ChemMedChem最新文献

Two novel, structurally different perfluoroalkyl ionic liquids with bicyclic guanidinium cation have been synthesized and applied as a surfactant component for selected active pharmaceutical ingredients (APIs). The addition of perfluoroalkyl ionic liquid to hydrophobic APIs significantly improves their solubility. One of the key and characteristic properties of guanidine derivatives is their strong ability to chemisorb protons (proton affinity). This property enables them to form stable ionic-type aggregates (adducts) with selected hydrophobic APIs containing carboxylic groups. Therefore, these new compounds are, in fact, API-IL ionic adducts formed as hydrogen bond donor–acceptor systems. The obtained adducts are characterized by significantly better solubility than the initial APIs. The presence of perfluoroalkyl chains with unique surface-active properties enables to obtain a solubility of new adducts to reach level sufficient for typical ophthalmic preparations. (e.g., eye drops or lens care). The ionic API-IL adducts obtained in the described studies can be considered as examples of a new class of active derivatives with pharmaceutical potential.

Prodrug-based self-assembled nanoassemblies, with carrier-free structures and high drug loading, are garnering attention for chemotherapy. Additionally, the synergistic effects of prodrug nanoassemblies combined with multiple cell death pathways deserve further exploration. Ferroptosis has emerged as a powerful nonapoptotic cell death modality, showing significant potential for tumor inhibition. Therefore, prodrug nanoassemblies combined with ferroptosis inducers may achieve amplified antitumor efficacy. Herein, a GPX4 inhibitor (ML210)-loaded SN38 prodrug nanoparticle system is developed to enhance antitumor efficacy via ferroptotic-chemotherapy synergy. In this system, SN38 is conjugated to 1-octadecanol by a disulfide linkage to construct the self-assembly prodrug. DSPE-PEG_2k is applied to stabilize nanoassemblies. It is proven that ML210 is successfully encapsulated into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibit good stability and a GSH-responsive release profile. Furthermore, ML210-loaded nanoassemblies show stronger cytotoxicity, greater proliferation inhibition, and obvious ferroptosis activation. In the CT26 mouse model, ML210-loaded prodrug nanoassemblies demonstrated superior antitumor effects. The strategy—using prodrug as “carriers” for ferroptosis inducers—offers a promising approach for synergistic antitumor therapy.

Photo-labile protecting groups (PPG) allow for the selective activation of an originally caged moiety by light exposure at a specific wavelength. Incorporation of PPG in nanoparticles (NPs) enables precise spatiotemporal control over NPs surface properties. Thus, physicochemical and biological properties of NPs can be modified even after administration in a biological environment. In this study, this mechanism is used to control the cell uptake of NPs. To this end, polymeric core–shell NPs are used composed of poly(D, L-lactide-co-glycolide) and a poly(ethylene glycol)-b-poly(D, L-lactide) block copolymer, modified with positively charged cell-penetrating peptide (CPP). Surface charge of CPP-NPs (+23.50 mV), measured as zetapotential, is effectively diminished by the attachment of coumarin-derived PPG to CPP (+12.50 mV), resulting in reduced cell uptake. Upon light irradiation with light-emitting diode (λ = 365 nm) the PPG is cleaved, restoring the zetapotential (+24.67 mV) and triggering an enhanced cell uptake. This opens the door to trigger the cellular uptake of NPs that are intended to transport drugs to their target cells in the future.

Cardiovascular diseases (CVDs) have become a leading cause of deaths globally. Recent studies have shown that increasing the level of high-density lipoproteins (HDL) is one of the potential avenues to halt CVD progression. This could be achieved by modulating the neutral lipid transfer activity of cholesteryl ester transfer protein (CETP), a key target in developing effective cardioprotective drugs. This study aims to identify important structural fingerprints and functional moieties as "good" and "bad" contributors toward CETP inhibition, using machine learning (ML) and quantitative structure–activity relationship-based approaches. Results suggest unsaturated heterocyclic rings and trifluoromethyl substitutions as potential promoters and aliphatic carboxylic acid and ester moieties as the detractors in CETP inhibition. Molecular dynamics (MD) simulations of CETP in complexation with recently reported Obicetrapib with “good” fingerprints versus a clinically failed inhibitor, Torcetrapib shows superior inhibitory potential of the former due to stronger binding and better shape complementarity with the CETP hydrophobic tunnel. By leveraging the potentials of ML and MD simulations, this comprehensive study helps judicious pick of the right functional moieties for designing next generation CETP drugs targeting CVD.

Alzheimer's disease (AD), the most prevalent form of dementia, leads to progressive cognitive decline due to pathological hallmarks including amyloid plaques, neurofibrillary tangles, synaptic loss, neuroinflammation, and neuronal cell death, highlighting the urgent need for multitarget therapeutic strategies. The p38α mitogen-activated protein kinase (p38α MAPK) pathway is a key regulator of neuroinflammation and has been implicated in AD pathogenesis. Additionally, dysregulation of p38α MAPK is associated with tumorigenesis, making it a promising target for both neurodegenerative and proliferative diseases. In this article, a series of benzoxazole derivatives is designed and synthesized to evaluate their dual inhibitory potential against p38α MAPK and acetylcholinesterase (AChE), aiming for a multifaceted therapeutic approach to AD. A total of 31 compounds are synthesized and assessed for their antiproliferative activity, p38α MAPK inhibition, and AChE inhibitory effects. In vitro assays demonstrate that several compounds exhibit potent dual inhibition of p38α MAPK and AChE, while molecular docking studies provide insights into their binding interactions within the active sites. These findings suggest that benzoxazole-based scaffolds offer a promising framework for the development of dual-acting inhibitors targeting both neuroinflammation and tumorigenesis. Further in vivo and mechanistic studies are warranted to explore their therapeutic potential.

To assess the influence of the nature of the anticholinesterase pharmacophore on the properties of potential multitarget Alzheimer's disease (AD) agents, new conjugates of tacrine (3a, b) and amiridine (5a, b) with ethyl-2-aminomethylidene-4,4,4-trifluoro-3-oxobutanoate linked by an alkylene spacer with n = 4,6 were synthesized. All conjugates are effective cholinesterase inhibitors with predominant inhibition of butyrylcholinesterase (BChE). The inhibitory activity of tacrine conjugates 3a, b toward acetylcholinesterase (AChE) and BChE increases with spacer elongation: IC₅₀ AChE up to 0.185 µM, IC₅₀ BChE up to 0.0806 µM. Amiridine conjugates 5a, b are less active as AChE inhibitors and their anti-AChE activity (IC₅₀ up to 3.09 µM) remains virtually unchanged with spacer elongation, while anti-BChE activity increases significantly (n = 6, IC₅₀ = 0.063 µM), which leads to increased selectivity toward BChE (up to 56). The effects are consistent with the results of kinetic studies and molecular docking of 3b and 5b. Both types of conjugates displace propidium from the AChE peripheral anionic site at the level of and above that of donepezil, and are capable of blocking self-aggregation of β-amyloid (up to 49.5%). The compounds demonstrate very weak antioxidant activity (tacrine conjugates) or its absence (amiridine). Thus, new conjugates are potential multitarget anti-AD agents with high selectivity toward BChE for amiridine derivative 5b.

The cover image shows a 2D interaction maps of the imidazo[1,5-a]pyrazine (top left), quinoline carboxamide (top right), benzimidazole (bottom left), pyrrolo[2,3-d]pyrimidine (middle), and pyrrolo[2,3-b]pyridine (bottom right) scaffolds in the TgCDPK1 ATP binding site using Schrödinger. More details can be found in the Research Article by James W. Janetka and co-workers (DOI: 10.1002/cmdc.202500440).

The escalating multidrug-resistant bacterial infections underscore the urgent need for alternatives to conventional antibiotics. Antimicrobial photodynamic therapy emerges as a promising strategy, leveraging light-activated photosensitizers like methylene blue (MB) to generate bactericidal reactive oxygen species (ROS) that disrupt microbial membranes and DNA. This approach minimizes resistance development due to the nonspecific action of ROS and demonstrates efficacy against both Gram-positive and Gram-negative pathogens. A pH-responsive mixed-ligand metal-organic framework (ML-MOF) is synthesized as a nanocarrier for MB. Encapsulation of MB into ML-MOF (MB@ML-MOF50) resulted in a loading capacity of 29.67%, with a controlled and sustained release profile of 85% at pH 5.1 (infection-mimicking conditions). MB@ML-MOF50 exhibited twice the singlet oxygen generation efficiency (S = 0.2098) compared to free MB (S = 0.1058), confirming enhanced photodynamic activity. MB@ML-MOF50 under 650 nm laser irradiation achieved complete bacterial inhibition (0% survival) at 25 µM, surpassing free MB. Biofilm eradication studies using the crystal violet (CV) assay revealed 37.26% inhibition of Escherichia coli (E. coli) biofilm and 25.42% inhibition of Staphylococcus aureus (S. aureus) biofilm after 15 min of laser exposure compared to a nonirradiated control, indicating the potential for disrupting persistent infections. MB@ML-MOF50 is a promising multifunctional nanoplatform for targeted, pH-responsive, and enhanced photodynamic antibacterial therapy.

The Frontiers in Medicinal Chemistry (FiMC), which represents the largest international Medicinal Chemistry conference in Germany, took place from April 1^st to 4^th, 2025, in Erlangen. The conference was a great success, bringing together more than 200 participants from around 20 countries. The outstanding program of the 4 day conference included 41 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 91 posters were presented in a highly interactive poster session.

Herein, the antimycobacterial screening of a series of rifamycin analogues, modified at their C-3 extension, is reported. Overall, these compounds display potent activity against a wild-type Mtb strain assayed in three different growth media. Several promising C-3 extensions are identified through this screen, with compounds featuring rigid tertiary alicyclic hydrazones displaying superior activity to amino compounds. In addition, a general correlative trend between logP and biological activity is observed. This study adds to the growing literature surrounding structure activity relationship pertaining the important C-3 extension of rifamycin, which in addition to a poorly understood role in target engagement, has utility for modulating physicochemical properties, a key condition in antimycobacterial drug discovery.