Medicinal Chemistry Research最新文献

A series of D-galactose-conjugated substituted 4-formylsydnone thiosemicarbazones 4a-j were designed and synthesized from appropriate substituted 3-aryl-4-formylsydnones 2a-j and tetra-O-acetyl-β-d-galactopyranose 3. These synthesized thioureas exhibited the remarkable inhibitory activity against both selected Gram-(+)- and Gram-(–)-bacteria. Amongst them, thiosemicarbazones 4a,b,c,f,j were the most potent inhibitors against Gram-(+) bacterial strains with MIC values of 0.78–1.56 μg/mL, while compounds 4b,c,g,j had the most inhibitions against Gram-(–) bacterial ones with MIC values of 0.78–1.56 μg/mL. The thiosemicarbazones 4b, 4c, 4 f and that contain simultaneously two methyl or methyl/nitro substituents on benzene ring exhibited the strong inhibition against both Gram-(+), including MRSA bacterium, and Gram-(–) bacterial strains with MIC values of 0.78–1.56 μg/mL. In addition, compound 4j had strongest potent inhibitory activity against S. aureus DNA Gyrase and compound 4b was the strongest inhibitor against S. aureus Topoisomerase IV. Almost all of the most potential compounds had low toxicity to WI-38 normal cell line. The in silico studies, including predictive ADMET and induced fit docking simulations, for the most potential compounds were performed. Molecular dynamics simulations applied for two most potential complexes 4b/URN and 4j/4URO to understand their mechanism of active interaction for these respective enzymes.

Periodontal disease begins with bacterial plaque buildup in the oral cavity, inciting an inflammatory response that results in subsequent tissue damage. Even after standard treatment like scaling and root planning (SRP) to remove plaque and biofilm, the host immune response can remain hyper-active, perpetuating further tissue destruction. In these cases, aggressive periodontitis is resistant to SRP and the inflammatory response may persist, even in the absence of plaque, presenting a significant clinical challenge. Previous experiments have provided a validated model of periodontal inflammation by exposing murine macrophages to lipopolysaccharide (LPS) from Aggregatibacter actinomycetemcomitans (Aa), a pathogen linked to aggressive periodontitis. Using this model, we have previously demonstrated that the periodontal disease microenvironment triggers epigenetic changes, notably heightened lysine-specific demethylase 4B (KDM4B) activity. Data indicate that the KDM4B inhibitor ML324 can reverse the macrophage-mediated pro-inflammatory response induced by Aa LPS in vitro, providing compelling evidence for KDM4B as a rational therapeutic target for periodontal disease. In the present studies, a cohort of compounds was developed as potential KDM4B inhibitors. Synthesis and characterization of derivatives led to the discovery of compound 14 with an IC₅₀ of 170 nM against KDM4B and immunosuppressive activity in the Aa LPS challenge model. These results suggest KDM4B inhibitors as potential therapeutic agents for modulating the immune response for periodontal disease.

Cytochrome P450 3A4 (CYP3A4) is a crucial enzyme involved in the Phase I metabolism of numerous medications used in clinical practice. Its potential significance in pediatric pharmacotherapy is underscored by the unique metabolic profile of children, which differs markedly from adults, especially in neonates, infants, and young children due to developmental changes in enzyme activity. This review explores the critical role of CYP3A4 in the metabolism of drugs used in the pediatric population, with a particular focus on combination drug therapies. Given the high potential for drug-drug interactions in combination therapies, understanding the modulation of CYP3A4 activity is essential for optimizing therapeutic outcomes and minimizing adverse effects. This paper further examines the structural similarities between these medications and bergamottin, a known CYP3A4 inhibitor found in citric fruits such as grapefruit. Variability in CYP3A4 activity, influenced by genetic polymorphisms, developmental stage, and external factors, necessitates careful consideration in the prescribing and management of drugs in children. This review corroborates the need for personalized medicine approaches and enhanced pharmacovigilance to ensure the safe and effective use of CYP3A4-metabolized drugs in the pediatric population.

Graphical Abstract

Psoriasis is a chronic, multifactorial skin disorder characterized by the hyperproliferation of keratinocytes and persistent inflammation. It is driven by a complex interplay of genetic, immunological, and environmental factors. The heterogeneous nature of this disease presents significant challenges for effective diagnosis and treatment. Recent advancements in omics technologies such as genomics, transcriptomics, proteomics, and metabolomics have revolutionized our ability to understand the molecular basis of psoriasis. These technologies offer novel insights into disease mechanisms, identifying potential biomarkers for early diagnosis, disease progression, and therapeutic response. Further, longitudinal studies utilizing real-world patient data and advanced computational models will enable dynamic disease monitoring, offering prospects for predictive diagnostics and earlier intervention. As personalized treatment plans become more sophisticated, the evolution of omics-guided therapeutic strategies could revolutionize the standard of care in psoriasis, fostering a transition from reactive to preventative approaches. This review aims to elucidate the critical role of omics approaches in unraveling the intricate biological pathways involved in psoriasis and exploring how specific omics data serve as powerful tools for classifying patients and tailoring treatment options based on individual molecular profiles. Further, longitudinal studies utilizing real-world patient data and advanced computational models will enable dynamic disease monitoring, offering prospects for predictive diagnostics and earlier intervention. As personalized treatment plans become more sophisticated, the evolution of omics-guided therapeutic strategies could revolutionize the standard of care in psoriasis, fostering a transition from reactive to preventative approaches. Addressing current challenges in data integration and clinical applicability will be pivotal in advancing towards this future, with the potential to significantly improve patient outcomes and quality of life.

A series of 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide compounds (8a-8k) were synthesized as p38 MAP kinase inhibitors, which could potentially be used as anticancer agents. The synthesized compounds were assessed for their effectiveness in inhibiting cancer using the MCF-7 cancer cell line. The results showed that compound 8a had the highest potency, with an IC₅₀ value of 39.76 ± 0.25 µM. Compound 8f and 8d exhibited noteworthy activity, with IC₅₀ values of 40.43 ± 2.04 µM and 42.15 ± 2.15 µM, respectively. Compound 8a was found to effectively bind with the active site of p38α MAP kinase, with the PDB ID 1W7H. The docking score was found to be −8.8 kcal/mol. The ADME experiments, following Lipinski’s rule of five and Ergan’s egg graph, showed that all the synthesized compounds had excellent oral bioavailability and acceptable stomach absorption. Compound 8a stood out as the most potent drug in the series, exhibiting considerable docking affinity, ADME profile, and p38 MAP kinase inhibitory action. The findings indicated that compound 8a has promising p38 kinase inhibition and can be a possible therapeutic drug for further investigation.

In this work, a novel series of fifteen pyrazole-linked hydrazide-hydrazone derivatives (4a-o) were designed, synthesized, characterized, and evaluated for their antihyperglycemic activity against α-amylase and α-glucosidase. In vitro results revealed that all synthesized compounds (4a-o) showed good to excellent antihyperglycemic activity with IC₅₀ in the range of 30.58 ± 0.56–290.70 ± 2.77 μM for α-glucosidase and in the range of 29.08 ± 0.56–160.70 ± 0.80 μM, as compared to the standard inhibitor acarbose (IC_{50(α-glucosidase)} = 98.12 ± 2.10 µM and IC_{50(α-amylase)} = 126.50 ± 2.01 µM). Among the series, compound 4m with hydroxy group in para position at phenyl ring was also found as the most potent inhibitor of α-amylase and α-glucosidase with IC₅₀ values of 29.08 ± 0.86 and 30.58 ± 0.56 μM, respectively, indicating their better potency than the standard acarbose. In silico molecular docking and molecular dynamic simulations further confirmed the binding modes and binding affinities of compound 4m and acarbose. The Structure-Activity Relationship (SAR) analysis of the effects of some functional groups in the co-structure of 4m were confirmed by IFD and MDS for both α-amylase and α-glucosidase inhibitor recognition.

Inhibition of α-glucosidase is a widely recognized approach for managing hyperglycemia, particularly postprandial glucose spikes. In this study, the α-glucosidase inhibitory activity and interaction mechanisms of aromatic compounds isolated from the rhizomes of Alpinia galanga were investigated using the p-nitrophenol-α-D-glucopyranoside (pNPG) bioassay and molecular docking. The isolated aromatic compounds (1–4) showed significant α-glucosidase inhibitory activity with IC₅₀ values between 25 and 104 µM compared to the positive control acarbose (IC₅₀ = 1236.42 ± 1.30 µM). The experimental data showed that the most potent inhibitor of α-glucosidase (E)-p-coumaryl alcohol-γ-O-methyl ether (3) inhibited the enzyme via a mixed-type mechanism, with an IC₅₀ value of 25.00 ± 1.01 µM. Molecular docking indicated that compound 3 decreased the catalytic efficiency of α-glucosidase by competitively binding to the active pocket, thereby blocking the substrate. The binding activity is mainly mediated by hydrogen bonds and hydrophobic interactions. The results suggest that these aromatic compounds from A. galanga could serve as potential therapeutic agents for the control of postprandial hyperglycemia and the treatment of type 2 diabetes.

Although purine biosynthesis is a primary metabolic pathway, there are fundamental differences between how purines are synthesized in microbes versus humans. In humans, the purine intermediate, 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) is directly synthesized from 5-aminoimidazole ribonucleotide (AIR) and carbon dioxide by the enzyme AIR carboxylase. In bacteria, yeast and fungi, CAIR is synthesized from AIR via an intermediate N⁵-carboxyaminoimidazole ribonucleotide (N⁵-CAIR) by the enzyme N⁵-CAIR mutase. The difference in pathways between humans and microbes indicate that N⁵-CAIR mutase is a potential antimicrobial drug target. To identify inhibitors of E. coli N⁵-CAIR mutase, a fragment-based screening campaign was conducted using a thermal shift assay and a library of 4,500 fragments. Twenty-eight fragments were initially identified that displayed dose-dependent binding to N⁵-CAIR mutase with K_d values ranging from 9–309 µM. Of the 28, 14 were obtained from commercial sources for retesting; however, only 5 showed dose-dependent binding to N⁵-CAIR mutase. The five fragments were assessed for their ability to inhibit enzyme activity. Four out of the 5 showed inhibition with K_i values of 4.8 to 159 µM. All fragments contained nitrogen heterocycles with 3 out of the 4 containing 5-membered heterocycles like those found in the substrate of the enzyme. The identified fragments show similarities to compounds identified from studies on B. anthracis N⁵-CAIR mutase and human AIR carboxylase suggesting a common pharmacophore.

Oligonucleotides, comprising single or double strands of RNA or DNA, are vital chemical compounds used in various laboratory and clinical applications. They represent a significant class of therapeutics with a rapidly expanding range of uses. Between 1998 and 2023, 19 oligonucleotides have received approval from the U.S. Food and Drug Administration (FDA). Their synthesis methods have undergone significant evolution over time. This review examines several oligonucleotide synthesis techniques, including phosphodiester, phosphotriester, and phosphoramidite approaches. It begins with a discussion of an early synthesis method involving a phosphoryl chloride intermediate, which proved unstable and prone to hydrolysis. The review then transitions to the solid-phase synthesis method, which uses polymer resins as a solid support, emphasizing its advantages over both phosphotriester and phosphoramidite techniques. This is followed by an exploration of recent advancements in oligonucleotide enzymatic synthesis, concluding with a discussion on modifications to bases, sugars, and backbones designed to improve their properties and therapeutic potential.