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Mass Spectrometric Analysis
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
The quinoxaline group of antibiotics has been studied by FD and FAB methods. In a study of the chromophore’s role in intercalation of DNA by these antibiotics the quinoxaline groups were replaced with similar chromophores by direct synthesis with cultured media [265]. A total of eight analogs of echinomycin (Figure 3) were isolated and identified by FD. The molecular weights were obtained from either M+ or (M + H)+ and (M + Li)+ ions. In this way, the substitution of one quinoxaline by the new chromophore was distinguished from the substitution of both quinoxaline groups. The characterization of a triostin derivative in mycelial cultures supplemented with 6-methylquinoline- 2-carboxylic acid provided the first evidence that echinomycin is biosynthetically derived from triostin by S-methylation and subsequent rearrangement [266]. Using FAB, six analogs of triostin were also characterized [267]. The molecular weights were obtained from the (M - H)− ions in the negative ion mode. Efforts to obtain useful mass spectra were unsuccessful until a mixture of α-thioglycerol and glycerol was used for the matrix.
Prospects of Pre-clinical [6.6.0] Bicyclic Nitrogen Heterocycles in the Treatment of Tuberculosis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Neha P. Agre, Mariam S. Degani, Sanjib Bhakta
Quinoxaline is a bioisostere of quinoline, containing additional nitrogen at the position 4 of the ring, depicted in Figure 2. Structural representation of the quinoxaline scaffold.
FLT3: A Receptor Tyrosine Kinase Target in Adult and Pediatric AML
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Mark Levis, Patrick Brown, Donald Small
There are a large number of inhibitors that have little clinical potential but are useful as research agents. The “tyrphostin” AG1296 was the first small molecule reported to directly inhibit FLT3 autophosphorylation. This bicyclic quinoxaline, along with the closely related AG1295, was initially described as a PDGFRα inhibitor with an IC50 of 0.8 µM in cell-based autophosphorylation assays of PDGF-stimulated cells (145,146). Both AG1296 and AG1295 were subsequently recognized as FLT3 inhibitors, with IC50 ranges similar to those for PDGFRα. In an important early finding, AG1295 was found to be selectively cytotoxic to primary AML blasts harboring FLT3/ITD mutations (125). A number of tricyclic quinoxalines, with very similar potency and selectivity profiles, were developed as FLT3, PDGFRα, and KIT inhibitors (132). Two of these compounds, AGL2033 and AGL2043, are much more water soluble than the original tyrphostins, opening the potential for clinical development. Other agents that have thus far only been used for research purposes are the Bis(1H-2-indolyl)-l-methanones, which inhibit both PDGFR and FLT3 (147). D64406 inhibits FLT3 with an IC50 of 300 nM. It also inhibits PDGFRα and PDGFRβ with IC50 ranges, as determined using in vitro kinase assays, of 1.0 µM and 0.2 µM, respectively. The effects of D64406 on EOL 1 cells provide an interesting illustration of the difficulties in interpreting this type of data. EOL 1 cells, derived from a patient with eosinophilic leukemia, express constitutively activated FLT3 as well as a Fip1L1-PDGFRα fusion protein (120,148). In cytotoxicity assays, the IC50 of D64406 for EOL 1 cells is 0.1 µM, which is lower than the IC50 for inhibition of either FLT3 or PDGFRα kinase activity (147). The observed cytotoxic effect may be due to partial inhibition of either both receptors or inhibition of a completely different target. It is entirely possible that greater antileukemic efficacy is achieved by simultaneously inhibiting two or more receptors within a cell. This multitargeted approach to RTK inhibition is being advanced with other FLT3 inhibitors.
Inhibitors of protease-activated receptor 4 (PAR4): a review of recent patents (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Xiangying Yu, Shanshan Li, Xiong Zhu, Yi Kong
In the past few decades, breakthroughs have been made in developing of small moleculePAR4 inhibitors, and two types of compound (IDTs and Quinoxaline analogues) were extensively studied. IDTs compounds BMS-986120 and BMS-986141 have entered clinical trials. The phase I clinical trial (NCT02439190) showed that BMS-986120 reduced the formation of thrombus in the human deep coronary artery injury model, and no serious adverse reactions were reported. Quinoxaline analogues compounds are developed more recently and showed higher bioactivity than IDTs in the PAR4 FLIPR assay. However, the development of small molecule PAR4 inhibitors also faces some challenges. Firstly, the phase II clinical trial of BMS-986120 and BMS-986141 have been performed for several years but efficacy data has not been disclosed. Secondly, Quinoxaline analogues only were reported in patents not in literature, and also in vivo pharmacodynamics data have not been reported. Thirdly, the crystal structure of PAR4 has not yet been revealed, it is not possible to conduct computer-aided design analysis to develop compounds. Fourthly, the in vivo pharmacodynamics of PAR4 inhibitors only can be properly evaluated using human and primates animals, because primates animals and human platelets express PAR1 and PAR4, while mice, rabbits and rat express PAR3 and PAR4, Guinea pig expresses PAR1, PAR3, and PAR4.
Novel Quinoxaline-2-Carbonitrile-1,4-Dioxide Derivatives Suppress HIF1α Activity and Circumvent MDR in Cancer Cells
Published in Cancer Investigation, 2018
Alexander M. Scherbakov, Alexander M. Borunov, Galina I. Buravchenko, Olga E. Andreeva, Igor A. Kudryavtsev, Lyubov G. Dezhenkova, Andrey E. Shchekotikhin
Antiproliferative activity and especially the hypoxic cytotoxicity ratio (HCR) of quinoxaline-2-carbonitrile-1,4-dioxide is strongly dependent on substituents on the 6- and 7-positions of quinoxaline scaffold. The introduction of the halogen atom in these positions leads to increasing antiproliferative activity in the main cases. Disubstituted derivatives 2c, f, i, and l showed the most potent cytotoxic activity against presented cell lines, whereas mono-substituted derivatives 2b, e, and g exhibited lower IC50 values and higher selectivity under hypoxic conditions. At the same time, the type of halogen atom on the 6- and 7-positions plays a key role in cytotoxicity: chlorine and bromine derivatives (e.g., 2b, e, and g) under hypoxic conditions display higher selectivity than compounds with fluorine in a quinoxaline core (e.g., 2c and f). Simultaneously, substituents in aryl residue on the 3-position of the quinoxaline seem to not have significant influence on cytotoxic properties.
Evaluation of anti-bacterial activity of novel 2, 3-diaminoquinoxaline derivatives: design, synthesis, biological screening, and molecular modeling studies
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Suresh Kumar Suthar, Narendra Singh Chundawat, Girdhar Pal Singh, José M. Padrón, Pavan V. Payghan, Yuvraj Kunwar Jhala
Globally, WHO has documented antimicrobial resistance in many first and second-line medications. [1] Lack of advanced medication, healthcare prescribed most expensive with serve toxicity and even less effective to treat chronic bacterial infection. Because of that, prolonged hospital stays and high cost of treatment with poor outcomes increase the tremendous burden on healthcare and may cause leading cause of death in the future. [2] The most advanced second line, antimicrobial medication (vancomycin and methicillin) has developed resistance against Staphylococcus aureus and a similar trend has been shown in the first line, fluconazole against candida fungal strain. [3] Even though there are many medications existing for antimicrobial treatment, no one causes severe adversative effects [4] such as local inflammation (penicillins), allergic reaction, phototoxicity (tetracyclines), effect on the liver, gray baby disorder, and myelosuppression (chloramphenicol) [5]. The bacterial agent can undergo a mutation that causes resistance to corresponding medication or antibiotics, and finally less effectively binds with target sites like alteration in MOA, chemical alterations of the drug, or by other means. [6] Among that, major threatening is bacteria-produced biofilm to reduced penetration effect or neutralized antibiotics effect. [7,8] Quinoxaline motif is a key structural unit; it exists in various biologically active compounds. In recent research, many small molecules of quinoxaline have a tremendous demand in medicinal chemistry, broadly known as potent antiproliferative and antimicrobial agents. The quinoxaline-bearing antibiotics; including, Triostin A and similar kinds of levomycin and echinomycin to introduce into dsDNA and are advantageously effective toward the bacterial diseases caused by gram-positive bacteria. [9,10]