Medicinal Chemistry Research最新文献

Protein phosphatase 2A (PP2A), a member of the phosphoprotein phosphatase (PPP) family, plays a pivotal role in regulating tau dephosphorylation, thereby maintaining the functional integrity of this brain-specific protein in microtubule assembly. Progressive downregulation of PP2A has been implicated in the pathogenesis of Alzheimer’s disease (AD). The identification of high-affinity PP2A ligands presents a promising avenue for monitoring early-stage dementia progression through alternative molecular mechanisms. Utilizing the catalytic binding pocket model of PP1 as a structural surrogate for PPPs, three distinct fragments derived from various natural PP2A inhibitors were found to exhibit equivalent binding functionality. Building upon this framework in small-molecule design, a synthetic spiroketal compound was developed based on the C1–C14 acidic fragment of okadaic acid (OA), a PP2A-selective inhibitor. This compound emerges as a promising candidate for further therapeutic and diagnostic investigation.

Bacterial resistance to β-lactam antibiotics has emerged as a major challenge in healthcare. This form of antibiotic resistance is driven by the ability of pathogens to produce β-lactamases, which are divided into four classes (A-D) according to the Ambler classification. The most concerning are metallo-β-lactamases (MBLs) of class B, with the New Delhi Metallo-β-lactamase (NDM) enzyme family being among the most clinically significant. These zinc-dependent enzymes can inactivate almost all β-lactam antibiotics, and, to date, no effective inhibitors for this type of β-lactamase have been developed. Certain derivatives of indole-2-carboxylic acid and azoles have been shown to inhibit New Delhi metallo-β-lactamase-1 (NDM-1) by coordinating with Zn²⁺ ions and specifically interacting with key amino acid residues in the active site of the enzyme. However, the antibacterial potential of azolylindoles as metallo-β-lactamase inhibitors remains unexplored. In searches of novel scaffolds for the development of metallo-β-lactamase inhibitors a strategy for modifying a known NDM-1 inhibitor chemotype based on indole-2-carboxylic acid is proposed. This approach leads to the synthesis of previously unreported 2-azolylindoles incorporating triazole, thiadiazole, oxadiazole, tetrazole, and tetrazolylmethyl moieties. Synthetic methodologies for the preparation of intermediates and target compounds were optimized and adapted. Obtained compounds have demonstrated the ability to inhibit NDM-1 across a broad concentration range (IC₅₀ = 40 nM–15 µM), highlighting the significant influence of the azole nuclei structure on in the enzyme inhibition. The docking-predicted binding poses of the most active compounds in active site of NDM-1 closely matched with the experimental ligand orientation and revealed interactions with key amino acid residues and Zn²⁺ ions. For the most potent lead-compounds, the effect on the activity of meropenem and cefepime against NDM-1-producing strains of E. coli and K. pneumoniae was evaluated, as these antibiotics are highly relevant in antimicrobial therapy. Cytotoxicity of the synthesized series was evaluated using the noncancerous HaCaT keratinocyte cell line. The most active NDM-1 inhibitors, including the paternal acid 1 and the tetrazole analogue 19, demonstrated low cytotoxicity (IC₅₀ > 50 µM), supporting their potential as safe candidates. In contrast, compounds containing triazole, thiadiazole, or oxadiazole moieties showed increased cytotoxicity, which also limits the further development of compounds 25 and 26 as NDM-1 inhibitors. Thus, among all synthesized compounds, only 2-tetrazolylindole derivative was identified as a potential candidate for further development of novel MBL inhibitors.

Withania coagulans Dunal, also known as “Indian cheese maker”, is a medicinal plant that is widely used in traditional South Asian medicine. This review illustrates a critical and comprehensive synthesis of the botanical description, phytochemistry, and pharmacological opportunities of W. coagulans. The intent was to assess W. coagulans potential for therapeutic use, focusing on safety and current knowledge gaps. Phytochemistry reports a diverse profile of withanolides, flavonoids, alkaloids, tannins, and saponins that account for the reported varied bioactivity including antidiabetic, anti-inflammatory, antimicrobial, hepatoprotective, hypolipidemic, neuroprotective, and antioxidant activities. Mechanistic studies reported various activities modulation through reported pathways such as NF-κB, MAPKs and AMPK pathways, with activity largely determined using in vitro and animal studies. While clinical studies are limited, translational potential is inhibited by identified issues such as, but not limited to, poor bioavailability and limited toxicity characterization. However, advancements in several formulations’ strategies including nanoformulations can help to bolster the pharmacokinetics parameters. This review also responded to analytical methodology for compound identification, also highlighting challenges associated with regulation and pharmaceutical development. Overall, W. coagulans may potentially serve as a phytopharmaceutical; nonetheless, as a priority, research studies that adhere to standardized clinical trials and systematic review will be beneficial for clinical use with evidence-based therapeutic systems.

The primary cause of Sickle cell disease (SCD) is a mutation in the HBB gene, which plays an important role in haemoglobin production. This genetic mutation brings about the synthesis of an unusual variant of haemoglobin, haemoglobin S (HbS), which possesses a unique molecular configuration in contrast to the standard adult haemoglobin (HbA). SCD arises from an atypical HbS (α2βS2) where in the amino acid glutamic acid residue at position 6 in the β-globin chain of haemoglobin is substituted with valine. The genetic determinants of SCD include possessing two copies of the rs334 mutation (referred to as HbSS or SCA) or having one copy of the rs334 mutation in conjunction with other mutations that produce alternative forms such as mutation in the β-globin gene (e.g., HbC, cause to HbSC) or reduced β-globin production, as seen in β-thalassemia. The treatment for the management of sickle cell anemia includes hydroxyurea, folic acid, amino acid supplements, penicillin prophylaxis, antimalarial prophylaxis, and blood transfusions are the principal therapies in the clinical management of sickle cell anaemia. Investigations into the antisickling attributes of medicinal plants have yielded promising results. In vitro studies have shown that phytomedicine-based alternative therapy can reverse sickling and alleviate crises. This review focuses on identifying the diverse advantages of phytomedicines and nutraceuticals utilised in the management and treatment of sickle cell anaemia.

The therapeutic efficacy of cisplatin, a commonly used chemotherapeutic drug, is limited by its substantial nephrotoxicity. Despite its clinical significance, cisplatin-induced kidney damage is still a significant problem that calls for the creation of preventative measures for renal function. The potential of natural products as nephroprotective agents against cisplatin-induced nephrotoxicity has been brought to light by recent studies. This review offers a thorough summary of the most recent research examining the protective properties of several natural substances, such as flavonoids, alkaloids, terpenoids, polyphenols, and other bioactive chemicals produced by plants. Nephroprotective mechanisms include anti-inflammatory, anti-apoptotic, anti-fibrotic, and antioxidant properties that work together to reduce oxidative stress, inflammation, and cellular damage brought on by cisplatin. This review also addresses the difficulties in putting these results into clinical practice, such as concerns about safety, dose, and bioavailability. All things considered, the natural items under evaluation exhibit encouraging nephroprotective potential, indicating that they could be useful supplements or substitute therapies for the management of cisplatin-induced nephrotoxicity. This review explains the importance of natural substances against the nephrotoxicity induced by cisplatin in rodents. To confirm their safety and therapeutic effectiveness in humans, more investigation and clinical testing are required.

An acetophenone thiosemicarbazone series 6a-m containing lactose moiety were synthesized and explored for their inhibition against the enzymes responsible in Type 2 diabetes mellitus (T2DM), including α-amylase, α-glucosidase, DPP-4, and PTP1B. Two thiosemicarbazones exhibited the highest inhibitory activity against these enzymes, 6i against α-glucosidase (IC₅₀ = 7.15 ± 0.12 μM) and 6m against α-amylase, DPP-4, and PTP1B (with IC₅₀ = 7.82 ± 0.14 µM, 1.32 ± 0.02 µM, and 3.74 ± 0.14 μM when compared to the corresponding standard drugs). These compounds also exhibited the high anti-glycation and antioxidant activity in DPPH and ABTS^•+ scavenging assays. They were noncytotoxic for WI-38 cell line with IC₅₀ >85 μM. Molecular docking study applied to these two most potential inhibitors on enzymes, including 3TOP for inhibitor 6i, 1OSE, 3W2T, and 1NNY for inhibitor 6m. These ligands had active interactions with the residues in the catalytic pocket of these corresponding enzymes that was consistent with their obtained inhibitory efficacy against each enzyme tested. The 300 ns molecular dynamics simulations applied for the complexes, including 6m/1OSE, 6i/3TOP, 6m/3W2T, and 6m/1NNY, to validate the obtained in vitro biological activity data of these inhibitors. The obtained results indicated that these inhibitors had stable dynamic interactions in the catalytic pockets of the respective enzymes to promote their activity.

This study focused on synthesizing novel chalcone-ketamine derivatives and evaluation of their anti-inflammatory properties. Eighteen compounds were synthesized via a one-pot condensation of ketamine with various aldehydes under basic conditions. Compounds were characterized by FTIR, NMR, mass spectrometry, and elemental analysis. Molecular docking studies revealed that several of these molecules possessed low binding affinities for COX-2 than COX-1. An in vitro enzyme inhibition analysis of molecules also suggested similar trend with compounds 1n and 1q exhibiting the greatest preferential inhibition of COX-2 than COX-1. Key structural modifications such as specific functional groups in compounds 1n and 1q were identified through SAR analysis. QSAR modeling revealed a predictive correlation between structural features and inhibitory potential of synthetized molecules. Molecular dynamics (MD) simulations of the best-docked complex were carried out to assess the stability and dynamics of compound-receptor complexes followed by Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations. Density functional theory studies were also performed on molecules 1n, 1q and ketamine to determine the energy of frontier molecular orbitals, HOMO-LUMO band gap and Mulliken charges on the optimized structures. Significant steric and electrostatic descriptors were found to influence COX-2 selectivity. In vivo analgesic and anti-inflammatory effects of 1n and 1q were further evaluated in hotplate, acetic acid-induced writhing, and carrageenan-induced paw edema models, with both compounds showing significant anti-inflammatory activities. Biochemical analysis indicated significant reductions in inflammatory mediators (IL-1β, TNF-α, COX-2) in the paws of mice treated with 1n and 1q than disease controls. In conclusion, novel chalcone-ketamine derivatives were synthesized with preferential inhibitory activity for COX-2 than COX-1.

Excoecaria cochinchinensis Lour. is a well-known medicinal plant in Vietnam, whose parts, particularly leaves, are applied as essential medicine in folk remedies. In this study, the chemical constituents of the plant’s aerial parts, together with their feasibility in enzyme inhibition and antioxidants, were investigated. Seven compounds, including a new coumarino lignan – excochinlignan (1), five known flavonol derivatives (2-6) and one monophenolic (7), were isolated and identified via chromatographic and spectroscopic approaches. In vitro biological evaluation of these compounds revealed the potential of kaempferol (2) and its glycosides (3-6) in all assays. Among them, kaempferol (2) was determined as the most active antioxidant (IC₅₀ 2.86 μM) while its 3-O-xylose derivatives (3) displayed the most significant α-glucosidase (IC₅₀ 65.88 μM) and tyrosinase (IC₅₀ 58.97 μM) inhibition. In silico evaluation via molecular docking simulation suggested the supportive effect of 3-O-xylose, C-4′ hydroxyl and C-4 ketone moieties in the structure of the isolated flavanols (2-6) on their enzyme inhibition and antioxidant properties.

Human toxocariasis is a globally neglected parasitic disease, commonly treated with benzimidazole anthelmintics. However, their efficacy is considered unsatisfactory, requiring the research and development of new drugs. Studies have shown that hetero-cyclic compounds with nitrogenous molecules are known for their properties of inducing oxidative stress on pathogens. This study aimed to evaluate the efficacy of the (E)-N’-benzylidenefuran-2-carbohydrazide (PFUR) and ten derivatives against Toxocara canis in preclinical tests. The compounds were tested in vitro, in duplicate, at a concentration of 1.0 mg/mL to 0.062 mg/mL in a microplate containing 100 Toxocara canis larvae in RPMI-1640 medium. The compound PFUR 2 showed activity against 100% of the larvae at the minimum larvicidal concentration (MLC) of 0.25 mg/mL and was selected for the subsequent tests. Furthermore, this compound also demonstrated non-cytotoxicity to murine macrophages and an adequate estimate of oral bioavailability, as determined by the “rule of five” in computational models. After, two in vivo tests were conducted on Swiss mice. In the groups treated with PFUR 2 (10 mg/kg/5 d, IG), 10 days and 30 days after inoculation with 500 T. canis eggs, there was a reduction of 23% (p > 0.05) and 62.4% (p < 0.05) in the intensity of infection, respectively, compared to the PBS control. In both experiments, the PFUR 2 compound presented results similar to those of mebendazole (40 mg/kg/5 d, IG) (p > 0.05). The results of this study demonstrated the potential of this compound as a candidate for a new anthelmintic.

The escalating challenge of antimicrobial resistance (AMR) necessitates the development of novel therapeutic agents. In this study, we present an efficient, eco-friendly, and metal-free multicomponent synthesis of a new series of pyrazole-fused 2-amino-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives (7a–j) via a piperidine-catalyzed, solvent-free liquid-assisted grinding (LAG) method. This green synthetic approach yields the target compounds in excellent yields without the need for purification or toxic reagents. The synthesized compounds were evaluated in vitro for antimicrobial activity against gram-positive (Bacillus cereus, Staphylococcus aureus), gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, and pathogenic fungi (Candida albicans, Candida tropicalis). Notably, derivatives 7b, d, e, and j exhibited significant activity, with minimum inhibitory concentration (MIC) values comparable to or exceeding those of standard drugs. Structure–activity relationship (SAR) analysis and in silico ADME profiling of the active compounds (7b, d, e and j) revealed favorable pharmacokinetic and safety profiles, highlighting their potential as promising antimicrobial candidates. This work underscores the value of green synthetic methodologies in drug discovery and provides a foundation for the further development of pyrano[3,2-h] quinoline-based antimicrobial agents.

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