The Study of Mixing Purple Sweet Potato and Turmeric Extract as Green Corrosion Inhibitor for API-5L in NaCl 3,5% Environment

Green inhibitors have become a major option for corrosion prevention since people are more aware of environmental damage. It is true that chemical inhibitors are more powerful at preventing corrosion, but its side effects are very harmful to the environment. Purple sweet potato (Ipomoea batatas L) in single use has been proven as an active inhibitor for certain applications. To improve this property, purple sweet potato is used as a mixed with other plants that contain antioxidant agents, such as ginger, melinjo, turmeric, jeera, etc. This paper discussed the effect of applying mixed extract of purple sweet potato with turmeric (Curcuma longa) as a green inhibitor to corrosion rate of API 5L steel in a 3.5% NaCl environment. Turmeric extract contains curcumin and kaempferol antioxidants while purple sweet potato extract contains antocyanin antioxidants. Corrosion rates were analyzed based on weight loss and polarization methods. The results showed the highest inhibitor efficiency was 82.54% achieved by 16 ml of turmeric mixed with 2 ml of purple sweet potato, and the optimum inhibitor efficiency was 74.2% achieved by 8 ml of turmeric mixed with 6 ml of purple sweet potato.

Click Synthesis, Anticancer Activity, and Molecular Docking Investigation of some Functional 1,2,3-triazole Derivatives

1,2,3-triazole skeleton is a privileged building block for the discovery of new promising anticancer agents. In this report, new 1,4-disubstituted 1,2,3-triazoles with the bioisoster triazole moiety were straightforwardly prepared under copper-catalyzed azide-alkyne [3+2] cycloaddition reactions (CuAAC) regime using a variety of both functional organic azides and terminal alkynes. The resulting functional 1,4-disubstituted 1,2,3-triazole compounds were fully characterized and subsequently tested for their antiproliferative activity against four different cancer cell lines. The cytotoxicity tests carried out with these 1,2,3-triazole derivatives show average IC50 values ranging from 15 to 50 µM by comparison with the standard reference drug, namely doxorubicin. The phosphonate 1,2,3-triazole derivative was found to exhibit the best antiproliferative activity among the studied compounds against the HT-1080 cell lines. It was chosen to evaluate its mode of action in these cancer cell lines. The cell cycle study showed that the phosphonate derivative, compound 8, is the most active inhibitor of the cell cycle at the G0/G1 phase, inducing apoptosis independently of Caspase-3 and causing an increase in the mitochondrial membrane potential (ΔΨm) in the HT-1080 cell lines. Molecular docking studies of this phosphonate derivative into the MMP-2 and MMP-9 metalloproteinases receptors demonstrated the relevance of triazole scaffolds and the pendant phosphonate group in establishing -anion, -alkyl and hydrogen bonding type interactions with residual components in the active MMP pocket.

Synthesis of Sulfanoquinoxaline-2,3-Dione Hydrazones Derivatives as a Selective Inhibitor for Acetylcholinesterase and Butyryl Cholinesterase

Some Sulfanoquinoxaline-2,3-diones hydrazone derivatives (1-8) were synthesized from the reactions of 2,3-dioxoquinoxaline-6-sulfonohydrazine with seven substituted benzaldehydes and acetophenone. All the synthesized compounds were biologically evaluated against cholinesterase’s (acetylcholinesterase and butyryl cholinesterase). Compounds 1-8 were found to be a good selective inhibitor for acetylcholinesterase and butyryl cholinesterase. Among the series, compounds 3 (IC50 = 75 ± 10 µg/mL) and 5 (IC50 = 80 ± 10 µg/mL) were found to be the most active inhibitors against acetylcholinesterase, while compounds 6 (IC50 = 110 ± 10 µg/mL), 8 (IC50 = 130 ± 10 µg/mL) and 7 (IC50 = 150 ± 10 µg/mL), were found to be most active inhibitor against butyryl cholinesterase. The IC50 values for all the synthesized compounds were lower than standard, eserine (IC50 = 70 ± 20 µg/mL). Their considerable acetylcholinesterase and butyryl cholinesterase inhibitory activities make them a good candidate for the development of selective acetylcholinesterase and butyryl cholinesterase inhibitors.

Synthesis of Some Phenylisoindoline-1,3-Diones and their Acetylcholinesterase and Butyryl Cholinesterase Inhibitory Activities

Aims: To synthesize some phthalimides derivatives and evaluate the compounds for their possible biological properties. Methods: The substituted phenylisoindoline-1,3-dione were synthesized from the reactions of N-phenyl phthalimide with different substituted aromatic aldehyde. The synthesized compounds were characterized using nuclear magnetic resonance spectroscopic analysis. The acetylcholinesterase and butyryl cholinesterase inhibitions were determined by Spectro photochemical analysis of acetylthiocholine and butyryl choline chloride. Results: Compounds 6 (IC50 = 30±3 µg/mL) and 4 (IC50 = 141±60 µg/mL) were found to be the most active inhibitors against acetylcholinesterase, while compounds 4 (IC50 = 102±10 µg/mL), 5 (IC50 = 105 ± 20 µg/mL) and 2 (IC50 = 190 ± 10 µg/mL), were found to be most active inhibitor against butyryl cholinesterase. Conclusion: The considerable acetylcholinesterase and butyryl cholinesterase inhibitory activities of the synthesized compounds makes them good candidates for the development of selective acetylcholinesterase and butyryl cholinesterase inhibitors.

Association of Hemophilia a Inhibitor Status and Patient-Reported Outcomes with Work Productivity and Health-Related Quality of Life

Introduction: Persons with hemophilia suffer from recurrent bleeds, especially hemarthrosis, which results in joint damage. Hemophilia inhibitor status impacts bleeding, which is associated with acute and chronic pain. To better characterize the impact of inhibitor status, we compared patient-reported outcomes (bleed rate, pain, and joint health), work productivity and activity impairment (WPAI), and health-related quality of life (HRQoL) by inhibitor status, and investigated the correlation of patient-reported outcomes with WPAI and HRQoL. Methods: The U.S. Hematology Utilization Group Studies Part VIII prospectively collected data to examine the cost and burden of hemophilia in persons with hemophilia A (PwHA) aged ≥2 years obtaining care at four federally-supported hemophilia treatment centers. From April 2019 to May 2021 we enrolled PwHA with and without inhibitors at a 1:2 ratio. Parents/adult participants completed a survey at enrollment to collect sociodemographic and clinical characteristics, self-reported bleeds in the last month, pain, and joint stiffness (5-item scale). We also measured WPAI and HRQoL using EQ-5D-3L. Clinical chart review documented hemophilic severity, inhibitor level and treatment regimen. Participants were classified into three groups: 1) active inhibitor (inhibitor titer ≥1.0 Bethesda Units (BU) six months prior to enrollment), 2) tolerized inhibitor (history of inhibitor titer ≥1.0 BU, immune tolerance induction (ITI) and/or currently using factor VIII for prophylaxis), and 3) no inhibitor. Patient-reported data were compared across these groups using Chi-square tests for categorical variables and generalized linear models for continuous variables. Association of bleeds, pain, and joint stiffness with HRQoL and WPAI were assessed using Pearson correlation. Results: Among 80 PwHA enrolled, 9 (11%) had active inhibitors, 22 (27.5%) had tolerized inhibitors, and 49 (61.3%) had no inhibitors. Mean age was 24.9±14.3 (standard deviation) years, 66.3% were adults, 87.5% had severe hemophilia, and 87.5% used prophylaxis. Mean age of the non-inhibitor group (29.3±13.5) was older than the tolerized inhibitor group (16.3±9.5 years, p<0.05) or the active inhibitor group (21.9±19.1, p>0.05). The non-inhibitor group had a lower rate of severe hemophilia (81.6%) or prophylactic treatment (81.6%) than those in the active (100%) or tolerized groups (95.5%, p=0.13). Larger proportions of participants with active inhibitors (66.7%) and no inhibitors (57.1%) reported having bleeds in the last month compared to those with tolerized inhibitors (22.7%, p=0.01). Participants without inhibitors had a greater mean number of bleeding episodes (1.09±standard error (SE) 0.26 vs. 0.23±0.38, p=0.03), specifically joint bleeds (0.58±0.16 vs. 0.08±0.24, p=0.03,) than the tolerized group. Those with active inhibitors reported significantly higher mean joint stiffness scores (35.1±2.6 vs. 27.5±1.9, p=0.006) or more joint pain (77.8% vs. 54.5%, p=0.23) than the tolerized group. Mean EQ-5D index score was significantly lower in the active inhibitor group (0.79±SE (0.07) than in the tolerized group (0.96±0.05, p=0.03). Joint bleeding, chronic pain, and joint stiffness were negatively correlated with the EQ-5D visual analogue scale, and index scores (all correlation coefficients |r|>0.43, all p<0.001). Number of bleeds and the joint stiffness score in children were positively correlated with their parents' level of impairment while working (r=0.41, p=0.04; r=0.62, p=0.001) and overall work impairment (r=0.41, p=0.046; r=0.60, p=0.002). Joint bleeding, chronic pain, and joint stiffness in adults were positively correlated with proportion of work time missed (r=0.31, p=0.03; r=0.39, p=0.006; r=0.48, p=0.0004), overall work impairment (r=0.37, p=0.007; r=0.41, p=0.003; r=0.42, p=0.002), and activity impairment (r=0.33, p=0.02; r=0.63, p<0.0001; r=0.59, p<0.0001), respectively. Conclusions: This study is limited to a small sample skewed toward a younger age in the tolerized inhibitor group. PwHA in the active and no inhibitor groups experienced greater clinical burden as measured by bleeds compared to the tolerized group. Those with active inhibitor displayed lower HRQoL scores than the tolerized inhibitor group. Bleeds, chronic pain and joint stiffness were inversely correlated with HRQoL, resulting in lower work productivity and activity. Figure 1 Figure 1. Disclosures Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Khairnar: University of Maryland, Baltimore: Ended employment in the past 24 months; Roche: Current equity holder in publicly-traded company; Genentech Inc - A Member of The Roche Group: Current Employment. Decker-Palmer: Genentech Inc. --A member of the Roche Group.: Current Employment, Current equity holder in publicly-traded company. Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy; University of Southern California: Consultancy. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

1293. In vitro Activity of Ceftibuten in Combination with VNRX-5236 against Clinical Isolates of Enterobacterales from Urinary Tract Infections Collected in 2018-2020

Background Increasing resistance among agents commonly prescribed to treat urinary tract infections indicate that new oral agents are urgently needed. Ceftibuten in combination with VNRX-7145 is under development as an oral treatment for complicated urinary tract infections caused by serine β-lactamase-producing Enterobacterales, including isolates carrying ESBLs and carbapenemases. In vivo, VNRX-7145 (VNRX-5236 etzadroxil) is cleaved into to the active inhibitor, VNRX-5236. This study assessed the in vitro activity of ceftibuten/VNRX-5236 against 592 isolates of Enterobacterales from urinary tract infections (UTIs) from a 2018-2020 global culture collection. Methods MICs of ceftibuten with VNRX-5236 fixed at 4 µg/mL and comparators were determined following CLSI M07-A11 guidelines against 592 Enterobacterales. Isolates were from community and hospital UTI infections collected from 133 sites in 31 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints. Results A substantial percentage of isolates were non-susceptible to extended-spectrum β-lactams, levofloxacin (LVX), trimethoprim-sulfamethoxazole (SXT), and amoxicillin-clavulanate (AMC) (Table). The addition of VNRX-5236 reduced ceftibuten MIC90 values by ≥8-fold to ≥128-fold, depending on the resistant subset. Ceftibuten/VNRX-5236 had potent activity against all Enterobacterales, with MIC50/90 values of 0.06/0.25 µg/mL and 98.3% inhibited at ≤2 µg/mL. Ceftibuten/VNRX-5236 maintained activity against resistant subsets (MIC90 range, 0.5 to 2 µg/mL; 91.5% to 97.1% inhibited at ≤2 µg/mL), including serine carbapenemase-positive isolates (MIC90 0.5 µg/mL; 100% inhibited at ≤1 µg/mL). Ceftibuten/VNRX-5236 in vitro potency was similar to that of newer parenteral and investigational oral therapies. Results Table Conclusion Ceftibuten/VNRX-5236 exhibited promising in vitro activity against recent Enterobacterales from UTIs, and may have potential as an oral treatment option for complicated urinary tract infections, including those caused by serine β-lactamase-expressing Enterobacterales (ESBL, KPC, OXA-48/OXA-48-like) for which there are currently few oral treatment options available. Disclosures Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Mark G G. Wise, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

In Vitro Activity of Ceftibuten/VNRX-5236 against Urinary Tract Infection Isolates of Antimicrobial-Resistant Enterobacterales

Ceftibuten/VNRX-7145 is a cephalosporin/boronate β-lactamase inhibitor combination under development as an oral treatment for complicated urinary tract infections caused by Enterobacterales producing serine β-lactamases (Ambler class A, C and D). In vivo , VNRX-7145 (VNRX-5236 etzadroxil) is cleaved to the active inhibitor, VNRX-5236. We assessed the in vitro activity of ceftibuten/VNRX-5236 against 1,066 urinary isolates of Enterobacterales from a 2014-2016 global culture collection. Each isolate tested was pre-selected to possess a multidrug-resistant (MDR) phenotype that included non-susceptibility to amoxicillin-clavulanate and resistance to levofloxacin. MICs were determined by CLSI broth microdilution. VNRX-5236 was tested at a fixed concentration of 4 μg/ml. Ceftibuten/VNRX-5236 inhibited 90% of all isolates tested (MIC 90 ) at 2 μg/ml; MIC 90 s for ESBL- ( n =566), serine carbapenemase- ( n =116), and acquired AmpC-positive ( n =58) isolate subsets were ≤0.25, >32, and 8 μg/ml, respectively. At concentrations of ≤1, ≤2, and ≤4 μg/ml, ceftibuten/VNRX-5236 inhibited 89.1, 91.7, and 93.1% of all isolates tested; 96.5, 97.7, and 98.4% of ESBL-positive isolates; 75.9, 81.9, and 81.9% of serine carbapenemase-positive isolates; and 70.7, 81.0, and 87.9% of acquired AmpC-positive isolates. Ceftibuten/VNRX-5236 at concentrations of ≤1, ≤2, and ≤4 μg/ml inhibited 85-89, 89-91, and 91-92% of isolates that were not susceptible (defined by CLSI and EUCAST breakpoint criteria) to nitrofurantoin, trimethoprim-sulfamethoxazole, and/or fosfomycin, (as part of their MDR phenotype), oral agents commonly prescribed to treat uncomplicated urinary tract infections. The potency of ceftibuten/VNRX-5236 (MIC 90 , 2 μg/ml) was similar (within one doubling-dilution) to intravenous-only agents ceftazidime-avibactam (MIC 90 2 μg/ml) and meropenem-vaborbactam (MIC 90 1 μg/ml). Continued investigation of ceftibuten/VNRX-5236 is warranted.

Investigation of Molecular Modeling And Molecular Dynamics Simulation In BRCA-1 And BRCA-2 Genes of Amygdalin Ligand

Breast cancer is the most common type of cancer and the most fatal type among women. BRCA-1 and BRCA-2 are tumor suppressor genes known to cause breast cancer. Drug studies have become very important to target the production of more accurate drugs by reducing the cost with the previous designs of drugs in this field. Amygdalin is used in the treatment of especially cancer, characterized by the loss of red blood cell production. In this study, which was conducted for the first time, it was aimed to examine the use of amygdalin in breast cancer treatment by coupling to the active regions of BRCA-1 and BRCA-2 genes by molecular docking method. The best attachment scores were selected. Amygdalin was taken from PubChem database in sdf format. According to the molecular insertion results, the free energy of the amygdalin ligand for binding to the BRCA-1 protein was -4.8 kcal/mol and the free energy for binding to the BRCA-2 protein was -7.2 kcal/mol also include Ki values. MD simulation was performed using Desmond. Insertion results show that the amygdalin ligand binds more strongly to the BRCA-2 protein than to the BRCA-1 protein. MD simulation for the highly active inhibitor Amigydalin in complex with protein BRCA-2 revealed that the stabilization of ligand was achieved due to the formation of uninterrupted hydrophobic interactions. Due to the binding power of amygdalin ligand, it reveals a unique structure for breast cancer and it is thought to be a reference for designing new molecules with the same structure against cancer and applying these molecules in vivo and in vitro studies.

Optimization and Validation of an In Vitro Standardized Glycogen Phosphorylase Activity Assay

Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway and a potential therapeutic target in the management of type 2 diabetes. It catalyzes a reversible reaction: the release of the terminal glucosyl residue from glycogen as glucose 1-phosphate; or the transfer of glucose from glucose 1-phosphate to glycogen. A colorimetric method to follow in vitro the activity of GP with usefulness in structure-activity relationship studies and high-throughput screening capability is herein described. The obtained results allowed the choice of the optimal concentration of enzyme of 0.38 U/mL, 0.25 mM glucose 1-phosphate, 0.25 mg/mL glycogen, and temperature of 37 °C. Three known GP inhibitors, CP-91149, a synthetic inhibitor, caffeine, an alkaloid, and ellagic acid, a polyphenol, were used to validate the method, CP-91149 being the most active inhibitor. The effect of glucose on the IC50 value of CP-91149 was also investigated, which decreased when the concentration of glucose increased. The assay parameters for a high-throughput screening method for discovery of new potential GP inhibitors were optimized and standardized, which is desirable for the reproducibility and comparison of results in the literature. The optimized method can be applied to the study of a panel of synthetic and/or natural compounds, such as polyphenols.

Anti-Quorum Sensing and Antioxidant Activity of Essential Oils Extracted From Juniperus Species, Growing Spontaneously in Tebessa Region (East of Algeria)

The chemical composition of essential oils (EOs) extracted from the aerial parts of 2 species of Juniperus was determined by Gas Chromatography-Mass Spectrometry (GC-MS). In total, 65 and 58 compounds accounting for 90.3% and 89.8% of the whole chemical composition of Juniperus oxycedrus (JO) and Juniperus phoenicea (JP) were identified, respectively, with α-pinene, α-amorphene, terpinen-4-ol, α-terpinene, and β-elemene, as major components. For the first time, the capacity to inhibit quorum-sensing for Chromobacterium violaceum CV026 and CV12472 by the investigated EOs was evaluated. Both oils exhibited good violacein inhibition on CV12472 with 100.0 ± 0.0% inhibition at minimal inhibition concentration (MIC) values. Besides, the quorum-sensing inhibition of CV026 was high at MIC for JO essential oil from fruits (JOF, 16.3 ± 2.0 mm), JO leaves (JOL, 12.5 ± 3.5 mm), JP fruits (JPF, 19.7 ± 2.5 mm), and JP leaves (JPL, 21.1 ± 5.0 mm). On both CV12472 and CV026, essential oil from J. phoenicea leaves was the most active inhibitor. All investigated EOs inhibited swarming motilities in flagellated Pseudomonas aeruginosa (PA01) in a concentration-dependent manner, and those from JP were more active than EOs from JO. Moreover, these EOs showed good antioxidant potential according to DPPH● and FRAP methods, especially the EO from JO leaves with an IC50 DPPH● inhibition value of 20.2 ± 1.0 mg/mL. Based on the obtained results, the investigated EOs are good candidates to combat microbial resistance be used as alternatives to conventional antibiotics, and equally find applications in food biosafety as preservatives.