MedChemComm最新文献

Ischemic reperfusion injury is a major global health threat, with the development of effective therapeutics still urgently needed. While both peptide therapeutics and small-molecule agonists have been extensively investigated to treat this condition, in this study, we explored the pharmacological potential of retro-inverso apelin peptides, including parent and modified forms, by evaluating their binding activity and physiological effects. We further assessed two metabolically stable apelin peptide analogues previously developed in our lab and compared them to a small-molecule agonist, BMS-986224, for biased agonist properties. Using radioligand displacement assays and blood pressure assays, we found that the retro-inverso peptides lacked apelin receptor binding affinity and physiological activity. However, our metabolically stable analogues and the small molecule demonstrated good receptor binding. Notably, we showed the metabolically stable apelin-13 analogue, NMeLeu13A2, to exhibit little to no blood pressure-lowering effects but retain cardiorestorative effects in the Langendorff assay. In contrast, CbzPEG₆–NMeLeu17A2 not only provided cardioprotective effects but also significantly lowered blood pressure. These findings highlight the potential of NMeLeu13A2 for targeted therapeutics and underscore the promise of apelin-based analogues in addressing ischemic reperfusion injury.

Correction for ‘Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion’ by Pradeep Kodam et al., RSC Med. Chem., 2026, https://doi.org/10.1039/d5md00345h.

The diverse expression of antigenic subtypes on tumor cells can substantially influence the specific binding and tumor cytotoxicity of antibody-recruiting molecules (ARMs). Therefore, the development of multivalent ARMs with high selectivity and affinity for binding to different subtypes on tumor cells can be expected to improve clinical performance. In this study, multivalent ARMs incorporated with multivalent dinitrophenyl (DNP) haptens and an integrin-specific arginine–glycine–aspartic acid (RGD) macrocyclic peptide were synthesized using a chemoenzymatic approach. The molecules specifically recognized integrin α_vβ₃-positive tumor cells and exhibited robust antibody recruitment capacity and tumor-killing effects depending on the multivalent effects. Notably, the D3 molecule showed excellent anti-DNP antibody recruitment capacity in the α_vβ₃-positive tumor cells and antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)-mediated tumor cytotoxicity. Given the variable expression of integrin receptor subtypes among individuals, the multivalent ARMs developed in this study that specifically target α_vβ₃-positive tumor cells to enhance cancer cytotoxicity represent a promising strategy for tumor immunotherapy.

The field of targeted protein degradation has garnered significant attention over the past two decades, highlighted by the FDA approval of several therapeutics and the entry of numerous drug candidates into clinical development, the majority of which are cereblon (CRBN) based therapeutics. Synthetic strategies to access these modalities have evolved from low-yield, multi-step syntheses to more efficient methodologies emphasizing late-stage and/or one-step functionalization. In this review, we discuss 22 recently published literature studies focusing on synthetic methodologies compatible with glutarimide scaffolds, which serve as key cereblon-binding ligand for E3 ubiquitin ligase recruitment. The methodologies covered include modern one-electron transformations such as metal-catalyzed reductive couplings, decarboxylative cross-electrophile couplings, and electro/photocatalytic couplings. In addition, we highlight optimized two-electron transformations including Buchwald–Hartwig, Suzuki–Miyaura and Sonogashira couplings that tailored for glutarimide-containing substrates. Novel synthetic approaches, such as N–H insertion, click chemistry, C–H functionalization, and carbene-mediated cyclopropanation/cyclopropenation, are also discussed for their potential in enabling the rapid development of novel cereblon-mediated degraders.

MER tyrosine kinase (MERTK) is highly expressed on the protective and reparative phenotype of microglia, which is in response to neuroregeneration following the neuronal damage induced by multiple sclerosis (MS). A specific imaging tool, which can differentiate anti-inflammatory and immunosuppressive responses of microglia, could be highly beneficial for the early detection and clinical management of MS. To identify potential ¹⁸F-radiotracers to image anti-inflammatory responses of microglia, herein a series of fluorinated pyrimidine-5-carboxamide derivatives were prepared from a database of MERTK ligands. Several potent MERTK ligands were discovered with promising selectivity profiles over other off-targets (AXL, TYRO3 and FLT3). A cell-based assay was employed to assess cellular inhibitory MERTK potency, which may be regarded as being particularly relevant to an in vivo imaging situation. This study reports the discovery of several new, potent, and selective fluorinated compounds against MERTK, paving the way for PET tracer development to image protective microglial phenotype in MS patients.

A new series of quinoline-3-carboxylate derivatives 3a–k were developed as prospective dual inhibitors of EGFR and HER-2. Structural elucidation was accomplished via¹H NMR, ¹³C NMR, DEPT NMR, elemental analysis and mass spectrometry. The synthesized compounds were evaluated for antiproliferative activity against breast (MCF-7) and colon (HT-29) cancer cell lines. Compounds 3a and 3f had the highest antiproliferative efficacy, especially against HT-29 colon cancer cells (IC₅₀ = 23 and 25 nM, respectively), surpassing erlotinib (IC₅₀ = 30 nM). Kinase inhibition experiments further validated the dual action of 3a and 3f, yielding IC₅₀ values of 68 nM and 30 nM against EGFR and HER-2, respectively, for 3a and IC₅₀ values of 71 and 33 nM against the same two kinases for 3f. Compounds 3a and 3f induced apoptosis by the activation of caspases 3, 8, and 9, alongside the overexpression of Bax and the downregulation of Bcl-2. In silico molecular docking studies were performed to investigate the binding interactions of the most active compound, 3a, with EGFR and HER-2 kinase domains. The compound showed strong binding affinities, forming critical hydrogen bonds and hydrophobic interactions with key active-site residues. Additionally, SwissADME analysis of 3a revealed full compliance with major drug-likeness filters, highlighting its potential as an orally available, dual EGFR/HER-2 inhibitor with favorable pharmacokinetic properties.

This study aimed to reduce the hepatotoxicity of traditional fibrate drugs. A molecular hybridization strategy was adopted to synthesize a series of syringaldehyde-based fibrate derivatives. Screening revealed that T2 exhibited the most pronounced reduction in TG and TC levels in a dose-dependent manner in the Triton WR 1339-induced hyperlipidemia model. Moreover, a high-fat dietary regimen (HFD)-induced hyperlipidemia model was utilized to assess the lipid-lowering potential of T2. The findings indicated that T2 exerted a significant lipid-lowering effect and reduced the ALT and AST levels, thereby ameliorating pathological alterations in the liver tissue. Additionally, the activity of SOD was significantly enhanced. It was observed that the content of the lipid peroxidation product MDA was reduced considerably, and the levels of IL-6 and TNF-α were decreased. These changes suggest that T2 is capable of exerting anti-inflammatory and antioxidant effects. Findings from research on the lipid-lowering mechanism indicate that T2 enhances PPAR-α protein expression in the liver and interacts strongly with its active site. These results suggest that T2 is a potential novel multifunctional lipid-lowering fibrate candidate compound.

AMP-activated protein kinase (AMPK) acts as a central cellular sensor at the interface of metabolic and signaling networks, that supports cell survival in energetically unfavorable environments. Due to its role in the direct mediation of fatty acid oxidation via acetyl-CoA carboxylase 2 (ACC2), there has been intensive development of small molecule AMPK activators for the treatment of metabolic diseases, such as diabetes and non-alcoholic fatty liver disease. In cancer, AMPK inhibitors may be more effective in disrupting catabolic processes that support cancer cell survival and drug resistance. We have previously reported a structure–activity study of substituted oxindoles based on the multi-kinase inhibitor sunitinib to determine the structural requirements for AMPK inhibition and found that a 5-(2-cyanoethyl)-substituted oxindole displayed selectivity for AMPK over VEGFR-2. Interestingly, the GSK3β inhibitor AZD1080, a 5-cyano-oxindole, was also found to inhibit AMPK in a limited screen. Here, we report a further series of 3,5-substituted oxindoles that demonstrate that 5-cyano-oxindoles can inhibit both GSK3β and AMPK, but the 5-(2-cyanoethyl)-substitution and the orientation of the 3-substituent of the oxindole are critical determinants for AMPK inhibition and selectivity. These findings could have critical importance in evaluating metabolic targeting in cancer as GSK3β promotes anabolic pathways and suppresses AMPK activity.

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for Parkinson's disease. We report herein the discovery of pyrrolopyrimidine analogs as potent and selective LRRK2 kinase inhibitors. Elucidation of the structure–activity relationship (SAR) of the kinase-inhibitor-focused screening lead compound 1 led to the development of compound 39 (GSK3357679) that shows excellent cellular potency, oral bioavailability, brain-penetration, and excellent PK/PD correlation in animal studies. The SAR optimization of the biological and pharmacokinetic profiles of the compounds are described. The pharmacodynamic characteristics for extended oral dosing studies in rodents are also presented.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are closely linked neurodegenerative and metabolic disorders, sharing overlapping pathological mechanisms. In this study, structure-based drug design combined with molecular hybridization strategies was employed to develop dual-acting compounds targeting both conditions. A series of twenty hybrid molecules, comprising 2-oxoindolin-3-thiosemicarbazones (3a–i) and thiazolines (4a–k) were successfully synthesized and characterized using spectroscopic techniques and elemental analysis. Biological evaluations demonstrated that compounds 3d and 3h exhibit potent inhibitory activity against α-glucosidase (α-Glu) and α-amylase (α-Amy), surpassing the efficacy of acarbose. These findings highlight their promising antidiabetic potential and support further investigation into their therapeutic relevance for AD and T2DM comorbidity (3d (α-glucosidase K_i = 41.41 ± 2.53 nM; α-amylase IC₅₀ = 1.25 ± 0.02 nM), 3h (α-glucosidase K_i = 44.19 ± 2.41 nM; α-amylase IC₅₀ = 2.87 ± 0.16 nM and acrabose (α-glucosidase K_i = 101.20 ± 7.53, α-amylase IC₅₀ 9.73 ± 0.20). Furthermore, compounds 3i and 4i exhibited significantly higher inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) compared to the reference drug tacrine. Notably, compound 4i demonstrated exceptional multi-enzyme inhibition, with kinetic parameters indicating strong binding affinity: 3i (AChE K_i = 59.71 ± 2.24 nM; BChE K_i = 8.43 ± 0.97 nM), 4i (AChE K_i = 53.31 ± 1.74 nM; BChE K_i = 10.72 ± 2.19 nM), and tacrine (AChE K_i = 132.35 ± 5.90 nM; BChE K_i = 137.42 ± 4.01 nM). Molecular docking and dynamics simulations corroborated these findings by revealing stable and favorable interactions within the active sites of both enzymes. Additionally, in silico ADME profiling indicated desirable pharmacokinetic properties, further supporting the therapeutic potential of these compounds as dual-action agents for the management of Alzheimer's disease and type 2 diabetes mellitus.