Bioorganic & Medicinal Chemistry Letters最新文献

Glycogen synthase kinase 3β (GSK-3β) is a potential therapeutic target for the treatment of a variety of human diseases. Here, we report the design and synthesis of a series of thieno[3,2-c]pyrazol-urea derivatives and evaluation of their GSK-3β inhibitory activity. Among these analogues, the compound without substitution on terminal phenyl ring (3a) was found to be the most potent GSK-3β inhibitor with an IC₅₀ of 74.4 nM, while substitution on the terminal phenyl (3b–3p) led to decreased potency, independent of the position, size, or electronic properties of the substituents. Kinase selectivity assay revealed that 3a showed good selectivity over a panel of kinases, but was less selective over CDK1, CDK2 and CDK5. Additionally, the pharmacological properties of the synthesized compounds were investigated computationally by the SwissADME and the results showed that most of the compounds have good ADME profiles.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in many physiological and pathological mechanisms through its numerous receptors. Among these, the 5-HT_2B receptor is known to play a key role in multiple brain disorders but remains poorly understood. Positron emission tomography (PET) can contribute to a better understanding of pathophysiological mechanisms regulated by the 5-HT_2B receptor. To develop the first PET radiotracer for the 5-HT_2B receptor, RS-127445, a well-known 5-HT_2B receptor antagonist, was labeled with fluorine-18. [¹⁸F]RS-127445 was synthesized in a high radiochemical purity and with a good molar activity and radiochemical yield. Preliminary PET scans in rats showed good brain penetration of [¹⁸F]RS-127445. However, competition experiments and in vitro autoradiography showed high non-specific binding, especially to brain white matter.

Fructose metabolism by ketohexokinase (KHK) is implicated in a variety of metabolic disorders. KHK inhibition is a potential therapeutic strategy for the treatment of diseases including diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. The first small-molecule KHK-inhibitors have entered clinical trials, but it remains unclear if systemic inhibition of KHK by small-molecules will eventually benefit patients. Here we report the discovery of BI-9787, a potent, zwitterionic KHK inhibitor characterized by high permeability and favorable oral rat pharmacokinetics. BI-9787 was identified by optimizing chemical starting points generated via a ligand-based virtual screening of Boehringer’s virtual library of synthetically accessible compounds (BICLAIM). It serves as a high-quality in vitro and in vivo tool compound for investigating the role of fructose metabolism in disease.

Methionine aminopeptidase (MetAp) enzymes catalyze the post-translational removal of the initiator methionine residue in newly synthesized proteins, a process that is often essential in the maturation of proteins. Consequently, these enzymes serve as important targets for drug development. Rickettsia prowazekii (Rp) is an obligate coccobacillus and the causative agent of the louse-borne epidemic typhus and despite adequate treatment causes a latent infection. This research aimed to identify potential anti-rickettsial agents by screening 400 compounds from the MMV Pandemic Response Box against RpMetAp1. Overall, 19 compounds were identified that possessed IC₅₀ values from 10 µM to 340 nM. The most potent inhibitor was MMV 1580488 (17), which was observed to have an IC₅₀ of 340 nM. The selected hits serve as chemical leads that can be used for the development of potent inhibitors of the RpMetAp1 enzyme.

Click chemistry is a flexible method featuring only the most feasible and efficient chemical reactions. The synthesis of 1,2,3-triazole from azides and terminal acetylenes using copper(I) as a catalyst is an extremely powerful reaction due to the extreme dependability, good selectivity, and biocompatibility of the starting materials. Triazole molecules are more than simple passive linkers; through hydrogen bonding and dipole interactions, they rapidly bind with biological targets. Its applications in drug development are expanding, ranging from target-oriented in situ chemistry and combinatorial mechanisms for lead generation to bioconjugation methods to study proteins and DNA. The click chemistry has frequently been used to speed up drug discovery and optimization processes in the past few years. The click chemistry reaction based on copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a biochemical process with applications in medicinal chemistry and chemical biology. Thus, click reactions are an essential component of the toolkit for medicinal chemistry and help medicinal chemists overcome the barriers in chemical reactions, increase throughput, and improve the standards of compound libraries. The review highlights the recent advancements in the copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry approach for synthesizing biologically important triazole moieties with a greater emphasis on synthesis methodologies and pharmacological applications. Additionally, the triazole-based FDA-approved drugs are also discussed with their mode of action to highlight the importance of the click chemistry approach in synthesizing the bioactive triazole compounds.

Amyloid plaque formation in the brain is mainly responsible for the onset of Alzheimer’s disease (AD). Structure-based peptides have gained importance in recent years, and rational design of the peptide sequences for the prevention of Aβ-aggregation and related toxicity is imperative. In this study, we investigate the structural modification of tetrapeptides derived from the hydrophobic C-terminal region of Aβ₄₂ “VVIA-NH₂” and its retro-sequence “AIVV-NH₂.” A preliminary screening of synthesized peptides through an MTT cell viability assay followed by a ThT fluorescence assay revealed a peptide 13 (Ala-Ile-Aib-Val-NH₂) that showed protection against Aβ-aggregation and associated neurotoxicity. The presence of the α-helix inducer “Aib” in peptide 13 manifested the conformational transition from cross-β-sheets to α-helical content in Aβ₄₂. The absence of fibrils in electron microscopic analysis suggested the inhibitory potential of peptide 13. The HRMS, DLS, and ANS studies further confirmed the inhibitory activity of 13, and no cytotoxicity was observed. The structure-based peptide described herein is a promising amyloid-β inhibitor and provides a new lead for the development of AD therapeutics.

Alzheimer’s disease is age-related multifactorial neurodegenerative disease manifested by gradual loss of memory, cognitive decline and changes in personality. Due to rapid and continuous growth of its prevalence, the treatment of Alzheimer’s disease calls for development of new and efficacies drugs, especially those that could be able to simultaneously act on more than one of possible targets of action. Aminoquinolines have proven to be a highly promising structural scaffold in the design of such a drug as cholinesterases and β-secretase 1 inhibitors. In this study, we synthesised twenty-two new 4-aminoquinolines with different halogen atom and its position in the terminal N-benzyl group or with a trifluoromethyl or a chlorine as C(7)-substituents on the quinoline moiety. All compounds were evaluated as multi-target-directedligands by determining their inhibition potency towards human acetylcholinesterase, butyrylcholinesterase and β-secretase 1. All of the tested derivatives were very potent inhibitors of human acetylcholinesterase and butyrylcholinesterase with inhibition constants (K_i) in the nM to low μM range. Most were estimated to be able to cross the blood–brain barrier by passive transport and were nontoxic toward cells that represented the main models of individual organs.

Mitochondrial pyruvate carrier (MPC) inhibitors promote the development of hair follicle stem cells without affecting normal cells, which is promising for the treatment of hair loss. Herein, a series of cyano-cinnamate derivatives of UK-5099 were designed and synthesized. All these new compounds have been tested for their ability to promote cellular lactate production in vitro. Compound 4i (LA content:0.322 μmol/10⁶cell) showed better cellular lactate production activity than UK-5099 (LA content:0.185 μmol/10⁶cell). Further compound 4i was also tested on shaved mice by topical treatment and promoted obvious hair growth on mice.

Many reports have shown that stabilization of secondary structure by stapling functional peptides enhances the intracellular bioactivity. However, no report has discussed the correlation between stabilization and biological activity based on the configuration of amino acid residues used as anchors for stapling. To clarify this, we investigated the helix content and apoptotic efficiency of an apoptosis-inducing peptide, Bim, and four stapled Bim peptides containing stapling-related Cys residues introduced with different configurations within the sequence. The results demonstrated that the configuration of Cys residues in stapled Bim peptides affected the secondary structure and intracellular activity of the peptides, and furthermore, there was a correlation between these latter two variables.

The delivery of functional molecules to the cell nucleus enables the visualization of nuclear function and the development of effective medical treatments. In this study, we successfully modified the Hoechst molecule, which is a well-documented nuclear-staining agent, using the strain-promoted azide-alkyne cycloaddition (SPAAC) reaction. We prepared Hoechst derivatives bearing an azide group (Hoe-N3) and characterized their SPAAC reactions in the presence of corresponding molecules with a dibenzylcyclooctyne unit (DBCO). The SPAAC reaction of Hoe-N3 with alkylamine bearing DBCO, fluorescent TAMRA, or Cy5 molecules bearing DBCO led to the formation of the coupling products Hoe-Amine, Hoe-TAMRA, and Hoe-Cy5, respectively. These Hoechst derivatives retained their DNA-binding properties. In addition, Hoe-TAMRA and Hoe-Cy5 exhibited properties of dual accumulation in the cell nucleus and mitochondria. Initial incubation of these molecules in living cells resulted in its accumulation in mitochondria, while after mitochondrial depolarization, it was smoothly released from mitochondria and translocated into the cell nucleus. Thus, mitochondrial depolarization could be monitored by measuring the emission of Hoe-TAMRA and Hoe-Cy5 at the cell nucleus.