Medicinal Chemistry Research最新文献

The non-bonded interaction between the positive electrostatic potential associated with a σ*-orbital (the σ hole) of a substituted carbon atom and an atom with a lone pair of electrons is referred to as tetrel bonding and can be expressed in both intermolecular and intramolecular manifolds. Intermolecular tetrel bonding can contribute to the inventory of interactions that convene protein-ligand complexes while intramolecular tetrel bonds can influence the conformation of a molecule. While the energy associated with a carbon-based tetrel bond is calculated to be of a modest value, ranging from ~5 kcal/mole for a close contact between optimal partners to ~1 kcal/mole for a more relaxed and what is perhaps the more typical interaction, the prevalence of carbon tetrel bonding in drug design may be underappreciated. The energy of a carbon-based σ-hole tetrel bonding interaction has been equated with that calculated for the more prominent n→π* multipolar-type of tetrel bonding interaction or a C-H→π bond, both of which are recognized as interactions of value in drug design. In this review, we provide a perspective on the evidence in support of intermolecular and intramolecular σ-hole tetrel bonding interactions in the context of geometric parameters associated with drug and drug-like molecule structures deposited in the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB).

Diabetes mellitus (DM) is a complex disease, and its treatment/management frequently requires the use of different drugs with distinct modes of action. Unfortunately, many of the current medications come with an increasing plethora of adverse effects. Consequently, DM poses a significant challenge to the global health system. Carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase have emerged as well-known therapeutic targets for the regulation of postprandial glucose levels. Herein, we report the design and synthesis of 20 novel molecular hybrids encompassing thienopyrimidinone and thiazolidinedione pharmacophores that can inhibit α-amylase and α-glucosidase and prevent oxidative stress. Several derivatives showed more potency than the standard drug acarbose. Compound 12q (IC₅₀ = 38.89 ± 0.50 µM) with alkyl chain length n = 4 exhibited four-fold superior potency to acarbose (IC₅₀ = 174.40 ± 2.63 µM) against α-amylase, while compound 12t (IC₅₀ = 41.94 ± 4.76 µM) also with alkyl chain length n = 4 exhibited seven-fold higher activity than acarbose (IC₅₀ = 282.80 ± 1.46 µM) against α-glucosidase. Enzyme kinetic studies further revealed these compounds (12q and 12t) to be mixed inhibitors of the respective enzymes and were extensively engaged in interactions with their targets based on molecular docking simulations.

Lung cancer represents a significant public health challenge, with non-small cell lung cancer (NSCLC) being the predominant subtype, underscoring the urgent need for improved therapeutic strategies. The limited efficacy of conventional chemotherapy has catalyzed the exploration of alternative treatment modalities. Natural products play a pivotal role in drug discovery, with structural modifications being integral to pharmaceutical research. This study presents novel coumarin derivatives that exhibit potential as candidate molecules for the treatment of lung adenocarcinoma. Among the synthesized compounds, compound 4f demonstrated potent inhibitory effects on PC9 cells, with an IC₅₀ value of 4.08 μM. In vitro analyses demonstrated that 4f significantly inhibited the proliferation and migration of PC9 cells by downregulating the expression of mTOR, which subsequently induced autophagic cell death. In vivo studies indicated that 4f effectively targets mTOR, leading to the suppression of tumor growth while exhibiting a favorable safety profile. These findings support the advancement of new coumarin derivatives as promising therapeutic agents for lung adenocarcinoma.

Benzoxathiolone derivatives have in vitro activity against monoamine oxidase A (MAO-A) and MAO-B, making them potential lead compounds for the treatment of neuropsychiatric and neurodegenerative disorders. They also have antibacterial activity against numerous bacteria. The aim of this study was to synthesise two series of benzoxathiolone derivatives with different ester (series 1) and sulfonic ester (series 2) substitutions on position C6. The in vitro half-maximal inhibitory concentration (IC₅₀) of these derivatives was determined against both MAO-A and MAO-B, after which their mode of inhibition was determined by constructing Lineweaver-Burk graphs. Additionally, the minimum inhibitory concentration (MIC) of these derivatives was also determined against Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. All derivatives had activity against both MAO-A and MAO-B. With regards to MAO-A, derivatives 1c (0.054 µM), 1f (0.052 µM), and 2a (0.072 µM) were the most active. The positive control, harmine (0.003 µM), was however more active. With regards to MAO-B, derivatives 2a (0.001 µM), 2b (0.003 µM), 2c (0.010 µM) and 2d (0.012 µM), were more active than both positive controls, i.e., safinamide (0.088 µM) and isatin (2.80 µM). Comparing the activity of the derivatives against MAO-A versus MAO-B, the sulfonic ester derivatives were more active against MAO-A while the ester derivatives were more active against MAO-B. Halide substituents on the phenyl ring notably increased MAO-A activity. For MAO-B, enhanced activity was specifically observed with para-position substitution on the ester derivatives. As for the antibacterial assays, only 1d (16 µg/ml) had activity against S. aureus.

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.