MedChemComm最新文献

Autoimmune disorders are heterogeneous dynamic conditions characterized by dysregulated immune responses and caused by interruption of tolerogenic circuits. Although immunosuppressive drugs, including biological agents, are effective therapeutic options, several patients do not respond to these treatment or develop resistance mechanisms. Galectins, a family of soluble glycan-binding proteins, play central roles in the modulation of autoimmune inflammation. Galectin-1 (Gal-1), a prototype member of this family, interacts with specific N-acetyllactosamine (LacNAc) ligands present in N- and O-glycans via its conserved carbohydrate recognition domain (CRD). The immunomodulatory activity of Gal-1 involves regulation of T cell effector populations, inducing apoptosis of Th1 and Th17 cells, differentiation of tolerogenic dendritic cells and induction of myeloid-derived suppressor cells. To develop a rational galectin-based therapeutic strategy, we evaluated whether Gal-1 retains its function upon multivalent presentation on nanoparticles. Specifically, we report the design strategy, synthesis and characterization of galectin-1-conjugated glucose-stabilized gold nanoparticles, and compare their activities with unconjugated galectin-1. This formulation offers novel opportunities for treating a variety of autoimmune diseases, as well as chronic inflammatory disorders.

To overcome neomycin's limited efficacy against complex Gram-positive and Gram-negative co-infections, we have developed a novel guanidinium-linked neomycin–lipid conjugate (guanidino Neo-lipid). This multifunctional construct integrates three synergistic components: a neomycin core for ribosomal targeting, a hydrophobic lipid chain to facilitate membrane interaction and cellular uptake, and a cationic guanidinium moiety that enhances electrostatic binding to negatively charged bacterial membranes. The resulting conjugate demonstrates significantly improved antibacterial activity in liquid cultures and effectively disrupts biofilm formation. This approach offers a promising therapeutic strategy for treating persistent infections caused by both Gram-positive and Gram-negative pathogens, including co-infective scenarios.

Infected wounds are challenging to heal because they are complicated by bacterial infections, persistent inflammation, and impaired cell proliferation. Recently, imidazolium poly(ionic liquids) (PILs), as highly effective antibacterial agents, have been developed for infected wound healing. However, traditional imidazolium-based PILs containing halogen groups have shown potential cytotoxicity. In this study, we designed halogen-free metal–phenolic imidazolium PILs (HMPIPs) with antibacterial, anti-inflammatory and cell proliferation properties. Firstly, poly(vinyl-butylimidazolium dihydroxyphenylpropionic acid) (PVD) was synthesized via radical polymerization, anion exchange, and catechol deprotection. Subsequently, the HMPIPs were individually coordinated with metals ions (Zn²⁺, Mg²⁺, Cu²⁺, and Fe³⁺). The results indicated that PVD@Zn could form stable MPIP microparticles. In vitro assays revealed that PVD@Zn exhibited potent antibacterial activity against Escherichia coli (MIC: 512 μg mL⁻¹) and Staphylococcus aureus (MIC: 128 μg mL⁻¹), likely due to the synergistic effects of the imidazolium group's positive charge. Additionally, PVD@Zn exhibited anti-inflammatory effects by suppressing reactive oxygen species (ROS) and nitric oxide (NO) levels, and downregulating TNF-α, IL-1β, IL-6, and iNOS through Zn²⁺-mediated regulation. Notably, it enhanced L929 fibroblast proliferation by 22% via upregulation of amino acid biosynthesis pathways. In vivo assays further demonstrated that PVD@Zn significantly accelerated wound closure (97% contraction within 11 days), effectively reduced bacterial load (93% eradication), and exhibited minimal systemic organ toxicity. The multifunctional HPIPs, PVD@Zn, demonstrated antibacterial, anti-inflammatory, and pro-proliferative properties, potentially reducing the risk of drug overuse during wound healing. This system holds promise for future clinical application as an encapsulated therapeutic agent.

A series of new substituted lactose-conjugated 2-iminothiazolidin-4-ones 7a–h were synthesized and scanned for their inhibitory activity against enzymes responsible for type 2 diabetes, including α-amylase, α-glucosidase, DPP-4, and PTP1B. Three lactose-conjugated 2-iminothiazolidin-4-ones 7c, 7e, and 7f exhibited the highest inhibitory activity against the selected enzymes. Compounds 7c and 7e were the strongest inhibitors for DPP-4 and α-amylase, respectively, whereas 7f exhibited strong inhibition against α-glucosidase and PTP1B. These compounds had also high anti-glycation and antioxidant activities and were not cytotoxic to the WI-38 cell line. A molecular docking study was applied to the three most potent inhibitors 7c, 7e, and 7f in inhibition against enzymes 1OSE, 3TOP, 3W2T, and 1NNY. These ligands had active interactions with the residues in the catalytic pocket of these enzymes consistent with their inhibitory efficacy against each enzyme tested. Molecular dynamics simulations were applied for four typical complexes 7e/1OSE, 7f/3TOP, 7c/3W2T, and 7f/1NNY to validate the obtained in vitro data of these compounds. The obtained results indicated that these inhibitors had stable dynamic interactions in the catalytic pocket of the respective enzymes to promote their activity. The presence of the di-imine bridge bond helped to connect the thiazolidin-4-one ring and the aromatic ring, communicating the influence of the alternative groups on the overall activity of the target molecule. Additionally, the β-lactose portion contributes to the binding of the target molecule to the residue at the active site and increases the inhibitory activity of the target compounds.

Previous studies have demonstrated the essential role of the envelope glycoprotein (Env) gp120 and gp41 N-terminal heptad repeat (NHR) region in human immunodeficiency virus type 1 (HIV-1) life cycle steps. Based on the multitarget-directed ligand (MTDL) design strategy, we herein report a series of bifunctional entry inhibitors consisting of an aroyl indoleoxoacetyl piperazine-based attachment inhibitor, IAC, and a gp41 NHR-targeting peptide fusion inhibitor SP22. We found that one of these chimeras, named ISP, showed potent inhibitory potency against HIV-1, about 180- and 54-fold over that of its parent inhibitors, IAC and SP22, respectively. Our work provides a potent peptide-based bifunctional HIV-1 entry inhibitor and offers new insights into the design of therapies against infection of other enveloped viruses.

The fenarimol analogue EPL-BS1246 was previously discovered to be potent against Madurella mycetomatis, the causative agent of the neglected tropical disease mycetoma. Further evaluation of a small set of fenarimol analogues in vivo revealed a correlation between efficacy and the lipophilicity (log D) of the analogues. To explore both this correlation and the series structure–activity relationship (SAR), we have evaluated a total of 185 fenarimol analogues derived from five different daughter chemotypes. Potent (MIC₅₀ < 9 μM) in vitro activity was found for 22 analogues, five of which gave promising results in an in vivo larval survival assay. Again, a trend towards prolonged larval survival (better in vivo activity) was noted in analogues with log D values <2.5. Insights into the SAR could be gleaned that suggested optimal substituents for the rings forming the fenarimol core.

The triazole scaffold has garnered considerable attention over the preceding decade as a privileged pharmacophore in the rational design of chemotherapeutic agents targeting neglected tropical diseases (NTDs). This review provides a comprehensive elucidation of the multifaceted research dedicated to the structural optimization of the triazole nucleus and its consequential outcomes on biological efficacy. Emphasis is placed on the methodical investigation of diverse substituents appended to the triazole core, underscoring the profound influence of seemingly marginal modifications on critical pharmacological parameters. Through a comprehensive deconstruction of structure–activity relationships (SAR), this exposition identifies the essential functional moieties underpinning biological efficacy that potentiate anti-parasitic, anti-fungal, and anti-viral activities across a spectrum of NTD-relevant biological targets. These insights deepen the knowledge of triazole based hybrid molecules and guide future rational design of novel compounds. By synthesizing and analyzing findings from a wide array of studies, this review aims to serve as a valuable resource for researchers interested in the continued development of triazole derivatives to manage neglected tropical diseases effectively.

Multitarget directed ligands represent an innovative strategy in the management of Alzheimer's disease (AD) by addressing its multifactorial etiology. These agents are designed to simultaneously modulate multiple key targets involved in the disease progression, offering a holistic approach for the effective treatment of AD. The current work presents the synthesis and evaluation of novel dihydroquinazoline-based multitargeting agents for the management of Alzheimer's disease. Most of the compounds showed good selectivity for AChE and MAO-B, and two compounds, viz.K2V-9 and K2V-12, emerged as potent inhibitors against both the targets. Compound K2V-9 displayed IC₅₀ values of 1.72 ± 0.01 μM and 0.950 ± 0.52 μM against AChE and MAO-B, respectively. Compound K2V-12 showed IC₅₀ values of 1.10 ± 0.078 μM and 1.68 ± 0.25 μM against AChE and MAO-B, respectively. Moreover, amyloid β self-aggregation inhibition studies were performed, where K2V-9 and K2V-12 showed percentage inhibitions of 37.34% and 48.10%, respectively, after 48 h. Both compounds were found to be non-toxic and neuroprotective and showed the capability of reducing the ROS levels in SHSY-5Y cells. Reversibility and kinetic studies of these lead compounds showed that both molecules produced reversible and mixed-type of inhibition against the targeted enzymes. In the docking and molecular dynamics simulation studies, K2V-9 and K2V-12 were found to be well accommodated in the active cavity with good thermodynamic stability.

Polo-like kinase 4 (PLK4), a member of the serine/threonine protein kinase family, serves as a central regulator of centriole duplication and plays a critical role in eukaryotic mitosis. Overexpression of PLK4 in several cancer types underscores its potential as a therapeutic target. In our previous studies, compound 28t demonstrated acceptable kinase inhibitory activity but exhibited poor cellular activity. Consequently, 28t was selected as a lead compound for further optimization. Through functional group migration and rational drug design strategies, we conducted structural modifications that ultimately yielded 23 novel indazole-based PLK4 inhibitors. Among these, compound C05 exhibited exceptional kinase inhibitory activity (IC₅₀ < 0.1 nM). At the cellular level, C05 demonstrated potent antiproliferative effects against IMR-32 (neuroblastoma), MCF-7 (breast cancer), and H460 (non-small cell lung cancer) cell lines, with IC₅₀ values of 0.948 μM, 0.979 μM, and 1.679 μM, respectively. Notably, compound C05 demonstrated favorable kinase selectivity towards PLK4 among the 10 kinases tested, achieving an inhibition rate of 87.45%. Further pharmacological experimental studies, including apoptosis induction, cell cycle arrest analysis, and clonogenic formation experiments, revealed that C05 outperformed the positive control LCR-263 in both potency and efficacy. Western blot analysis demonstrated that compound C05 effectively suppressed PLK4 autophosphorylation at 4 μM. Unfortunately, compound C05 demonstrated poor metabolic stability in human liver microsomes (HLMs), exhibiting a short half-life (T_1/2) of 2.69 minutes under standard incubation conditions. Notwithstanding the suboptimal metabolic stability, the compelling biological activity profile of compound C05 warrants further structural refinement.

Antimicrobial resistance (AMR) is a mounting global health crisis demanding novel, sustainable therapeutic strategies beyond traditional antibiotics. Ultra-short cationic β-peptides have emerged as a promising class of synthetic antimicrobial foldamers with broad-spectrum activity, remarkable proteolytic stability, and low resistance potential. Designed through rational approaches, these 2–10 residue peptides leverage amphipathicity, structural rigidity, and electrostatic interactions to disrupt microbial membranes, biofilms, and even intracellular pathogens. Notably, they exhibit synergistic effects with conventional antibiotics and minimal toxicity to mammalian cells. Emerging in vivo studies in murine models further suggest that ultra-short β-peptides can reduce pathogen burden and improve survival, although the available data remain limited and warrant careful interpretation. This review provides a comprehensive overview of their design, mechanism of action, antimicrobial spectrum, including bacteria, fungi, viruses, and protozoa, and relevance to One Health frameworks. Key translational bottlenecks, including delivery challenges, immunogenicity, pharmacokinetics, and regulatory hurdles, are critically assessed. We also identify major research gaps and propose future directions to fully harness the therapeutic potential of ultra-short β-peptides against multidrug-resistant infections.