Medicinal Chemistry Research最新文献

Anthranylhydrazide derivatives were synthesized as potential 4-hydroxyalkenals scavengers. The syntheses were achieved from diversely substituted isatoic anhydride 1a-1c by reaction of methylhydrazine leading to the methyl hydrazide derivatives Ia-Ic. Studies of the scavenging activity with 4-hydroxyhexenal (4-HHE) were conducted either in organic or aqueous media using TLC or ¹H NMR monitoring. Compounds Ia and Ib were found to be able to form, without any catalysis, stable acylhydrazone adducts which were fully characterized. Compound Ib displayed the best scavenging activity towards 4-HHE with faster reactions in both organic and aqueous media. The stability of the adduct IIb could be assessed in aqueous media. This activity was also further discussed with the help of computer assisted conformational analysis which allowed to characterize stable conformations of IIa and IIb with NH/π interactions.

The natural product cortistatin A and its derivative didehydro-cortistatin A exhibit potent biological activity in different disease states, indicating the potential utility of their derivatives as treatments for a variety of diseases. The synthesis of the unique ring system found in these compounds is challenging, and therefore we designed analogs with a conventional steroidal scaffold that retained the A-ring functionalities with the stereochemistries found in the natural product, building on a previous report of simplified didehydro-cortistatin A analogs. The steroidal derivatives were synthesized in 9 steps from prednisone with different isoquinoline isomers incorporated at C17 via a Stille coupling in the last step. The analogs exhibited antiproliferative activity in HCT 116 colon cancer cells with low micromolar potency (HCT 116 IC₅₀ = 4.80–11.5 µM) and rapid onset. The methodology described here can be used to prepare additional simplified didehydro-cortistatin A analogs for future biological applications.

Understanding the clearance pathways of drug candidates and the fraction metabolized (f_m) by drug-metabolizing enzymes is a major focus during drug discovery and development process. While selective cytochrome P450 (CYP) inhibitors are widely available, the lack of potent pan- uridine 5’-diphospho-glucuronosyltransferases (UGT) inhibitors with minimal cross-inhibition on CYP enzymes limits the ability to evaluate the contribution of UGT to drug clearance in vitro and in vivo. This study screened five potential inhibitors—triclosan, salicylamide, valproic acid, benzoic acid, and borneol—across twelve human UGT isoforms using human liver microsomes (HLM) and Supersome®. Triclosan emerged as a potent pan-UGT inhibitor, exhibiting IC₅₀ values below 10 µM for all tested isoforms, ranging from 0.43–9.9 µM. However, triclosan also inhibited multiple CYP enzymes with IC₅₀ values ranging from 0.12 to 22 µM. The concurrent inhibition of multiple CYP enzymes limits the application of triclosan as a selective tool compound for UGT reaction phenotyping. The kinetic analysis revealed noncompetitive inhibition of UGT1A3-mediated telmisartan glucuronidation by triclosan, where the other tested compounds failed to inhibit UGT1A3. Notably, triclosan demonstrated high selectivity and potency toward CYP2C19 (IC₅₀ 0.12 µM), suggesting its potential use in CYP2C19 reaction phenotyping in HLM. Additionally, triclosan selectively inhibited flavin-containing monooxygenase 3 (FMO3) but not FMO5.

This study was designed to synthesize a series of carvacrol-based fibrate derivatives based on a molecular hybridization strategy. In acute hyperlipidemic mice, the target compound T7 exhibited a noticeable effect on lowering lipid and demonstrated a dose-dependent characteristic. In the high-fat diet (HFD) mouse model, T7 notably decreased triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels, and elevated high-density lipoprotein cholesterol (HDL-C) levels in both serum and liver tissues. Additionally, T7 appreciably increased the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) found in both serum and liver tissues. Liver histopathological examination indicated that it could inhibit hepatic lipid accumulation and alleviate liver injury. After administration, T7 exhibited anti-oxidative stress and anti-inflammatory effects. It could appreciably increase the activity of superoxide dismutase (SOD), decrease the activity of lipid peroxidation product malondialdehyde (MDA), and appreciably reduce the pro-inflammatory factors interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels. Molecular docking experiments demonstrated that T7 exhibited a strong binding affinity with the peroxisome proliferator-activated receptor-α (PPAR-α) receptor. T7 enhanced the PPAR-α expression in liver tissues, indicating that T7 may regulate lipid metabolism by activating the PPAR-α receptor. The hepatoprotective effect of T7 may be closely linked to its capacity to reduce oxidative stress and inflammatory responses. In conclusion, T7 may be a potential novel lipid-lowering candidate compound with the potential to improve liver injury.

The biosynthetic schemes for the production of halogenated peptidic natural products offer avenues for the discovery of peptide halogenases, and opportunities for development of biocatalysts for derivatization of peptides and proteins. Here, a short review of recent discoveries regarding biocatalytic protein and peptide halogenation is provided. Halogenation in two major classes of peptidic natural products is discussed, those that are produced as ribosomal peptides and post translationally modified, and those that are produced by assembly line-like non ribosomal peptide synthetases. Mechanistic considerations and biocatalytic applications of peptide halogenases are briefly discussed.

Kava, the root of Piper methysticum – plants dominantly cultivated in the South Pacific Islands, is traditionally consumed in the form of an aqueous suspension for its stress-reducing benefits. Beyond its traditional use, kava has demonstrated anticancer, anti-inflammatory, anxiolytic and other potentials. These effects are largely attributed to its major components, termed kavalactones. However, clinical findings of purported hepatotoxic risk have raised its safety concerns with a few causes hypothesized, including the potential of drug-herb interactions due to kavalactone perturbation of cytochrome P450 enzymes. In order to rigorously evaluate kava in the preclinical and clinical settings for its potential benefits and risks in future studies, a critical assessment of the possible contributing factors and mechanisms behind its purported hepatotoxic risk is essential. This review examines the current data on kava and kavalactones to modulate cytochrome P450 enzymes, including biochemical, cell-based, animal, and clinical data, and assess their potential contribution to kava’s hepatotoxic risk due to drug-herb interactions.

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Glutathionylation is an important Phase II biotransformation pathway that utilizes glutathione transferases (GSTs) to conjugate glutathione with reactive electrophiles represented by a great diversity in chemical structures. After further processing, the resulting metabolite is highly polar and rapidly eliminated. This pathway thus represents an important route of xenobiotic detoxification. Cats and dogs possess a combined repertoire of at least 27 cytosolic glutathione transferases belonging to the GST-A, -M, -P, -T, -Z and -O classes, with the greatest genetic diversity observed for the GSTA, GSTM, GSTP, and GSTT classes. GST transcript and protein expression have been demonstrated for most tissues in dogs, but less so in cats. In contrast to humans, these two species have fewer actively expressing GSTM genes, but a larger number of active GSTT genes. Dogs and cats also express distinct GSTP1-like and GSTT1-like enzymes. These differences in GST type and multiplicity, as well as residue changes that impact the secondary and tertiary structure of the cat and dog GST proteins, affect substrate selectivity and catalytic efficiency. Further research is required, especially in cats, to understand how species differences in glutathionylation modulate the risk of toxicity following exposure to certain drugs and environmental contaminants.

Cholinergic neuron damage and oxidative stress are prominent hypotheses explaining the pathogenesis of Alzheimer’s disease (AD). In this study, dual-acting compounds combining carbamate and diazepine structures were designed to function as both butyrylcholinesterase (BChE) inhibitors and antioxidants. Selective inhibition of BChE, particularly during the late stages of AD when its activity increases, was targeted. Introducing different diazepine derivatives (14, 15 and 16) provided insights into inhibitor basicity and enzyme-binding affinity. Among the synthesized compounds, heptyl carbamate (6b) demonstrated an IC₅₀ value of 32 ± 25 nM for BChE, with 96.5% purity confirmed by HPLC. Post-carbamoylation, the released compounds 15 and 16 exhibited antioxidant activities (70.2–85.3%) at 0.0136–0.1088 mM, comparable to ascorbic acid and α-tocopherol. The prepared carbamates demonstrated selectivity for BChE over acetylcholinesterase (AChE). Docking studies corroborated biological data, revealing compound 6b as the most potent. These findings highlight the therapeutic potential of these dual-acting compounds in addressing the multifaceted pathology of AD.

Antimicrobial resistance (AMR) has become a massive concern because it causes the loss of human life and an economic burden in many parts of the world. Antimicrobial peptides (AMPs) can be investigated as an alternative solution to combat AMR because their mechanism has the potential to reduce microbe resistance. In this study, the native P01 peptide from Chondrus crispus macroalgae was modified to P01.1, P01.2, and P01.3 peptides via residue mutations and capping of the N- and C-termini to systematically improve their α-helical content, bacterial membrane interaction, and antibacterial activity. C-terminus amidation and mutations to remove helix breaker residues in P01 to give P01.1 peptide enhanced its α-helical stability. Acetylation of the N-terminus P01.1 to give P01.2 peptide further enhanced the α-helical content of the peptide. Mutations of low-to-high helical former residues in P01.2 to give P01.3 peptide further improve its α-helical stability. The binding activity of peptides to a model of Gram-positive membrane is in the following order P01.3 > P01.2 > P01.1 > P01; this is correlated with their antibacterial activity against Gram-positive S. aureus with MICs in the following order P01.3 = 15.63 μg/mL > P01.2 = 125 μg/mL > P01.1 and P01 larger than 250 μg/mL. In a model of Gram-negative membrane, the peptide-membrane binding is in the following order P01.3 = P01.2 > P01.1 > P01; however, P01.3, P01.2, and P01.1 have the same antibacterial activity against Gram-negative E.coli (MIC = 3.91 μg/mL) while P01 has no activity. In conclusion, the α-helical stability and amphipathicity of the peptide have correlation with the membrane binding and antibacterial activity of the peptide.

Graphical Abstract

The estrogen sulfotransferase (EST), also called sulfotransferase 1E1 (SULT1E1), plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens. The identification and characterization of EST inhibitors has been an active field of research. The EST inhibitors can not only be used as tool compounds to characterize the biochemical and pathophysiological functions of EST, but also have therapeutic potential due to the implications of EST and its regulation in hormone-dependent and independent pathological conditions. This review article is intended to provide a historical perspective and summary of the recent progress in the development and characterization of EST inhibitors.