Chiral Pool Synthesis,Biological Evaluation and Molecular Docking Studies of C-Furanosidic LpxC Inhibitors

Inhibitors of the bacterial deacetylase LpxC are a promising class of novel antibiotics, being selectively active against Gram-negative bacteria. To improve the biological activity of reported C-furanosidic LpxC inhibitors, the stereochemistry at positions 3 and 4 of the tetrahydrofuran ring was varied. In chiral pool syntheses starting from d -gulono-γ-lactone and d -ribose, a series of (3S,4R)-configured dihydroxytetrahydrofuran derivatives was obtained, of which the (2S,5S)-configured hydroxamic acid 15 ((2S,3S,4R,5S)-N,3,4-trihydroxy-5-(4-{[4-(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-carboxamide) was found to be the most potent LpxC inhibitor (K_i=0.4 μm ), exhibiting the highest antibacterial activity against E. coli BL21 (DE3) and the D22 strain. Additionally, molecular docking studies were performed to rationalize the obtained structure–activity relationships.     

Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity

The emergence of multidrug-resistant bacteria is a global health threat necessitating the discovery of new antibacterials and novel strategies for fighting bacterial infections. We report first-in-class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli. Whereas DNA gyrase ATPase inhibition experiments, DNA gyrase supercoiling assays, and in vitro antibacterial assays suggest binding of the hybrids to the E. coli GyrA and GyrB subunits, an interaction with the GyrA fluoroquinolone-binding site seems to be solely responsible for their antibacterial activity. Our results provide a foundation for a new concept of facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.     

Conjugation of Cisplatin Analogues and Cyclooxygenase Inhibitors to Overcome Cisplatin Resistance

Cyclooxygenase (COX) is an enzyme involved in tumorigenesis and is associated with tumor cell resistance against platinum‐based antitumor drugs. Cisplatin analogues were conjugated with COX inhibitors (indomethacin, ibuprofen) to study the synergistic effects that were previously observed in combination treatments. The conjugates ensure concerted transport of both drugs into cells, and subsequent intracellular cleavage enables a dual‐action mode. Whereas the platinum(II) complexes showed cytotoxicities similar to those of cisplatin, the platinum(IV) conjugates revealed highly increased cytotoxic activities and were able to completely overcome cisplatin‐related resistance. Although some of the complexes are potent COX inhibitors, the conjugates appear to execute their cytotoxic action via COX‐independent mechanisms. Instead, the increased lipophilicity and kinetic inertness of the conjugates seem to facilitate cellular accumulation of the platinum drugs and thus improve the efficacy of the antitumor agents. These conjugates are important tools for the elucidation of the direct influence of COX inhibitors on platinum‐based anticancer drugs in tumor cells.     

Exploiting the Thiobarbituric Acid Scaffold for Antibacterial Activity

Thiobarbituric acid (TBA) has been considered a privileged structure for developing antimicrobial agents. Diversity was obtained at positions N and at C5 through acylation, Schiff base formation, Knoevenagel condensation, and thioamide and enamine formation. The present work describes the synthesis of small libraries based on the TBA moiety and above‐mentioned reactions. Preliminary antimicrobial activity screening of the prepared compounds against selected bacteria (both Gram‐positive and ‐negative) showed the best results for the Boc‐Phe‐TBA derivative. These results could be useful for designing and building libraries based on other amino acids with distinct protecting groups.     

Studies of Benzamide‐ and Thiol‐Based Histone Deacetylase Inhibitors in Models of Oxidative‐Stress‐Induced Neuronal Death: Identification of Some HDAC3‐Selective Inhibitors

Less stress : We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. Novel benzamide‐based ligands selectively inhibit HDAC3 but provide no neuroprotection in the HCA–cortical neuron model of oxidative stress.

     

In silico Optimization of a Fragment‐Based Hit Yields Biologically Active,High‐Efficiency Inhibitors for Glutamate Racemase

A novel lead compound for inhibition of the antibacterial drug target, glutamate racemase (GR), was optimized for both ligand efficiency and lipophilic efficiency. A previously developed hybrid molecular dynamics–docking and scoring scheme, FERM‐SMD, was used to predict relative potencies of potential derivatives prior to chemical synthesis. This scheme was successful in distinguishing between high‐ and low‐affinity binders with minimal experimental structural information, saving time and resources in the process. In vitro potency was increased approximately fourfold against GR from the model organism, B. subtilis. Lead derivatives show two‐ to fourfold increased antimicrobial potency over the parent scaffold. In addition, specificity toward B. subtilis over E. coli and S. aureus depends on the substituent added to the parent scaffold. Finally, insight was gained into the capacity for these compounds to reach the target enzyme in vivo using a bacterial cell wall lysis assay. The outcome of this study is a novel small‐molecule inhibitor of GR with the following characteristics: K_i=2.5 μM , LE=0.45 kcal mol^?1 atom^?1, LiPE=6.0, MIC₅₀=260 μg mL^?1 against B. subtilis, EC_{50, lysis}=520 μg mL^?1 against B. subtilis.     

Inhibitors of the Large Ribosomal Subunit from Haloarcula marismortui

The crystal structures that have been obtained for 23 different inhibitors bound to the large ribosomal subunit from Haloarcula marismortui are reviewed here. These structures provide important insights into how anti-ribosomal antibiotics inhibit protein synthesis, how species specificity arises, and the relationship between ribosomal mutations and antibiotic resistance. These structural studies also provide compelling evidence that the conformation of the peptidyl transferase center of the large ribosomal subunit is intrinsically variable, and that conformational equilibria play a role in determining its functional properties.     

Mitochondria-Mediated Cardiovascular Benefits of Sodium-Glucose Co-Transporter 2 Inhibitors

Several recent cardiovascular trials of SGLT 2 (sodium-glucose cotransporter 2) inhibitors revealed that they could reduce adverse cardiovascular events in patients with T2DM (type 2 diabetes mellitus). However, the exact molecular mechanism underlying the beneficial effects that SGLT2 inhibitors have on the cardiovascular system is still unknown. In this review, we focus on the molecular mechanisms of the mitochondria-mediated beneficial effects of SGLT2 inhibitors on the cardiovascular system. The application of SGLT2 inhibitors ameliorates mitochondrial dysfunction, dynamics, bioenergetics, and ion homeostasis and reduces the production of mitochondrial reactive oxygen species, which results in cardioprotective effects. Herein, we present a comprehensive overview of the impact of SGLT2 inhibitors on mitochondria and highlight the potential application of these medications to treat both T2DM and cardiovascular diseases.     

Antibacterial Activity of Alanine-Derived Gemini Quaternary Ammonium Compounds

The antibacterial activity of alanine-derived gemini quaternary ammonium salts (chlorides and bromides) with various spacer and alkyl chain lengths was investigated. The studied compounds exhibited a strong bactericidal effect, especially bromides with 10 and 12 carbon alkyl chains and 3 carbon spacer groups (TMPAL-10 Br and TMPAL-12 Br), with a short contact time. Both salts dislodged biofilms of Pseudomonas aeruginosa and Staphylococcus epidermidis, and were lethal to adherent cells of S. epidermidis. Bromide with 2 carbon spacer groups and 12 carbon alkyl chains (TMEAL-12 Br) effectively reduced microbial adhesion by coating polystyrene and silicone surfaces. The results obtained suggest that, after further studies, gemini QAS might be considered as antimicrobial agents in medicine or industry.     

Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells

Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR⁺. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2-nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches.     

The Antibacterial Drug Candidate SBC3 is a Potent Inhibitor of Bacterial Thioredoxin Reductase

Antibiotic resistance is a growing problem for public health and associated with increasing economic costs and mortality rates. Silver and silver-related compounds have been used for centuries due to their antimicrobial properties. In this work, we show that 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate/NHC*-Ag-OAc (SBC3) is a reversible, high affinity inhibitor of E. coli thioredoxin reductase (TrxR; K_i=10.8±1.2 nM). Minimal inhibition concentration (MIC) tests with different E. coli and P. aeruginosa strains demonstrated that SBC3 can efficiently inhibit bacterial cell growth, especially in combination with established antibiotics like gentamicin. Our results show that SBC3 is a promising antibiotic drug candidate targeting bacterial TrxR.     

Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer’s disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide–π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition.     

LSD1小分子抑制剂的合成及抗肿瘤活性研究

设计并合成了一系列以苯甲酰肼类结构为母核的赖氨酸特异性组蛋白去甲基化酶1(LSD1)小分子抑制剂,并研究其体外抗肿瘤活性。首先,通过体外酶水平单浓度抑制实验进行了初步评价,并随后进一步考察目标化合物对多种LSD1高表达肿瘤细胞株增殖的抑制作用,化合物结构经质谱及核磁共振表征确证。活性评价结果显示,3-(((3R,5S)-3,5-二甲基吗啉代)磺酰基)-N'-(7-羟基-2,3-二氢-1H-茚-1-亚基)苯甲酰肼、N'-(1-(5-氯-2-羟基苯基)亚乙基)-3-(((3R,5S)-3,5-二甲基吗啉代)磺酰基)苯甲酰肼和N'-(4-氯-7-羟基-2,3-二氢-1H-茚-1-亚基)-3-((4-吗啉代哌啶-1-基)磺酰基)苯甲酰肼可显著抑制肿瘤细胞的增殖,并有4个目标化合物对体外多种LSD1高表达的肿瘤细胞株增殖有抑制作用,其中3-(((3R,5S)-3,5-二甲基吗啉代)磺酰基)-N'-(7-羟基-2,3-二氢-1H-茚-1-亚基)苯甲酰肼对BGC823、HCT116、A2780s的半数抑制浓度分别为0.32、0.54、0.90μmol/L。     

Structurally Refined β‐Lactones as Potent Inhibitors of Devastating Bacterial Virulence Factors

Disarmed forces : Inhibition of the central virulence regulator ClpP by structurally refined β‐lactones resulted in dramatically reduced production of devastating virulence factors, including pyrogenic toxin superantigens derived from pathogenic multiresistant Staphylococcus aureus strains. Targeting of this virulence regulator could present an attractive strategy for neutralizing the harmful effects of bacterial pathogens, and help the host immune response to eliminate the disarmed bacteria.

     

杀菌防腐剂聚六亚甲基胍的合成工艺优化及活性测试

文章采用盐酸胍与己二胺熔融缩聚法合成聚六亚甲基胍盐酸盐,采用单因素法对合成工艺进行了优化。最佳工艺条件为:盐酸胍与己二胺投料摩尔比为0.95∶1.0,反应温度160~180℃,反应时间为6小时。优化后的工艺解决了产品色泽、残留的问题,符合环保要求,适用于工业化生产。对聚六亚甲基胍盐酸盐进行理化性能检测、抑菌活性、毒理活性等测试。     

Identification of NLRP3PYD Homo-Oligomerization Inhibitors with Anti-Inflammatory Activity

Inflammasomes are multiprotein complexes that represent critical elements of the inflammatory response. The dysregulation of the best-characterized complex, the NLRP3 inflammasome, has been linked to the pathogenesis of diseases such as multiple sclerosis, type 2 diabetes mellitus, Alzheimer’s disease, and cancer. While there exist molecular inhibitors specific for the various components of inflammasome complexes, no currently reported inhibitors specifically target NLRP3^PYD homo-oligomerization. In the present study, we describe the identification of QM380 and QM381 as NLRP3^PYD homo-oligomerization inhibitors after screening small molecules from the MyriaScreen library using a split-luciferase complementation assay. Our results demonstrate that these NLRP3^PYD inhibitors interfere with ASC speck formation, inhibit pro-inflammatory cytokine IL1-β release, and decrease pyroptotic cell death. We employed spectroscopic techniques and computational docking analyses with QM380 and QM381 and the PYD domain to confirm the experimental results and predict possible mechanisms underlying the inhibition of NLRP3^PYD homo-interactions.