be used for drug design of first-in-class antiglaucoma drugs with antioxidant and neuroprotective properties.

Cyclic sulfones play an important role in the field of drug discovery and design due to their valuable properties and their broad range of applications. Herein, we report an efficient cerium(IV)-catalyzed allylic oxidation of a simple 3-sulfolene. This process provides a straightforward and facile approach to sulfol-2-en-4-one, a versatile synthetic intermediate. Notably, this study represents the first instance of cerium catalysis employed in allylic oxidation. Furthermore, we demonstrated the transformation of sulfol-2-en-4-one into 4-substituted sulfol-2-enes with therapeutic applications. In silico analysis performed using the SwissAdme tool indicated that the obtained 4-amine (7a - 7d) and 4-carbamate (9a and 9b) derivatives of sulfol-2-en-4-one met the rules imposed on small-molecule drugs. Moreover, these compounds inhibited the proliferation (MTT assay) of colon cancer and osteosarcoma cells. Notably, compounds 7b and 7c, which exhibited the best selectivity index (ratio of IC50 calculated for normal and cancer cells), induced cell cycle arrest and apoptosis (flow cytometry analysis). Considering the present results, the cerium-catalyzed allylic oxidation of sulfol-3-ene proves to be an efficient and practical method for synthesizing sulfol-2-en-4-one, a versatile chemical synthon for developing sulfolane derivatives, including those with promising anticancer potential.

CCR8 is a GPCR mainly expressed in tumor-infiltrating T-regulatory cells (Treg) and high CCR8 expression is associated with poor prognosis in cancer. CCR8 and its ligand CCL1 may be involved in Treg recruitment, conversion and/or immunosuppressive function. Recently, pharmacological inhibition of CCR8 in mouse models has been reported to result in tumor regression and small molecule inhibitors of CCR8 have entered the clinic. Aiming to find a new class of CCR8 antagonists, a high throughput screen (HTS) of the Idorsia compound library was performed. HTS hits with a promising profile were identified and subsequent characterization revealed hERG as a key parameter that required further optimization. We reasoned that a strategy focused on discrete structural modifications would offer significant potential to reduce hERG inhibition. The lead optimization campaign we report led to the identification of compound 52 (IDOR-1136-5177), a highly potent CCR8 antagonist representing a new chemical class of CCR8 inhibitors with excellent in vitro and in vivo properties.

Acute lung injury (ALI) is a severe condition often seen in intensive care unit patients. Due to limited treatment options, ALI is linked to high rates of mortality and morbidity. Bacterial and viral infections are significant contributors to ALI. For instance, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can lead to a strong inflammatory response that may progress to ALI, a leading cause of death in COVID-19 cases. Prior research has demonstrated that sulfonamides and sydnones exhibit anti-inflammatory and antiviral properties, which has led us to develop compounds containing both scaffolds. Most of the new sulfonamide-sydnone hybrids are expected to be orally bioavailable based on in silico ADME predictions. They effectively suppressed the development of ALI in lipopolysaccharide (LPS)-challenged mice and inhibited viral replication in Calu-3 cells, with minimal cytotoxicity in non-infected Calu-3 and Vero E6 cells. Molecular docking investigations indicated some possible viral targets for the action of the sydnones, highlighting the possible interaction with non-structural proteins of SARS-CoV-2. Additionally, combined experimental and theoretical studies indicated that the new compounds can strongly interact with human serum albumin, suggesting a possible extended residence time in the human bloodstream.