Medicinal Chemistry最新文献

Introduction: Histone deacetylases (HDACs) play a crucial role in gene expression, and their dysregulation is linked to various cancers. HDAC inhibitors, particularly hydroxamic acid derivatives, have shown promising anticancer effects, with several approved for clinical use. This research aimed to synthesize novel 7-hydroxycoumarin-based N-hydroxyamides, evaluate their HDAC inhibition, and assess their in vitro cytotoxic effects.

Methods: The structures of the synthesized compounds were established by analysis of their physicochemical, elemental, and spectroscopic data. HDAC, in vitro assays, and molecular docking were performed using standard procedures.

Results: The biological results showed that compounds 5d, 5e, 5j, 5l, and 7k exhibited potential cytotoxicity toward all five cancer cell lines. These compounds displayed potent cytotoxicity against the NCCIT cancer cell line with IC50 values of 4.53-1.45 μM. However, they exhibited weak to medium HDAC inhibitory activity with IC50 values ranging from 21.72 to 4.79 μM. Docking simulation studies with selected compounds revealed that compounds 5a and 7k formed stable interactions in the active site of HDAC enzyme with binding affinities ranging from -7.43 to -7.103 kcal/mol, respectively.

Discussion: The study revealed several compounds with potential HDAC inhibitory activity and cytotoxicity. However, they were still less effective in inhibiting HDACs than SAHA and Trichostatin A. Their reduced potency may be related to the length of the linker linked to the surface recognition group. This provides important insight into the future design of hydroxamic acids of this type.

Conclusion: The research results suggest that some hydroxamic acids (5a and 7k) warrant further evaluation, and these results could serve as a basis for designing more potent HDAC inhibitors and antitumor agents.

Introduction: The protozoan parasite Trypanosoma cruzi (T. cruzi) is the etiologic agent of Chagas disease, also known as American trypanosomiasis, which primarily affects the Americas and is highly prevalent in developing countries. Treatment consists of the drugs nifurtimox and benznidazole; however, both drugs have variable efficacy and cause serious adverse effects. In T. cruzi, the enzyme glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH) plays an essential role in energy production and additional nuclear functions, making it a pharmacological target for the development of new trypanocidal agents. In this study, the objective was to identify new potential TcGAPDH inhibitors with trypanocidal activity.

Methods: A virtual screening based on molecular docking of FDA-approved drugs was performed, followed by in vitro biological evaluation of trypomastigotes from two T. cruzi strains.

Results: Seven FDA-approved drugs (pemetrexed, gliquidone, irbesartan, enoxacin, norfloxacin, pazopanib, and fenoprofen) had the best affinity values and a suitable interaction profile at the active site of the TcGAPDH enzyme, which had better LC50 values than the reference drugs.

Discussion: Drug repositioning using computer-aided methods reduces cost and time to find new pharmacological treatments. In this study, gliquidone (antidiabetic), irbesartan (antihypertensive), pemetrexed, and pazopanib (anticancer) are drugs with high trypanocidal activity that could be candidates for evaluation in clinical phases or used to develop new drugs to combat Chagas disease. It highlights fenoprofen, an anti-inflammatory agent, which has biological properties that help to reduce the symptomatology of the disease in the chronic stage. Additionally, it is necessary to study the mechanism of action of these compounds in detail to confirm if they have an effect on the proposed pharmacological targets.

Conclusion: Seven FDA-approved drugs are candidates for further studies leading to the development of potential new treatments for Chagas disease.

Quinolones are nitrogen-containing heterocyclic compounds that exist in natural, semisynthetic, and synthetic forms, and play a vital role as antibiotics. Their complex structure and numerous potential modifications have made them a significant focus in synthetic chemistry over the past two to three decades. The most common compound associated with quinolones is nalidixic acid, which was discovered long ago. Since then, various researchers have focused on this core as a potential pharmacophore or starting nucleus for developing new drug candidates to manage diseases, such as cancer, urinary tract infections, Alzheimer's, and tuberculosis. In this paper, we aimed to summarize the activities of quinolone hybrids discovered over the past decades. The article delivers a thorough overview of quinolones with emphasis on synthetic innovations, their mechanism of action, resistance evasion, and classification from generation to generation, along with the newer agents. Furthermore, emerging concepts, including modulation of SOS response, induction of oxidative stress, and impact of sub-inhibitory concentrations, are also explored as supplementary strategies to enhance antibacterial efficacy. Beyond their well-known antibacterial activity, quinolones also exhibit a broad range of pharmacological properties, including antimalarial, antifungal, antiinflammatory, antitubercular, anticancer, antiviral, and immunomodulatory effects. This review highlights both their diverse clinical applications and the challenges associated with their use. This article also provides a knowledgeable asset for acknowledging quinolones' chemistry, pharmacology, and future therapeutic potential.

Oxindole and its derivatives have emerged as interesting scaffolds for developing innovative anticancer medicines due to their various biological activities and capacity to target critical molecular pathways in cancer growth. The oxindole nucleus has powerful anticancer capabilities, which are exerted through various methods, including kinase inhibition, apoptosis induction, disruption of microtubule dynamics, and signaling pathway modification (PI3K/Akt, MAPK, and p53). Furthermore, oxindole-based drugs have been beneficial in combating multidrug resistance and improving the efficacy of existing chemotherapeutic treatments. The current review examines the anticancer potential of the oxindole nucleus, including structure-activity correlations, molecular targets, and methods of action. Furthermore, we discuss current advances in oxindole-derived drug design and its clinical implications, providing insights into prospective therapeutic possibilities. Understanding the molecular characteristics of oxindole derivatives can help in the rational development of new anticancer medicines with higher efficacy and selectivity.

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.