Quinoxaline as Ubiquitous Structural Fragment: An update on the recent development of its Green Synthetic Approaches

: Quinoxaline is a versatile heterocyclic moiety that possesses a wide range of biological activities. Therefore, many researchers have been performing the synthesis of quinoxaline derivatives on a daily basis. In addition, high demands for their synthesis often result in an increased generation of different waste chemicals. However, to minimize the utilization and generation of toxic organic substances, the present review focuses on the various green synthetic approaches for the synthesis of quinoxaline and its derivatives. Moreover, due to the quick manufacturing of novel medications using a quinoxaline scaffold, multiple study reports are published in a short period of time. Therefore, to fully comprehend the current state of the quinoxaline scaffold in medicinal chemistry, it is necessary to combine recent findings with previous understanding. Besides, compared to conventional methods, these green methods minimize the use and generation of harmful chemicals and improve reaction efficiency in terms of product yields, purity, energy consumption, and post-synthetic procedures. Therefore, in this review, we have attempted to shed light on various green synthetic strategies leading to the synthesis of quinoxaline scaffold and its derivatives, such as ultrasound irradiation, microwave irradiation, grindstone technique, environmentally benign solvents/catalysts based, and reactant immobilized on a solid support, etc.

11H-Indeno[1,2-b]quinoxalin-11-one 2-(4-ethylbenzylidene)hydrazone

11H-Indeno[1,2-b]quinoxaline derivatives present an important type of nitrogen-containing heterocyclic compound that are useful intermediate products in organic synthesis and have potential pharmaceutical applications. A new 11H-indeno[1,2-b]quinoxalin-11-one-2-(4-ethylbenzylidene)hydrazone (compound 3) was synthesized. Compound 3 is the first example of an azine derivative based on the 11H-indeno[1,2-b]quinoxaline system. The Z,E-isomerism of compound 3 was investigated by DFT calculations. Bioavailability was evaluated in silico using ADME predictions. According to the ADME results, compound 3 is potentially highly bioavailable and has potential to be used for the treatment of neuroinflammation and ischemia–reperfusion injury.

Inhibition of Matrix Metalloproteinases and Cancer Cell Detachment by Ru(II) Polypyridyl Complexes Containing 4,7-Diphenyl-1,10-phenanthroline Ligands—New Candidates for Antimetastatic Agents

Primary tumor targeting is the dominant approach in drug development, while metastasis is the leading cause of cancer death. Therefore, in addition to the cytotoxic activity of a series of Ru(II) polypyridyl complexes of the type [Ru(dip)2L]2+ (dip: 4,7-diphenyl-1,10-phenanthroline while L = dip; bpy: 2,2′-bipyridine; bpy-SC: bipyridine derivative bearing a semicarbazone 2-formylopyridine moiety; dpq, dpq(CH3)2, dpb: quinoxaline derivatives) their ability to inhibit cell detachment was investigated. In vitro studies performed on lung cancer A549 cells showed that they accumulate in cells very well and exhibit moderate cytotoxicity with IC50 ranging from 4 to 13 µM. Three of the studied compounds that have dip, bpy-SC, or dpb ligands after treatment of the cells with a non-toxic dose (<1/2IC50) enhanced their adhesion properties demonstrated by lower detachment in the trypsin resistance assay. The same complexes inhibited both MMP-2 and MMP-9 enzyme activities with IC50 ranging from 2 to 12 µM; however, the MMP-9 inhibition was stronger. More detailed studies for [Ru(dip)2(bpy-SC)]2+, which induced the greatest increase in cell adhesion, revealed that it is predominately accumulated in the cytoskeletal fraction of A549 cells. Moreover, cells treated with this compound showed the localization of MMP-9 to a greater extent also in the cytoskeleton. Taken together, our results indicate the possibility of a reduction of metastatic cells escaping from the primary lesion to the surrounding tissue by prevention of their detachment and by influencing the activity of MMP-2 and MMP-9.

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.