New Tetraphenylethylene Benzoic Acid Derivatives as Antibacterial Agents for Gram-Positive Bacteria with Ultralow Inhibition Concentration.

Amphipathic benzoic acid derivatives: Synthesis and binding in the hydrophobic tunnel of the zinc deacetylase LpxC

Characterization of a renal medium chain acyl–CoA synthetase responsible for glycine conjugation in mouse kidney mitochondria

Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, trans-sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic acid derivatives as trans-sialidase (TS) inhibitors and anti-trypanosomal agents. Three compounds (14, 18, and 19) sharing a para-aminobenzoic acid moiety showed more potent trypanocidal activity than the commercially available drugs nifurtimox and benznidazole in both strains: the lysis concentration of 50% of the population (LC50) was <0.15 µM on the NINOA strain, and LC50 < 0.22 µM on the INC-5 strain. Additionally, compound 18 showed a moderate inhibition (47%) on the trans-sialidase enzyme and a binding model similar to DANA (pattern A).

Control of the work function of GaAs single crystals, under ambient conditions, was achieved by chemisorption of a series of benzoic acid derivatives with varying dipole moments. Quantitative Fourier transform infrared spectroscopy shows that the benzoic acid derivatives bind as carboxylates, via coordination to oxidized Ga or As atoms, with a surface coverage of about one layer and a binding constant of 2.1 104 M-1 for benzoic acid. Contact potential difference measurements reveal that molecules affect the work function by changing the electron affinity while band bending is not affected significantly. The direction of the electron affinity changes depends on the direction of the dipole moments, and the extent of the change increases linearly with the dipole's magnitude. Investigation of the surface composition by X-ray photoelectron spectroscopy shows that the etched surface, onto which the molecules adsorb, is covered by an oxide layer. This may prevent the molecules from affecting band bending.

Participation of a medium chain acyl-CoA synthetase in glycine conjugation of the benzoic acid derivatives with the electron-donating groups

We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.

The effects of a series of benzoic acid derivatives (ASA analogs) on prostacyclin (PGI2) synthesis by rabbit aorta rings and on human platelet function were examined to determine if antiplatelet activity could be separated from anti-PGI2 activity.Rings of rabbit aorta were incubated with or without drugs in Tris 0.05 M, pH 7.5 for 6 m at room temperature (R.T.). Supernatant was then transferred to platelet-rich plasma incubated at 37°C for 3 m. ADP was added 60 s later and aggregation was measured and compared to controls. Rings were also incubated with 14C-arachidonic acid (14C-AA) for 60 m at R.T. in Tris with or without drugs. Products were extracted and measured by radio-T.L.C. along with known standards. Platelet aggregation and release of ATP were measured using a ChronoLog Lumi aggregometer. The effects of these agents on PGI2 activity were similar to their effects on platelet aggregation. ASA however did not exhibit the marked inhibitory potency that it had on the second phase of platelet aggregation and ATP release. Changing the 2-acetoxy group of A.S.A. to a 2-acetyl or 3-propionyloxy resulted in a loss of inhibitory activity in both systems. 2-Propionyloxy substitution resulted in a similar spectrum of activity to ASA. The effects of these agents on the metabolism of 14C-AA by rabbit aorta rings generally confirmed the bioassay results although some of the agents had novel effects on blood vessel arachidonic acid metabolism.Despite potential species differences, this study demonstrates an inability to separate antiplatelet and anti-PGI2 effects with this series of benzoic acid derivatives. Further study of the effects of these agents on the metabolism of 14C-AA by rings of rabbit aorta may lead to a better understanding of PGI2 formation.

Soft-tissue bacterial infection can progress to severe sepsis and septic shock as a result of a disproportionate inflammatory response, characterized by an excessive release of cytokines and influx of immune cells. Reltecimod (previously known as AB103 or p2TA), a peptide derived from the T-cell receptor CD28, modulates the host immune response by targeting the co-stimulatory pathway, which is essential for the induction of multiple pro-inflammatory cytokines. Consequently, reltecimod has demonstrated beneficial effects against different bacterial infections, their exotoxins and endotoxins, and ionizing radiation. The dosing regimen of reltecimod was evaluated in three mouse models of infection. The effect of the number of reltecimod doses with respect to survival, cytokine/chemokine levels, and blood leukocyte profiles was assessed. Overall, mice treated with a single intravenous dose of reltecimod (5 mg/kg) at 1–2 h after infection showed significantly greater survival as compared with saline-treated controls. Mice treated with a second doses demonstrated improved survival compared with saline-treated controls. However, in all models of infection, administration of a single therapeutic dose of reltecimod was superior to two or multiple doses. Further examination showed that the single therapeutic dose of reltecimod was associated with an early (within 24 h) decrease in cytokine/chemokine levels and most circulating leukocyte subpopulations. A second dose of reltecimod did not improve these early positive effects and appeared to attenuate further changes. These results provided insight into the mechanism of action of reltecimod and established a basis for the dosing regimen utilized in clinical trials, where reltecimod is administered as a single dose.

Substituent effect on the oxidation peak potentials of phenol derivatives at ordered mesoporous carbons modified electrode and its application in determination of acidity coefficients (pKa)

Infectious diseases caused by pathogenic bacteria seriously threaten human lives. Although antibiotic therapy is effective in the treatment of bacterial infections, the overuse of antibiotics has led to an increased risk of antibiotic resistance, putting forward urgent requirements for novel antibacterial drugs. Traditional Chinese herbal medicine (TCHM) and its constituents are considered to be potential sources of new antimicrobial agents. Currently, a series of chemical compounds purified from TCHM have been reported to fight against infections by drug-resistant bacteria. In this review, we summarized the recent findings on TCHM-derived compounds treating drug-resistant bacterial infections. Further studies are still needed for the discovery of potential antibacterial components from TCHM.

Linezolid (ZYVOX), a novel synthesized antibacterial drug, was first approved in April 2001, as an antibacterial against vancomycin (VCM)--resistant enterococci in Japan. LZD has a wide spectrum of antibacterial activity against gram-positive bacteria with MIC90 of 0.5-4 mcg/mL. These antibacterial activities of LZD are similar to those of vancomycin (VCM). LZD also has similar antibacterial activities against drug-resistant bacteria including VRE and MRSA. Protein-synthesis inhibitors, e.g., macrolides, tetracycline, aminoglycosides, and chloramphenicol, are known to bind the 30S and 50S subunits of ribosomes and inhibit the elongation cycle of protein synthesis. In contrast, LZD was found to inhibit the process of formation of the 50S, 30S-mRNA, and fMet-tRNA complex in the ribosome cycle, but not the elongation cycle. Due to this novel mechanism of action, LZD does not have a cross-resistance to drug-resistant bacteria and development of its resistance is quite slow. The antibacterial activity of LZD against VRE is bacteriostatic. In vivo antibacterial activity of orally administered LZD was demonstrated in a mouse model of systemic infection by VRE. When administered orally prior to the abscess formation in a mouse model of soft tissue infection by VRE, LZD showed similar antibacterial activity against VRE infection to that against VCM-susceptible enterococci. LZD is rapidly absorbed following oral administration and bioavailability when compared with intravenous administration is almost 100%. LZD administered orally twice-daily showed excellent efficacy in clinical trials with VRE-infected patients.

Emerging Designs of Aggregation-Induced Emission Agents for Enhanced Phototherapy Applications

Fatty acid conjugated pyridinium cationic amphiphiles as antibacterial agents and self-assembling nano carriers

Bacterial resistance has become increasingly serious because of the widespread use and abuse of antibiotics. In particular, the emergence of multidrug-resistant bacteria has posed a serious threat to human public health and attracted the attention of the World Health Organization (WHO) and the governments of various countries. Therefore, the establishment of measures against bacterial resistance and the discovery of new antibacterial drugs are increasingly urgent to better contain the emergence of bacterial resistance and provide a reference for the development of new antibacterial drugs. In this review, we discuss some antibiotic drugs that have been approved for clinical use and a partial summary of the meaningful research results of anti-drug resistant bacterial drugs in different fields, including the antibiotic drugs approved by the FDA from 2015 to 2020, the potential drugs against drug-resistant bacteria, the new molecules synthesized by chemical modification, combination therapy, drug repurposing, immunotherapy and other therapies.

The emergence and spread of highly pathogenic avian influenza (H5N1) viruses among poultry in Asia, the Middle East, and Africa have fueled concerns of a possible human pandemic, and spurred efforts towards developing vaccines against H5N1 influenza viruses, as well as improving vaccine production methods. In recent years, promising experimental reverse genetics-derived H5N1 live attenuated vaccines have been generated and characterized, including vaccines that are attenuated through temperature-sensitive mutation, modulation of the interferon antagonist protein, or disruption of the M2 protein. Live attenuated influenza virus vaccines based on each of these modalities have conferred protection against homologous and heterologous challenge in animal models of influenza virus infection. Alternative vaccine strategies that do not require the use of live virus, such as virus-like particle (VLP) and DNA-based vaccines, have also been vigorously pursued in recent years. Studies have demonstrated that influenza VLP vaccination can confer homologous and heterologous protection from lethal challenge in a mouse model of infection. There have also been improvements in the formulation and production of vaccines following concerns over the threat of H5N1 influenza viruses. The use of novel substrates for the growth of vaccine virus stocks has been intensively researched in recent years, and several candidate cell culture-based systems for vaccine amplification have emerged, including production systems based on Madin-Darby canine kidney, Vero, and PerC6 cell lines. Such systems promise increased scalability of product, and reduced reliance on embryonated chicken eggs as a growth substrate. Studies into the use of adjuvants have shown that oil-in-water-based adjuvants can improve the immunogenicity of inactivated influenza vaccines and conserve antigen in such formulations. Finally, efforts to develop more broadly cross-protective immunization strategies through the inclusion of conserved influenza virus antigens in vaccines have led to experimental vaccines based on the influenza hemagglutinin (HA) stem domain. Such vaccines have been shown to confer protection from lethal challenge in mouse models of influenza virus infection. Through further development, vaccines based on the HA stem have the potential to protect vaccinated individuals against unanticipated pandemic and epidemic influenza virus strains. Overall, recent advances in experimental vaccines and in vaccine production processes provide the potential to lower mortality and morbidity resulting from influenza infection.