Medicinal Chemistry Research最新文献

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.

A collection of structurally related natural compounds derived from Papaver somniferum, the opium poppy, are known as the morphine alkaloids. Many generations of synthetic chemists have been drawn to the synthesis of morphine and its derivatives owing to their extraordinarily complex molecular architecture and exceptional biological activity. This overview highlights recent advance in the asymmetric synthesis of morphine alkaloids, focusing on various strategies for introducing and controlling chirality, which will hasten the feasibility of commercial production of morphinan.

This study aims to design and synthesize novel benzimidazole histone deacetylase (HDAC) inhibitors to explore their potential applications in the treatment of cancer and other related diseases. By comparing the structures of our reported benzimidazole HDAC inhibitors, we designed a series of compounds accordingly. We then used experimentally verified their inhibitory activity against HDAC enzymes. The results showed that several of the newly synthesized compounds showed good HDAC inhibition and anti-proliferative activity. Therefore, we conclude that these novel HDAC inhibitors have potential as drug candidates for the treatment of cancer.

In this work, with the aim to find new and biologically active natural compounds, the chemical content of the apolar and polar extracts (aerial part) of Silene popovii has been investigated. The obtained extracts of Silene popovii Schischk were purified by column chromatography (CC), and four compounds were isolated: one of them is a new saponin compound—silepovin (1), as well as three known secondary metabolites, 2-deoxy-α-ecdysone (2), cauloside A (3) and 20-hydroxyecdysone 22-benzoate (4). The structural elucidation of isolated compounds was performed using the 1D and 2D NMR spectroscopy analyses and LC-MS analysis, and all four structures were confirmed. For the new compound 1, an in vivo study of anti-inflammatory activity was conducted. The in vivo analysis has shown significant anti-inflammatory effects.

The reaction of N′’(aryl)benzothiohydrazides with 2-chloro-6-((substituted)amino)-3-nitro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxylate (13-15) under basic conditions (NEt₃) in acetonitrile proceeds via thiophene ring-opening processes and yields, upon addition of iodomethane, the respective 1,3,4-thiadiazoline-6-sulfanylthiopyran-4(1H)-one hybrids. The new compounds were characterized by HRMS and NMR spectral data and confirmed by single-crystal X-ray crystallography. The cytotoxicity affinities for compounds 10-17 were evaluated in cross-correlations with their anti-inflammation and radical scavenging capacities. Compound 13 exhibited the highest cytotoxic properties, with IC₅₀ values ranging from 160 nM in mammary T47D to less than 20.35 µM in colorectal CACO2 among 12 diverse cancer monolayers. Compound 17c significantly reduced lung and mammary cancer cell viability, with anti-tumorigenesis IC₅₀ values of less than 10 µM. These new compounds have the potential to be further optimized into novel selective cytotoxic treatments.