Medicinal Chemistry Research最新文献

Formononetin, derived from Orostachys japonica (a traditional Chinese medicine), has been reported to have anti-cancer activity. In continuation of work on the exploration of formononetin derivative development, we designed and synthesized a novel series of formononetin-piperazine hybrids as anticancer agents, followed by evaluation of their antiproliferative activities against three cancer cell lines. Among these derivatives, compounds 6g (IC₅₀ = 5.87 ± 0.96 μM) and 6h (IC₅₀ = 3.50 ± 0.65 μM) emerged as the most potent analogues, demonstrating the best inhibitory activities against MGC-803 human gastric cancer cells. The structure-activity relationships (SARs) indicated that the introduction of substituents at meta-position of piperazine-linked phenyl moiety was helpful to enhance the anticancer potency. Further mechanistic investigations revealed that 6g and 6h exerted multimodal antitumor effects through G2/M phase arrest induction, apoptosis promotion, and migration suppression in MGC-803 cells. Thus, 6g and 6h could be deeply developed for the development of formononetin-based anti-cancer candidates.

Twenty-seven asiatic acid derivatives were designed and synthesized in this paper, including twenty-two new compounds. The synthesized compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. The antitumor activities of all compounds against A549, Hela and HepG2 cancer cells in vitro were evaluated. Notably, AA-6a (IC₅₀ = 1.10 ± 0.25 μM) has better antitumor activity than gefitinib (IC₅₀ = 83.75 ± 1.72 μM) against A549 cells. AA-6b (IC₅₀ = 2.38 ± 0.36 μM) has better antitumor activity than gefitinib (IC₅₀ = 33.88 ± 1.51 μM) on Hela cells. AA-2b (IC₅₀ = 1.55 ± 0.21 μM) has the better antitumor activity than gefitinib (IC₅₀ = 48.37 ± 1.07 μM) against HepG2 cells.

Paeoniflorin is one of the active components of the root of peony, which has powerful and diverse pharmacological activities. However, low membrane permeability and gastrointestinal effects severely limit its absorption and bioavailability. In this paper, 190 paeoniflorin derivatives, including natural derivatives and synthetic derivatives, were collected. The pharmacological effects of the more active derivatives were summarized. In addition, the structure-activity relationship of paeoniflorin was appropriately summarized. This review aims to provide valuable assistance for further research and clinical application of paeoniflorin.

Plants have played a vital role in medicine from ancient times to the present. Many plant species have been used as medicinal remedies and as sources of bioactive compounds for modern pharmaceutical synthesis. The Tinospora genus, belonging to the Menispermaceae family, includes species such as T. cordifolia, T. sinensis, and T. crispa, which have long been utilized in traditional medicine, contributing significantly to human healthcare. Clinical evidence has further reinforced their potential as valuable sources of bioactive compounds for pharmaceutical development. A comprehensive review has been conducted based on publications over the past nine years to provide the latest insights into the phytochemistry and pharmacological properties of Tinospora species. Relevant literature was retrieved from databases such as PubMed, Google Scholar, and Web of Science (WOS) using keywords including “Tinospora”, “phytochemistry of Tinospora”, and “pharmacological activity of Tinospora”. From an initial pool of 150 related articles published between 2016 and 2025, 103 of the most relevant studies were selected. A total of nine Tinospora species have been analyzed in recent and ongoing research, revealing a diverse range of bioactive compounds, including terpenoids, steroids, lignans, alkaloids, phenylpropanoids, and benzenoids. Additionally, ten species have been investigated for their pharmacological activities, demonstrating notable effects such as neuroprotective and anti-neuroinflammatory activities, anti-inflammatory effects, anti-diabetic and anti-obesity properties, immunomodulatory functions, anticancer potential, larvicidal and antimalarial properties, and hepatoprotective effects. Toxicity and safety assessments have also been explored in several studies, further advancing our understanding of the medicinal applications of Tinospora species.

In this work, stable chemical precursors (3,5-DTBC) and alkylated derivatives were synthesized through strategic modifications guided by the redox and chelation properties of catechol. Leveraging the molecular principle that fusing two bioactive components often yields synergistic effects, catechol — a polyphenol with broad biological activities — was integrated into the nitrogen-containing heterocyclic core structure, imidazolidine-2,4-dione, to design a novel class of hybrid compounds (7a–q) with diverse pharmacological profiles. The primary objective was to explore efficient synthetic routes, characterize structures via physicochemical analyses, and possible evaluate cytotoxicity and AT1-inhibitory activity in vitro.

Alzheimer’s disease is a complex neurodegenerative disorder characterized by cognitive decline and memory loss, with acetylcholinesterase and monoacylglycerol lipase being two key enzymes involved in its pathogenesis. In this study, a series of carbamoyl flavonoid derivatives were synthesized and evaluated as potential dual inhibitors of acetylcholinesterase and monoacylglycerol lipase. Among them, compound B3 (a baicalein derivative) exhibited the most potent dual inhibition, with IC₅₀ values of 67.95 µM for acetylcholinesterase and 61.28 µM for monoacylglycerol lipase. Molecular docking and molecular dynamics simulations confirmed the strong binding affinity and stability of B3 within the active sites of both enzymes. The MM-GBSA binding free energy analysis revealed ΔG_bind values of –31.58 ± 2.24 kcal/mol for acetylcholinesterase and –41.24 ± 2.42 kcal/mol for monoacylglycerol lipase, indicating favorable interactions through hydrogen bonding, π-stacking interactions, and hydrophobic contacts. These findings suggest that carbamoyl flavonoid derivatives, particularly B3, hold promise as multifunctional inhibitors, providing a novel and effective strategy for the treatment of Alzheimer’s disease.

Prenylated flavonoids icariin and icaritin are the crucial ingredients of traditional Chinese medicinal Herb Epimedii. Icariin is an isoprenoid flavonoid glycoside, and icaritin is the aglycon of icariin. During the past decades, icariin and icaritin have generated a lot of interest in the biological and clinic applications, and icaritin has been an approved drug for advanced HCC in China in 2022. However, poor water solubility, low therapeutic efficiency and poor pharmacokinetic properties are the major obstacles, which had significantly limited their clinical application. Given the pivotal role of icariin and icaritin, this review comprehensively reviews the structural modifications of icariin and icaritin, which might help to provide novel insights for the development of novel derivatives of icariin and icaritin with favorable pharmacological profiles and promising clinical application potential.

This study aimed to develop inhibitors of monoglyceride lipase, a key enzyme in lipolysis linked to insulin resistance, using structural frameworks derived from dipeptidyl peptidase IV inhibitors. Two series of compounds were synthesized—one based on an amantadine scaffold and the other on a pyrimidinyl piperazine structure—and their design was guided by molecular docking studies that predicted favorable binding within the enzyme’s active site. Biological evaluation revealed that selected compounds exhibited potent inhibitory activity, with half maximal inhibitory concentrations in the low to mid nanomolar range. In particular, compounds from the pyrimidinyl piperazine series demonstrated high selectivity for monoglyceride lipase. These findings support the effectiveness of leveraging dipeptidyl peptidase IV inhibitor structures to design potent monoglyceride lipase inhibitors and suggest a promising therapeutic approach for improving insulin sensitivity and managing type 2 diabetes mellitus.

Butyrylcholinesterase (BuChE, EC 3.1.1.8) inhibitors have promising application prospects as they can alleviate cognitive impairment and have a positive impact on some pathological features of Alzheimer’s disease. In this study, two new phenolic glycosides (1 and 2), pholidotosins B and C, together with two bibenzyls (3 and 5), two stilbenes (4 and 6), and two dihydrophenanthrenes (7 and 8) were isolated from Pholidota chinensis Lindl.. Among them, thunalbene (4) and lusianthridin (8) exhibited the strongest inhibitory effects, with IC₅₀ values of 11.01 ± 0.26 μM and 10.49 ± 0.34 μM, respectively. The structure-activity relationship analysis indicated that the BuChE inhibitory activity of the isolated compounds 3–8 was influenced by the substituted position and number of hydroxy and methoxy groups in the two benzene ring skeletons, as well as the connection mode of the two benzene rings. In silico predictions of physicochemical properties, drug-likeness, and pharmacokinetics were performed. The isolated compounds 3–8 obeyed the rule of five by Lipinski and had better oral bioavailability. Furthermore, the Boiled-Egg chart revealed that thunalbene possessed favorable blood-brain barrier permeability and did not serve as a substrate for P-glycoprotein. The results of enzyme kinetic studies indicated that thunalbene reversibly inhibited BuChE in a mixed-type manner. The molecular docking results demonstrated that thunalbene bind to BuChE with a docking energy of −6.10 kcal/mol, potentially inducing conformational changes in the enzyme’s active structure. These findings highlight the potential of thunalbene as a natural BuChE inhibitor for the treatment of neurodegenerative diseases.

The monoamine oxidase (MAO) enzymes metabolise neurotransmitter amines and are drug targets for the treatment of neuropsychiatric and neurodegenerative disorders. Over the past several decades, MAO inhibitors have been used as antidepressants and antiparkinsonian agents. The present study investigated the MAO inhibition properties of a series of benzoxazole derivatives. Many benzoxazole-containing drugs have been marketed and are used for the treatment of a wide variety of conditions. Thirteen 2-methylbenzo[d]oxazole derivatives (1a–f, 2a–g) were synthesised and evaluated as in vitro inhibitors of human MAO. The results showed that the benzoxazole derivatives were potent MAO inhibitors. Compounds 1d and 2e were the most potent MAO-B inhibitors with IC₅₀ values of 0.0023 and 0.0033 µM, respectively. The most potent MAO-A inhibition was displayed by compounds 2c and 2e with IC₅₀ values of 0.670 and 0.592 µM, respectively. It may be concluded that the benzoxazole derivatives of this study could be useful lead compounds for the development of clinically useful MAO inhibitors.