Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

In this study, a series of potential ligands for the treatment of AD were synthesised and characterised as novel harmine derivatives modified at position 9 with benzyl piperazinyl. In vitro studies revealed that the majority of the derivatives exhibited moderate to potent inhibition against hAChE and Aβ_1 - 42 aggregation. Notably, compounds 13 and 17d displayed potent drug - likeness and ADMET properties, demonstrating remarkable inhibitory activities towards AChE (IC₅₀ = 58.76 nM and 89.38 nM, respectively) as well as Aβ aggregation (IC₅₀ = 9.31 μM and 13.82 μM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Aβ_1 - 42-induced SH - SY5Y damage, while maintaining low toxicity in SH - SY5Y cells. Further exploration of the mechanism through kinetic studies and molecular modelling confirmed that compound 13 could interact with both the CAS and the PAS of AChE. These findings suggested that harmine derivatives hold great potential as dual - targeted candidates for treating AD.

Natural products and analogues are a source of antibacterial drug discovery. Considering drug resistance levels emerging for antibiotics, identification of bacterial metalloenzymes and the synthesis of selective inhibitors are interesting for antibacterial agent development. Peptide nucleic acids are attractive antisense and antigene agents representing a novel strategy to target pathogens due to their unique mechanism of action. Antisense inhibition and development of antisense peptide nucleic acids is a new approach to antibacterial agents. Due to the increased resistance of biofilms to antibiotics, alternative therapeutic options are necessary. To develop antimicrobial strategies, optimised in vitro and in vivo models are needed. In vivo models to study biofilm-related respiratory infections, device-related infections: ventilator-associated pneumonia, tissue-related infections: chronic infection models based on alginate or agar beads, methods to battle biofilm-related infections are discussed. Drug delivery in case of antibacterials often is a serious issue therefore this review includes overview of drug delivery nanosystems.

To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives was designed, synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound 2g inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.

Alzheimer's disease (AD) is a progressive brain disease characterised by progressive memory loss and cognition impairment, ultimately leading to death. There are three FDA-approved acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine, AChEIs) for the symptomatic treatment of AD. Monoamine oxidase B (MAO-B) has been considered to contribute to pathologies of AD. Therefore, we reviewed the dual inhibitors of acetylcholinesterase (AChE) and MAO-B developed in the last five years. In this review, these dual-target inhibitors were classified into six groups according to the basic parent structure, including chalcone, coumarin, chromone, benzo-fused five-membered ring, imine and hydrazine, and other scaffolds. Their design strategies, structure-activity relationships (SARs), and molecular docking studies with AChE and MAO-B were analysed and discussed, giving valuable insights for the subsequent development of AChE and MAO-B dual inhibitors. Challenges in the development of balanced and potent AChE and MAO-B dual inhibitors were noted, and corresponding solutions were provided.

Two new series of pyrazolyl-thiazolidinone/thiazole derivatives 16a-b and 18a-j were synthesised, merging the scaffolds of celecoxib and dasatinib. Compounds 16a, 16b and 18f inhibit COX-2 with S.I. 134.6, 26.08 and 42.13 respectively (celecoxib S.I. = 24.09). Compounds 16a, 16b, 18c, 18d and 18f inhibit MCF-7 with IC₅₀ = 0.73-6.25 μM (dasatinib IC₅₀ = 7.99 μM) and (doxorubicin IC50 = 3.1 μM) and inhibit A549 with IC50 = 1.64-14.3 μM (dasatinib IC₅₀ = 11.8 μM and doxorubicin IC₅₀ = 2.42 μM) with S.I. (F180/MCF7) of 33.15, 7.13, 18.72, 13.25 and 8.28 respectively higher than dasatinib (4.03) and doxorubicin (3.02) and S.I. (F180/A549) of 14.75, 12.96, 4.16, 7.07 and 18.88 respectively higher than that of dasatinib (S.I. = 2.72) and doxorubicin (S.I = 3.88). Derivatives 16a, 18c, 18d, 18f inhibit EGFR and HER-2 IC50 for EGFR of 0.043, 0.226, 0.388, 0.19 μM respectively and for HER-2 of 0.032, 0.144, 0.195, 0.201 μM respectively.