Synthesis of quinoxaline derivatives and their antibacterial activity against pathogenic bacteria

Quinoxaline derivatives, in which nitrogen substitutes for one or more carbon atoms in the naphthalene ring, are a significant class of hetero-cyclic compounds, and are well known in the pharmaceutical industry, and have been shown to possess a broad spectrum of biological activities. These formulations make use of straightforward techniques to create quinoxaline derivatives from aryl-thiols (mercaptan) compounds. Inspired by the biological prominence of quinoxaline derivatives and trying to solve bacterial resistance problems, in this study, 24 quinoxaline derivatives were synthesized. These series were synthesized from the reaction of 2,3-dichloroquinoxaline (2,3-DCQ), 2- chloroquinoxaline (2-CQ), 2-chloro-3-methyl quinoxaline (3-MCQ) with two different aromatic aryl-thiols (mercaptan) and phenols in a single step to investigate the activities aromatic derivatives. The compounds were synthesized using different solvent systems, dimethylformamide (DMF)/ potassium triphosphate (K3PO4), methanol (MeOH)/ triethylamine (Et3N), acetone/ 0.1N sodium hydroxide (NaOH), and dimethylformamide/potassium carbonate (DMF/ K2CO3), depending on the nucleophilicity of the mercaptan compounds. A comparative study was used to compare the efficiency of these solvent systems to synthesize the same target compounds regarding the reaction time, percentage yield, purity of the compounds, and benignity towards the environment. The structures of twenty-four compounds were confirmed by applying spectroscopic analysis (1D and 2D nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), and gas chromatography mass spectrometry (GCMS)). In addition, four different bacteria were used to evaluate the antibacterial efficacy of the compounds (1-15): three Gram-negative (Escherichia coli (E. coli), Salmonella Typhimurium, Enterobacter aerogenes), and Gram-positive (Bacillus Pumilus). To assess a drug's efficacy against a particular bacterial species, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays are frequently performed. The synthesized molecules displayed a better role as antibacterial agents than their analogs. Compounds 8 and 14 have the strongest antibacterial activity for Bacillus pumilus, with an inhibition zone of 10 and 9 mm (MIC ranging at about 5 and 2.5 mg/mL, followed by MBC at 2.5 mg/mL). A similar pattern of antibacterial properties was observed against E. coli. Compounds 1 and 3 have an inhibition zone (IZ) of 7 and 6 mm and MIC of 1.25 and 5 mg/mL, respectively. Similarly, di-substituted derivatives 8, 13, and 14 have the best IZ of 11, 12, and 12 (mm) (MIC of 2.5, 5 and 5 mg/mL, followed by MBC of 2.5, 5 and 2.5 mg/mL). Due to impressive antibacterial properties, the compounds were also studied for their physio-chemical and drug-likeness properties via Swiss ADME software. It was found that molecules 9 and 11 displayed remarkable drug-likeness properties without violating the rules and a bio-availability score of 0.55. Like-wise molecular docking studies provided good interactions between protein and ligands (synthesized compounds). The molecular docking studies were performed on compounds 8, 12, 13, 14, 19 and 21. Compound 12 had the best docking score of -8.60 kcal/mol followed by compound 13 (-8.01 kcal/mol) for DNA gyrase protein. Compounds 12 and 13 are classified as di-substituted quinoxaline derivatives having electron-withdrawing -NO2 and -COOH, which enhanced the formation of Hbonding with amino acids. Compounds 12, 13 and 8 had a similar effect with PBP1a protein (-8.01 kcal/mol for compound 8, -8.16 kcal/mol for compound 12 and -7.97 kcal/mol for compound 13). The reaction conditions for the synthesized compounds were straightforward and produced using SNAr (aromatic nucleophilic substitution reaction) mechanism. Antibacterial assays and docking investigations revealed that the sulfur bridge made the molecule into a powerful antibacterial agent. Two symmetrical sulfur bridges were shown to have increased antibacterial activity, making them a prime option for medication development

A focused review of synthetic applications of Lawesson’s reagent in organic synthesis

Lawesson’s reagent (LR) is a well-known classic example of a compound with unique construction and unusual chemical behavior, with a wide range of applications in synthetic organic chemistry. Its main functions were rounded for the thionation of various carbonyl groups in the early days, with exemplary results. However, the role of Lawesson’s reagent in synthesis has changed drastically, and now its use can help the chemistry community to understand innovative ideas. These include constructing biologically valuable heterocycles, coupling reactions, and the thionation of natural compounds. The ease of availability and the convenient usage of LR as a thionating agent made us compile a review on the new diverse applications on some common functional groups, such as ketones, esters, amides, alcohols, and carboxylic acids, with biological applications. Since the applications of LR are now diverse, we have also included some new classes of heterocycles such as thiazepines, phosphine sulfides, thiophenes, and organothiophosphorus compounds. Thionation of some biologically essential steroids and terpenoids has also been compiled. This review discusses the recent insights into and synthetic applications of this famous reagent from 2009 to January 2021

A Focused Review of Synthetic Applications of Lawesson’s Reagent in Organic Synthesis

Lawesson’s reagent (LR) is a well-known classic example of a compound with unique construction and unusual chemical behavior, with a wide range of applications in synthetic organic chemistry. Its main functions were rounded for the thionation of various carbonyl groups in the early days, with exemplary results. However, the role of Lawesson’s reagent in synthesis has changed drastically, and now its use can help the chemistry community to understand innovative ideas. These include constructing biologically valuable heterocycles, coupling reactions, and the thionation of natural compounds. The ease of availability and the convenient usage of LR as a thionating agent made us compile a review on the new diverse applications on some common functional groups, such as ketones, esters, amides, alcohols, and carboxylic acids, with biological applications. Since the applications of LR are now diverse, we have also included some new classes of heterocycles such as thiazepines, phosphine sulfides, thiophenes, and organothiophosphorus compounds. Thionation of some biologically essential steroids and terpenoids has also been compiled. This review discusses the recent insights into and synthetic applications of this famous reagent from 2009 to January 2021

Optimizing reaction efficiency: Microwave-supported synthesis of quinoxaline-based compounds

The chemistry of chloroquinoxalines has garnered significant interest owing to the potential applications of this nitrogen-containing heterocyclic class in various fields. This manuscript delves into the investigation of heteroaromatic nucleophilic substitution reactions (SNAr) involving quinoxaline substrates, specifically 2-chloroquinoxaline and 2-chloro-3-methylquinoxaline, in the presence of thiols (mercaptan). The documented findings present the outcome of these reactions, which proceed experimentally under mild and metal-free conditions and lead to the selective formation of mono- and di-substituted products with commendable yields. Employing microwave-assisted synthesis for the preparation of compounds 1, 4, and 5 was crucial for optimizing reaction efficiency and maximizing product formation. The experimental findings revealed an increase in the overall yield of compounds 1, 4, and 5 by approximately 15–20%, accompanied by a significant reduction in reaction time by 75%

Synthesis of quinoxaline derivatives using different solvent systems, their potent antibacterial activities and molecular docking

In this study, a new series of quinoxaline derivatives were synthesized by the reaction of 2,3-dichloroquinoxaline with aromatic thiols, leading to the formation of 2,3-bis(arylthiol)quinoxaline, 4-chloro-12H-quinoxalino[2,3-b]1,4-benzothiazine and 5-nitro-1H-benzo[d]imidazole-2-thiol in good to excellent yields. The synthesized quinoxaline derivatives were structurally characterized using infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), elemental analysis and mass spectrometry. Their drug-like properties were evaluated using SwissADME. With the exception of compound 6, all compounds showed significant bioavailability predictions and were subsequently evaluated for their antibacterial activity. The results of the antimicrobial assays showed that the 2,3-bis(arylthiol)quinoxalines exhibited superior inhibitory activity compared to the other synthesized compounds. Further validation was provided by protein-ligand interaction studies using docking analysis. All compounds showed favourable docking values between −7.45 and −8.60 kcal/mol against DNA gyrase subunit B (DNAG) and −7.43 to −8.16 kcal/mol against penicillin-binding protein 1a (PBP1a). Compounds 5 and 6 in particular showed high docking values, confirming the antibacterial in vitro results

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p<0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p<0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status