Medicinal Chemistry Research最新文献

The glyoxalase system, inherent in mammalian cells, serves as a natural detoxification mechanism that regulates cytotoxic byproducts, especially methylglyoxal (MG). Consisting of glyoxalase I (Glo-I), glyoxalase II (Glo-II), and glutathione (GSH), this system plays a vital role in managing these harmful substances. Glo-I catalyzes the rate-limiting step in MG detoxification and is found to be overexpressed in different cancer types, rendering it a promising target for novel anticancer drugs. In a previous study, a series of diazenylbenzenesulfonamide derivatives were synthesized and evaluated for their activity against Glo-I. Among these compounds, HA1, A1, and HA2 were identified as Glo-I inhibitors with IC₅₀ values of 1.36 ± 0.09, 1.36 ± 0.01, and 1.22 ± 0.07 µM, respectively, and were subsequently chosen as lead compounds for further investigation. In the present study, the lead compounds were subjected to structural optimization to develop more potent inhibitors. Various derivatives with distinct chemical features were synthesized and tested in vitro against Glo-I to establish their structure-activity relationship and determine the key interactions within the enzyme’s active site. Several compounds exhibited potent inhibitory activity with sub-micromolar IC₅₀ values. Notably, compound (E)-8-hydroxy-5-((4-(N-(thiazol-2-yl)sulfamoyl)phenyl)diazenyl)quinoline-2-carboxylic acid (B9) emerged as the most potent compound, with IC₅₀ value of 0.44 ± 0.06 µM. The structure-activity relationship analysis of compound B9 underscored the significance of the 8-hydroxyquinoline moiety as well as the sulfathiazole moiety for its inhibitory activity. To gain deeper insights into the binding modes of the compounds within the enzyme’s active site, molecular docking studies were conducted, providing enhanced and accurate predictions.

Poly(ADP-ribose)polymerases (PARPs) have emerged as promising targets for the treatment of diseases, particularly in cancers, due to their significant biological functions involved in DNA damage. As a result, researchers worldwide have made substantial advances in this field. However, studies have revealed that PARPs inhibitors lack selectivity due to the conserved domain, limiting their clinical applications and emphasizing the need for selective inhibitors. In this perspective, we summarize the recent advancements in PARPs inhibitors, with a focus on selective inhibitors among PARP family. We discuss the designed strategy, structure-activity relationships, and crystal structure, while explaining the underlying mechanisms of selectivity, hoping to provide insights for the design of next generation of PARPs selective inhibitors.

Cyclin-dependent kinases (CDKs) play a major role in regulating transitions within the cell cycle. Given the roles of CDK4/6 in promoting oncogenesis, selective inhibition of CDK4/6 has emerged as a novel approach for the treatment of breast cancer and various other tumors. While first and second generation CDK4/6 inhibitors were instrumental in targeting cell cycle pathways, they had numerous drawbacks such as limited selectivity and off-target effects. For that reason, a third generation of inhibitors was introduced and provided improved selectivity towards CDK4/6 leading to fewer side effects. To date, four compounds have been approved by the FDA as selective inhibitors of CDK4/6: palbociclib, ribociclib, abemaciclib, and trilaciclib. In this mini review, we summarize the biological, clinical, and chemical aspects of trilaciclib, a first-in-class CDK4/6 inhibitor notable for its dual role in cell cycle regulation and myelopreservation. Trilaciclib was granted FDA approval on February 2021, to improve the outcome of patients with metastatic-stage small cell lung cancer (SCLC) by protecting bone marrow suppression during chemotherapy.

Cancer, a term encompassing a diverse group of diseases, is characterized by uncontrolled cell growth that disrupts normal bodily functions. It remains a major global health concern, claiming millions of lives annually. The causes of cancer are complex and multifaceted, involving lifestyle choices, genetics, and environmental factors. Many FDA-approved drugs feature heterocyclic cores due to their promising pharmacological properties. Notable anticancer agents include doxorubicin, daunorubicin, 5-fluorouracil, methotrexate, vinblastine, and vincristine. Indolizine, a heterocyclic compound with the formula C₈H₇N, stands out as a privileged scaffold in medicinal chemistry. This unique isomer of indole, with nitrogen located at a ring fusion position fused to a six-membered benzene ring, has emerged as a potent candidate for anticancer drug development. This review explores the structure-activity relationship (SAR) studies of various indolizine derivatives, highlighting their potential in targeting diverse cancer types. The review comprehensively analyzes the synthetic pathways employed to create potent indolizine derivatives, focusing on methods such as one-pot reactions, domino reactions, and other innovative approaches. Additionally, it critically examines the biological assays used to evaluate the anticancer activity of indolizine derivatives, providing a quantitative understanding of their potency against various cancer cell lines. Emphasizing different cancer types, including breast, lung, liver, and colorectal cancer, this review underscores the oncotherapeutic significance of indolizine derivatives.

Graphical abstract

Indolizines are one of the heterocycles widely evaluated in oncotherapeutics. Different categories of indolizines are utilized for the treatment of cancers. This report aims to cover all these findings over the last decade and cumulate them into a single record.

Two peptides with dual functionality, namely LLPSY and NAPALVY, exhibit inhibitory effects on both angiotensin-I-converting enzyme (ACE) and dipeptidyl peptidase-IV (DPP-IV), were successfully identified from the hydrolysates of Chinese chive seed (Allium tuberosum Rottl.). Peptide isolation involved reversed-phase chromatography, and peptide sequences were characterized through liquid chromatography-tandem mass spectrometry analysis and de novo sequencing. Notably, the Lineweaver-Burk plot analysis revealed that LLPSY (IC₅₀: 15.66 ± 1.11 µM) acted in a non-competitive manner, whereas NAPALVY (IC₅₀: 3.42 ± 0.79 µM) exhibited competitive inhibition, potently inhibiting ACE. Their stability tests against ACE further revealed that LLPSY acted as a real substrate, while NAPALVY functioned as a true inhibitor of ACE. In terms of DPP-IV inhibition, LLPSY (IC₅₀: 2.48 ± 0.10 mM) was identified as a competitive inhibitor, whereas NAPALVY (IC₅₀: 7.63 ± 0.52 mM) displayed noncompetitive inhibition. Both peptides exhibited true inhibitory effects on DPP-IV. Docking simulations provided insights into peptide-enzyme interactions. These novel Allium tuberosum Rottl.-derived peptides hold promise for controlling blood pressure and blood glucose.

Neurodegenerative disorders are caused by the progressive death of neuronal cells in specific regions of the brain and spinal cord. The most common neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease. The inhibition of enzymes that metabolise neurotransmitter amines is an important approach in the treatment of these disorders and monoamine oxidase (MAO) B inhibitors have thus been used for the treatment of Parkinson’s disease. Inhibitors of the MAO-A isoform, in turn, are used clinically for the treatment of affective (e.g., major depression) and anxiety disorders. Recent studies have shown that benzothiazole derivatives act as potent MAO inhibitors. Based on these findings, the present study group synthesised thirteen 2-methylbenzo[d]thiazole derivatives and evaluated their in vitro MAO inhibition properties. The results showed that the benzothiazole derivatives were potent and selective inhibitors of human MAO-B, with all compounds exhibiting IC₅₀ values < 0.017 µM. The most potent MAO-B inhibitor (4d) had an IC₅₀ value of 0.0046 µM, while the most potent MAO-A inhibitor (5e) had an IC₅₀ value of 0.132 µM. It may be concluded that active benzothiazole derivatives may serve as potential leads for the development of MAO inhibitors for the treatment of neuropsychiatric and neurodegenerative disorders.

Monopolar spindle kinase 1 (MPS1, also called TTK) is an attractive target for the treatment of cancers. Five MPS1 inhibitors have entered the clinical trials, but four of them were discontinued; thus, it is necessary to develop MPS1 inhibitors with novel scaffolds. In the present work, several computational tools were built to design MPS1 inhibitors. The deep recurrent neural network was used for generating potential highly active MPS1 inhibitors. The deep neural network was used to build a ligand-based consensus model for distinguishing the highly and weakly active MPS1 inhibitors. Five co-crystal structures were used to develop the consensus docking score for distinguishing actives and decoys. The ligand-based consensus model and the consensus docking score were used to evaluate the generated molecules, and finally, two scaffolds, which were less reported as MPS1 inhibitors previously, were selected. A total of 15 compounds with the two scaffolds were synthesized and tested by in vitro enzymatic inhibition assays. Five compounds had sub-micromolar to low micromolar in vitro potencies, and the most active compound was 10 with an IC₅₀ of 556 nM. The binding modes of the new compounds were revealed by molecular dynamic simulations. We believe that the computational strategies in the present work were helpful for discovering new potential scaffolds.

Oxazolidinones are synthetic antibiotic class of compounds characterized by chemical structure, cyclic carbamate with ‘S’ configuration of substituent at C-5 position. The synthesis of oxazolidinones has gained increasing interest due to their unique mechanism of action that assures high antibiotic efficiency and low susceptibility to resistance mechanisms. Biaryl oxazolidinones are second-generation oxazolidinone (e.g. Tedizolid) having potency against multidrug-resistant (MDR) gram-positive pathogens including MRSA, VRE, penicillin-resistant S. pneumoniae and linezolid-resistant strains. The current manuscript covers structure activity based synthesis of 21 oxazolidinone analogs prepared through various chemical modifications. These novel biaryl oxazolidinones are prepared with the objective to increase spectrum of activity against multidrug-resistant Gram-positive bacteria.