Medicinal Chemistry最新文献

In recent years, extensive research has been conducted by medicinal and organic chemists on derivatives of 8-Hydroxyquinoline (8-HQ) due to their potential as therapeutic agents for a wide range of diseases and disorders. These derivatives show promise in treating conditions such as cancer, HIV, tuberculosis, and neurodegenerative disorders. Additionally, the ability of 8-HQ to chelate metal ions adds to its value as a scaffold for developing treatments for various diseases. Over the past two decades, significant efforts have been made to create drug molecules based on 8- HQ that exhibit excellent therapeutic potency against different therapeutic targets. Recognizing the significance of 8-HQ in the field of therapeutics, this review provides an overview of its reported therapeutic activity in the literature over the past two decades. The review also addresses the challenges and opportunities in the development of 8-HQ, suggesting future research directions in this area.

Introduction: Hyperlipidemia is a prevalent condition that accelerates the development of cardiovascular diseases. Traditional treatments targeting lipid regulation often have limitations, such as hepatotoxicity. This study investigates the dual action of a novel compound, 5-(4-(3-thioxo- 3H-1,2-dithiol-5-yl)phenoxy)pentanoic acid (TDPPA), in reducing lipid levels and protecting the liver.

Methods: TDPPA was synthesized and structurally confirmed by 1H-NMR, 13C-NMR, and HRMS. Its lipid-lowering efficacy was first assessed in Triton WR-1339-induced acute hyperlipidemic mice. Mechanistic studies were then conducted in a high-fat emulsion-induced chronic hyperlipidemia model, incorporating histopathological analysis of the liver (H&E and Oil Red O staining). Liver index, serum lipid panels, hepatic function markers, HⁿS content, oxidative stress parameters, and pro-inflammatory cytokines were quantified via ELISA, while the interaction between TDPPA and PPAR-α was evaluated by molecular docking and Western blotting.

Results: TDPPA significantly reduced serum triglyceride (TG), total cholesterol (TC), and lowdensity lipoprotein cholesterol (LDL-C) in both acute and chronic models, while increasing highdensity lipoprotein cholesterol (HDL-C). Histology revealed marked reductions in hepatic lipid accumulation and inflammatory infiltration. Biochemical assays showed decreases in AST and ALT, enhanced antioxidant capacity (higher SOD and HⁿS, lower MDA), and suppression of TNF- α, IL-6, and IL-1β. Molecular docking and Western blot analysis indicated that these effects were associated with upregulation of PPAR-α protein expression.

Discussion and conclusion: TDPPA demonstrates potent lipid-lowering, antioxidant, and antiinflammatory activities, likely through a dual mechanism involving PPAR-α activation and HⁿSmediated hepatoprotection. These findings position TDPPA as a promising therapeutic candidate for hyperlipidemia with the benefit of liver protection.

Introduction: Hepatitis B virus (HBV) infection remains a significant public health challenge. Targeting HBV capsid assembly has the potential to achieve a functional cure for HBV infection, and the capsid assembly modulators (CAMs) have been regarded as promising therapeutic agents for HBV. In this work, we aimed to identify novel scaffold HBV CAMs through a multi-step virtual screening approach.

Methods: Pharmacophore-based virtual screening combined with hydrogen bond constraints was performed on the Specs and ChemDiv databases. Potential modulators were screened using qPCR (quantitative PCR) and CCK-8 assays. Molecular dynamics (MD) simulations and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis were employed to evaluate ligand-protein binding modes and pharmacokinetic properties.

Results: Twenty-one compounds were selected as potential HBV CAMs. Compounds B5, B19, and B21 exhibited excellent anti-HBV activity, with EC50 values of 1.74, 4.29, and 0.38 μM, respectively. MD simulations revealed their possible binding modes with the HBV core protein, confirming the critical role of Trp102-mediated hydrogen bonds.

Discussion: Hydrogen bonds are critical for establishing stable and high-affinity interactions between small molecules and targets. Three compounds, B5, B19, and B21, were identified as novel scaffold hits of CAMs through virtual screening with the combination of pharmacophore modeling and hydrogen bond constraints. MD simulations illustrated the critical contributions by Trp102, providing valuable insights for further structural optimization.

Conclusion: Compounds B5, B19, and B21 can serve as promising starting points for the development of more potent anti-HBV candidates through future hit-to-lead optimization.

Stereoisomerism in addition to conformational, geometrical, and optical isomerism, has considerable effects on the stability, reactivity, and functioning of molecules. Therefore, the objective of this article is to review the recent developments and research on stereoisomerism, including its consequences in various branches of science. The energetics and stability of conformational isomerism, which depict the concept of cis-trans and E/Z configurations of geometric isomerism, elucidate the molecular behavior and the efficacy of drugs, also discussed. The consequence of stereochemistry on pharmacology and drug design is elucidated by optical isomerism in terms of chirality and enantiomorphic effects. To exemplify the use of stereoisomerism in drug development, this review, offers wide case studies of NSAIDs, anticancer drugs, and antibiotic drugs. In this Article, the phenomenon of stereoisomerism is also primarily discussed concerning biomolecules such as proteins, carbohydrates, lipids, and nucleic acids. Recent advances in comparison operations include computer-aided drug design, advances in personalized medicine, and new therapies such as DNA and peptide drugs, including their possible impacts on the business and natural world. The primary aim of the review is to thoroughly investigate and examine stereoisomerism and its wide-ranging implications.

Introduction: Neglected tropical diseases (NTDs), such as Chagas disease (CD) and Cutaneous Leishmaniasis (CL), are significant global health concerns. The limited number of treatments and their severe adverse effects worsen the situation. Therefore, the development of molecules as a new pharmacological alternative is necessary. This work aimed to obtain new p- Toluenesulfonyl hydrazones derivatives to determine their potential antiparasitic activity against Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana).

Methods: Compounds were synthesized by condensing p-Toluenesulfonyl hydrazide with aromatic aldehydes using acetic acid as a catalyst. All compounds were structurally elucidated using infrared (IR) spectroscopy, proton and carbon nuclear magnetic resonance (¹H and ¹³C NMR), and Ultra-Performance Liquid Chromatography-tandem Mass Spectrometry (UPLCMS). The Queretaro (Qro) strain of T. cruzi and the M379 strain of L. mexicana were used for in vitro assays.

Results: Compound pT-21 (IC₅₀= 49.6 μM) was the most active agent against the T. cruzi Qro strain. Meanwhile, compounds pT-15 and pT-21 inhibited the proliferation of L. mexicana promastigotes with an IC₅₀ value of 59.2 and 13.8 μM, respectively. In addition, these compounds had low cytotoxic effects against Vero cell lines (CC₅₀ values >100 μM).

Discussion: In this study, compound pT-21 inhibited the proliferation of T. cruzi and L. mexicana in vitro. Its activity is attributed to the reactivity of the 5-nitrofuran ring (present in other drugs such as nifurtimox). Future research could focus on identifying the pharmacological target of compound pT-21 to facilitate rational drug design and enhance its potency against these parasites.

Conclusion: In summary, these results show that p-Toluenesulfonyl hydrazones serve as a scaffold to aid in the development of potent and selective agents against T. cruzi and L. mexicana.

Introduction: Heterocyclic compounds bearing oxygen and nitrogen atoms are key pharmacophores in modern drug design. Among them, 1,3,4-oxadiazoles are notable for their diverse biological activities, including anti-inflammatory, anticancer, antidiabetic, antibacterial, and enzyme inhibitory effects. This study focuses on the synthesis and evaluation of indazole-based 1,3,4-oxadiazole-benzenesulfonothioate hybrids as potential therapeutic agents.

Method: A multistep synthetic route was employed to develop a series of eighteen (18) analogues. The synthetic strategy involved the formation of methyl 5-methyl-1H-indazole-3-carboxylate, conversion to carbohydrazide, cyclization with CS₂, and final coupling with substituted benzenesulfonyl chlorides to yield the target hybrids (1-18).

Results: The urease inhibition potential of scaffolds ranged from IC₅₀ = 17.88 ± 0.36 to 37.98 ± 0.80 μM as compared to the standard drug thiourea (IC₅₀ = 29.45 ± 0.76 μM). The exceptional urease and α-glucosidase activity was shown by scaffolds (4, 7, 9, 11) due to the presence of electron- withdrawing groups (-F, NO₂, and Cl). In comparison, the α-glucosidase inhibition potential shown by all the scaffolds was in the range (IC₅₀ = 3.19 ± 0.27 - 12.24 ± 1.33 μM). Compound-9 showed promising inhibitory potential against urease, with an IC₅₀ = 17.90 ± 0.30 μM, and α- glucosidase (IC₅₀ = 3.19 ± 0.27 μM), both indicating minimum IC₅₀ values.

Discussion: The enhanced activity of compounds bearing electron-withdrawing groups (F, NO2, Cl) supports their role in modulating enzyme inhibition. In silico molecular docking further confirmed strong binding affinities with the active sites of target enzymes, correlating well with the experimental results.

Conclusion: The synthesized 1,3,4-oxadiazole derivatives demonstrate promising dual inhibitory activity against urease and α-glucosidase, suggesting their potential as lead compounds in the treatment of gastric infections and diabetes. This study contributes to the ongoing development of multifunctional therapeutic agents with improved efficacy and selectivity.

Cancer, bacterial, parasitic, viral, and neurological diseases like Alzheimer's continue to pose serious health risks around the world. We need new therapeutic agents that are more targeted, effective, and safer. Because of their wide range of biological actions, acridine and its derivatives have become increasingly popular among the numerous intriguing chemical classes. Over time, several synthetic analogs of these substances have shown great promise, exhibiting noteworthy antitumor properties (e.g., N-(2-(dimethylamino) ethyl) acridine-4-carboxamide (DACA) and triazole acridone (C-1305)), as well as strong antimicrobial (e.g., 4-amino-N- [amino(imino)methyl]-benzene sulphonamide), antiviral (e.g., derivatives of acridine sulphonamide), and anti-Alzheimer's (e.g., Citrusinine-I) properties. These substances have therapeutic potential, but side effects frequently prevent them from being used in clinical settings. This review discusses all the new developments in acridine and acridone derivatives since 2024. It focuses on how they are made and might be used in medicine. By shedding light on these innovations, the study aims to offer a fresh perspective on their role in shaping the future of medicinal chemistry and drug development. This work's main goal is to investigate and evaluate the most current progress in the synthesis as well as biological uses concerning derivatives of acridine along with acridone, especially those that have been published after 2024. The target of the study is to demonstrate the compounds' medicinal perspective by highlighting their antiviral, anticancer, antibacterial, and anti-Alzheimer effects. Furthermore, the research aims to tackle the difficulties related to their adverse effects, offering valuable perspectives for the creation of safer and more efficient medications in the field of medicinal chemistry in the future.

Pyrazole-based compounds have gained considerable attention in recent years due to their diverse and potent pharmacological properties. This review provides an up-to-date examination of the therapeutic potential of various substituted pyrazole derivatives, highlighting their roles in combating diseases such as cancer, tuberculosis, fungal and viral infections, inflammation, and others. Unlike previous reviews, this article emphasises newly reported analogues with significant bioactivity and structure-activity relationships (SAR), which may pave the way for future drug development. The novelty of this work lies in its integrated perspective that bridges medicinal chemistry innovations with therapeutic relevance, providing researchers with a valuable resource for designing next-generation drug candidates based on the pyrazole scaffold.

Fluorine-containing pyridine derivatives have emerged as pivotal structures in modern drug discovery due to their unique physicochemical properties and diverse pharmacological activities. The incorporation of fluorine into pyridine-based scaffolds enhances drug potency, selectivity, metabolic stability, and Pharmacokinetics (PK) of these compounds, making them highly attractive for therapeutic development. These derivatives have been integrated into numerous Food and Drug Administration (FDA)-approved drugs, underscoring their importance in medicinal chemistry. This review systematically compiles recent advances in the pharmacological applications of fluorine-containing pyridine derivatives, focusing on their anticancer, antidiabetic, antioxidant, and anti-Alzheimer's activities. By exploring the Structure-Activity Relationship (SAR) and mechanisms of action, this review provides valuable insights for the design and development of novel biologically active compounds. This comprehensive analysis aims to inspire new directions in drug discovery and highlight the therapeutic potential of fluorine- containing pyridine derivatives.