Medicinal Chemistry Research最新文献

Platycodin D (PD), a unique oleane-type triterpene saponin found in the roots of Platycodon grandiflorum (Jacq.) A. DC. (PG), has been included in the pharmacopoeia of many countries as a core indicator for quality control of PG. Modern studies have shown that PD has a wide range of pharmacological activities, including antitumor, anti-inflammatory, antioxidant, antifibrotic, antiviral, and multiorgan protective effects, and acts on the nervous system, digestive system, and internal organs of the human body through multiple pathways. In terms of extraction and purification, the traditional solvent method combined with green technologies such as ultrasound and microwave has significantly improved the extraction efficiency, while enzyme-catalyzed conversion of precursor substances and HPLC technology can achieve efficient purification of PD. Pharmacokinetic studies have shown that the oral bioavailability of PD is relatively low. However, the extract of PG can enhance its absorption through component synergy. Meanwhile, enteric-coated and gut microbiota regulation strategies provide new ideas for improving its efficacy. The content determination is mainly carried out by HPLC-ELSD, which is significantly affected by origin, processing methods, and environmental factors. This article systematically reviews the research progress in the extraction and purification, pharmacological activity, pharmacokinetics, and content determination of PD. Meanwhile, it advocates sustainable production and clinical transformation to fully utilize its therapeutic potential.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with methylphenidate used as a first-line treatment. Methylphenidate is primarily hydrolyzed by carboxylesterase 1 (CES1) to inactive ritalinic acid, with minor oxidative metabolism producing active p-OH-methylphenidate and 6-oxo-methylphenidate lactam. The functional single-nucleotide polymorphism (SNP) in CES1, resulting in a glycine (G) to glutamic acid (E) substitution at 143 (G143E), is reported to significantly impair CES1 activity. However, limited clinical research has explored the pharmacokinetics of methylphenidate and its oxidation metabolites in ADHD therapeutics in G143E carriers. Three G143E ADHD subjects were genotyped for the G143E variant, and four non-carriers were identified and enrolled in the pharmacokinetic study. Participants received a single oral dose of methylphenidate, and plasma concentrations of methylphenidate, 6-oxo-methylphenidate, and p-OH-methylphenidate were extracted and quantified. Pharmacokinetic data were analyzed, and in vitro incubation of 6-oxo-methylphenidate with G143E S9 has been conducted. No significant differences were observed in the pharmacokinetics of methylphenidate. CES1 G143E carriers exhibited significantly elevated plasma concentrations of 6-oxo-methylphenidate, with a higher peak plasma concentration (C_max), area under the curve from time zero to infinity (AUC_0→∞), and longer half-life (T_1/2). Reduced function in in vitro studies suggested the impaired CES-mediated biotransformation of 6-oxo-methyphnidate to 6-oxo-ritalinic acid. These results provide pilot data on the substrate-dependent impact of the CES1 G143E variant. Whether or not the elevated concentrations of 6-oxo-methyphenidate contribute to the clinical activity of methylphenidate treatment remains a matter of speculation. Registry: ClinicalTrials.gov, TRN: NCT03781752, Registration date: 4-March-2018.

African trypanosomiasis is a major health threat to humans and animals in 36 countries within sub-Saharan Africa. We previously identified quinolone hydrazides exhibiting sub-micromolar anti-trypanosomal activity. However, the most potent compounds had poor aqueous solubility of <5 µM, hindering advancement to efficacy studies in animals. Accordingly, we generated a series of nine quinolone hydrazide analogues and evaluated in vitro anti-trypanosomal activity, cell toxicity and selected physicochemical properties. Compounds 4 and 5, exhibited potent anti-trypanosomal activity of 0.362 ± 0060 µM and 1.251 ± 0.295 µM, respectively and showed no toxicity (CC₅₀ > 20 µM) against HEK 293 cells. The two compounds showed slightly improved aqueous solubility of 5 µM when compared to the previously identified lead compounds and good LogD values (2–3).

Polychlorinated biphenyls (PCBs) are globally distributed pollutants that continue to pose health risks for humans and wildlife. Many effects of PCBs differ between the non-ortho-substituted, dioxin-like (DL), and the ortho-substituted non-dioxin-like (NDL) congeners. Metabolism of PCB congeners by cytochrome P450 enzymes can strongly affect their toxicity. Here we report on metabolism of a NDL PCB congener, 2,2′,5,5′-tetrachlorobiphenyl (PCB52), by a P450 purified from the marine fish Stenotomus chrysops (scup). (Without sequence information this protein is necessarily referred to by its original name, scup P450B.) PCB52 was metabolized at rates from 0.2–2 pmol/min/mg of liver microsomal protein, correlated with immunodetected amounts of P450B, and antibodies to P450B inhibited PCB52 metabolism. We conclude that PCB52 is metabolized by scup P450B. The P450B N-terminal amino acid sequence shares identity with mammalian CYP2Bs. However, PCB52 is metabolized in mammals by CYP2As. Thus, scup P450B has properties of both mammalian CYP2A and CYP2B proteins. Comparative sequence analyses point to scup P450B being a fish CYP2Y. Notably zebrafish CYP2Y3 shares synteny with a cluster of CYP2 genes in mammals. Thus, catalytic function, sequence searching, and zebrafish synteny data lead us to conclude that scup P450B is a CYP2Y and a co-ortholog to genes in the mammalian CYP2ABFGST cluster.

Type 2 diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by chronic hyperglycemia and glucose intolerance. The search for safer and more effective antihyperglycemic drugs of plant origin is a priority due to the limited number of drugs available to treat metabolic syndrome. This review aims to compile various classes of plant-derived diterpenes and elucidate the mechanisms underlying their potential roles in key pathways involved in regulating diabetes and metabolic disorders. It also provides a critical evaluation of their preclinical efficacy, bioavailability, and translational potential. Studies show that diterpenes have a prominent effect on various biochemical pathways that help maintain glucose homeostasis by either interfering with insulin secretion and signaling pathways or modulating carbohydrate metabolism. Notable diterpenes include labdanes like andrographolide (targeting insulin signaling, inflammation, and gluconeogenesis), pimarane and abietane types (inhibiting α-glucosidase and protein tyrosine phosphatase 1B), and kauranes (enhancing insulin secretion and sensitivity). The SwissTargetPrediction software was utilized to predict the targets of major diterpenes from each class, suggesting that these compounds interact with a broad spectrum of protein classes (e.g., kinases, nuclear receptors, proteases), thereby reflecting multitarget pharmacological profiles. A few members of this group, such as stevioside and rebaudioside A, have progressed to clinical trials, demonstrating safety and modest reductions in postprandial glucose levels. Although other diterpenes have shown promise in preclinical models of diabetes and metabolic disorders, robust clinical data on their efficacy and safety are still lacking. These findings highlight the therapeutic potential of plant-derived diterpenes, but further research is needed to overcome limitations related to bioavailability, mechanistic clarity, and translational validation, thereby advancing them toward clinical application.

West Nile Virus (WNV) is a mosquito-borne emerging virus, which can result in the development of meningitis or encephalitis. Our medicinal chemistry effort was initiated to identify potent small-molecule inhibitors of WNV with the potential for lead optimization. The initial hit compound 8-(4-(2,5-dimethylbenzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione 1 was identified from a high-throughput screening (HTS) campaign of 197 K compounds using a cytopathic effect (CPE) cell-based assay against WNV, and showed antiviral inhibition against WNV (EC₉₀ = 0.93 µM), moderate cytotoxicity (CC₅₀ = 12 µM), low solubility (solubility = 9.7 µM) and metabolic stability [mouse and human microsomal stability (MLM and HLM) half-lives < 10 min]. To improve the antiviral activity and drug-like properties of this hit compound, a structure-activity relationship (SAR) campaign led to the discovery of a new potent inhibitor, 8-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-7-(2-fluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione 21, which retained its potency and efficacy and minimal cytotoxicity (EC₉₀ = 0.87 μM, CC₅₀ > 30 μM) as compared to hit compound 1. In addition to its desired anti-WNV activity profile, analog 21 showed improved microsomal stability (MLM t_1/2 = 21 min, HLM t_1/2 = 41 min) with acceptable pharmacokinetic properties for an initial in vivo proof-of-concept (POC) study, though the compound was inactive. Herein, we report the hit-to-lead optimization study that led to the discovery of this xanthine series.

The urate transporter 1 (URAT1) plays an important role in the reabsorption of uric acid, so URAT1 inhibitors are considered as the promising therapy for gout. To explore potent URAT1 inhibitors with new scaffold, we have designed a series of novel derivatives based on the scaffold hopping strategy by merging the structural feature of URAT1 inhibitor SHR4640 into probenecid. The subsequently structure-activity relationship study led to the discovery of a series of potent URAT1 inhibitors, including the typical acid derivative 8 (IC₅₀ = 2.5 μM) and non-carboxylic acid derivative 10 (IC₅₀ = 3.8 μM). Moreover, these compounds also exhibit excellent metabolic stability in human liver microsomes. In the docking study, compounds 8 and 10 fitted very well to the same binding pocket of Lesinurad. In hyperuricemic model mice, compounds 7, 8 and 10 exhibited significantly uric acid-lowering effect, and compound 8 revealed dose-dependent uric acid-lowering effect to the level of benzbromarone. Moreover, compound 8 has significant potential in alleviating chronic hyperuricemia, improving renal function, and reducing inflammation in chronic hyperuricemia mice. These results extend the chemical space in this field and might help to design more promising URAT1 inhibitors.

Alnus glutinosa (Betulaceae), commonly known as black alder, is a traditional medicinal tree with ecological, ethnobotanical, and pharmacological importance. This review presents the first comprehensive assessment of its medicinal potential, integrating botanical background, phytochemistry, and bioactivities. Scientific investigations have validated the traditional applications and revealed diverse pharmacological properties, including anticancer, antioxidant, antibacterial, antifungal, anti-inflammatory, hepatoprotective, and wound-healing effects. These effects can be attributed, in large part, to bioactive chemical compounds such as diarylheptanoids, flavonoids, phenolics, tannins, terpenoids, and steroids. These constituents modulate oxidative stress, inflammatory pathways, and other important cellular functions. This work highlights the therapeutic value of A. glutinosa and exposes crucial gaps in knowledge by combining chemical composition with pharmacological insights. Specifically, the work focuses on the relationship between the two. In particular, additional mechanistic investigations and clinical validation are required in order to advance its function in contemporary medical practice. Overall, the review provides a foundation for future studies on A. glutinosa, supporting its potential as a promising source of bioactive compounds for drug development.