Quinoxaline: A chemical moiety with spectrum of interesting biological activities

: Quinoxaline (C8H6N2), commonly called 1,4-diazanaphthalene, 1,4-benzodiazine, or benzopyrazine, is a very potent nitrogenous heterocyclic moiety consisting of a benzene ring fused with the pyrazine ring. A number of different methods for the synthesis of quinoxaline derivatives have been reported in the literature, but the most effective method, commonly used for the synthesis of quinoxaline analogues involves the condensation of substituted o-phenylenediamines with 1, 2- dicarbonyl compounds in the presence of different catalyst(s). The presence of different types of catalysts and their concentration affects the overall yield of the product. Quinoxaline not only plays an important role as an organic reaction intermediate but also has a wide spectrum of interesting biological activities viz. antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal activity, etc. Some commercially available drug molecules containing quinoxaline moiety are echinomycin (as antibacterial, antineoplastic, and nucleic acid inhibitor), triostins (cyclic desipeptide as an antibacterial agent), dioxidine and mequindox (as antibacterial agents), carbadox (controlling swine dysentery), desoxycarbadox (as swine growth promoter) and panadipion (as hepatoprotective agent), etc. A large number of quinoxaline analogues possessing different biological activities and their synthetic procedures have been patented worldwide.

Characteritization of Bio-Oil from Tectona Grandis as a Potential Scale Inhibitor

Calcium carbonate scales cause costly flow assurance problems in flowlines during petroleum production. Previous efforts to mitigate this problem using different chemical inhibitors though successful have resulted in environmental pollution during disposal. This study was designed to investigate the potential of bio-oil synthesized from Tectona grandis as an inhibitor to replace the conventional ones. Tectona grandis was obtained from Ibadan sawmill, Oyo state, Nigeria and characterized using Energy Dispersive X-Ray (EDX) analytical technique. Data generated by EDX analysis showed elemental composition of 78% carbon and 22% of other elements including nitrogen and oxygen. Tectona grandis was pyrolyzed at 5500C, a heating rate of 0.50C/sec, and a running time of 4 hours. 45.1% of the mixture of water and oil were collected and separated into phases in a centrifuge while the gasses were vented. The bio-oil was distilled at 120°C and analyzed using FTIR spectrometry. Spectra analyses showed the presence of -COOH and -CONH2 which are essential in the inhibition of calcium carbonate scale. With the help of a newly fabricated testing-rig system, calcium carbonate scales were formed by mixing equal mole of calcium chloride and sodium carbonate at the temperature range of 25-58°C and flow rates range of 8-15 ml/min, with/without inhibitor from 0, 5 g/l of maleic acid and 5 g/l of newly synthesized inhibitor. The mass of the calcium carbonate and the induction time was measured by the weighing balance and the conductivity meter respectively. For all of the experiments, the presence of maleic acid and newly synthesized inhibitor delayed the induction time by at least 10 mins and reduced the weight of calcium carbonates formed by at least 20%. Also, the mass of calcium carbonate scale formed at all the experiments showed less weight when newly synthesized inhibitor was used compared to when maleic acid inhibitor was used showing the effectiveness of the newly synthesized inhibitor over maleic acid. Therefore, this study shows high promise wood-based distilled oil as a potential calcium carbonate scale inhibitor and provides future direction for further studies.

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.

Ex-vivo Electrochemical pH Mapping of the Gastrointestinal Tract in the Absence and Presence of Pharmacological Agents

<i>Ex-vivo</i> pH profiling of the upper gastrointestinal (GI) tract (of a mouse) in both the absence and presence of pharmacological agents aimed at altering acid/bicarbonate production, is reported using an electrochemical pH probe, for the first time. Three pH electrodes were assessed for suitability using a GI tract biological mimic buffer solution containing 0.5 % mucin. These include a traditional glass pH probe, an iridium oxide (IrOx) coated electrode (both potentiometric) and a quinone (Q) surface-integrated boron doped diamond (BDD-Q) electrode (voltammetric). In mucin the timescale for both IrOx and glass to obtain stable pH readings was in the ~100’s of s, most likely due to mucin adsorption, in contrast to 6 s with the BDD-Q electrode. Both the glass and IrOx pH electrodes were also compromised on robustness due to fragility and delamination (IrOx); contact with the GI tissue was an experimental requirement. BDD-Q was deemed the most appropriate. Ten measurements were made along the GI tract, esophagus (1), stomach (5) and duodenum (4). Under untreated conditions (buffer only), the BDD-Q probe tracked the pH from neutral in the esophagus, to acidic in the stomach and rising to more alkaline in the duodenum. In the presence of omeprazole, a proton pump inhibitor, the body regions of the stomach exhibited elevated pH levels. Under melatonin treatment (a bicarbonate agonist and acid inhibitor), both the body of the stomach and the duodenum showed elevated pH levels. This study demonstrates the versatility of the BDD-Q pH electrode for real-time <i>ex-vivo</i> biological tissue measurements.

Ex-vivo Electrochemical pH Mapping of the Gastrointestinal Tract in the Absence and Presence of Pharmacological Agents

<i>Ex-vivo</i> pH profiling of the upper gastrointestinal (GI) tract (of a mouse) in both the absence and presence of pharmacological agents aimed at altering acid/bicarbonate production, is reported using an electrochemical pH probe, for the first time. Three pH electrodes were assessed for suitability using a GI tract biological mimic buffer solution containing 0.5 % mucin. These include a traditional glass pH probe, an iridium oxide (IrOx) coated electrode (both potentiometric) and a quinone (Q) surface-integrated boron doped diamond (BDD-Q) electrode (voltammetric). In mucin the timescale for both IrOx and glass to obtain stable pH readings was in the ~100’s of s, most likely due to mucin adsorption, in contrast to 6 s with the BDD-Q electrode. Both the glass and IrOx pH electrodes were also compromised on robustness due to fragility and delamination (IrOx); contact with the GI tissue was an experimental requirement. BDD-Q was deemed the most appropriate. Ten measurements were made along the GI tract, esophagus (1), stomach (5) and duodenum (4). Under untreated conditions (buffer only), the BDD-Q probe tracked the pH from neutral in the esophagus, to acidic in the stomach and rising to more alkaline in the duodenum. In the presence of omeprazole, a proton pump inhibitor, the body regions of the stomach exhibited elevated pH levels. Under melatonin treatment (a bicarbonate agonist and acid inhibitor), both the body of the stomach and the duodenum showed elevated pH levels. This study demonstrates the versatility of the BDD-Q pH electrode for real-time <i>ex-vivo</i> biological tissue measurements.

Leveraging peptide substrate libraries to design inhibitors of bacterial Lon protease

Lon is a widely-conserved housekeeping protease found in all domains of life. Bacterial Lon is involved in the recovery from various types of stress, including tolerance to fluoroquinolone antibiotics, and is linked to pathogenesis in a number of organisms. However, detailed functional studies of Lon have been limited by the lack of selective, cell-permeable inhibitors. Here we describe the use of positional scanning libraries of hybrid peptide substrates to profile the primary sequence specificity of bacterial Lon. In addition to identifying optimal natural amino acid binding preferences, we identified several non-natural residues that were leveraged to develop optimal peptide substrates as well as a potent peptidic boronic acid inhibitor of Lon. Treatment ofE. coliwith this inhibitor promotes UV-induced filamentation and reduces tolerance to ciprofloxacin, phenocopying establishedlon-deletion phenotypes. It is also non-toxic to mammalian cells due to its increased selectivity for Lon over the proteasome. Our results provide new insight into the primary substrate specificity of Lon and identify substrates and an inhibitor that will serve as useful tools for dissecting the diverse cellular functions of Lon.