Synthesis of Heteroaromatic Compounds

The synthesis of heteroaromatic compounds has been the subject of intense investigation for well over a century [...].

The synthesis of heteroaromatic compounds has been the subject of intense investigation for well over a century. Studies of the properties exhibited by this broad class of organic molecules have led to countless applications in materials science, agrochemistry and the pharmaceutical industry. This Special Issue, entitled "Synthesis of Heteroaromatic Compounds", is an outstanding collection of fourteen original research papers and six review articles that discuss the advances made in both conventional and green preparatory methods, as well as the properties and applications of heteroaromatic molecules in industrial and medicinal chemistry areas of study [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].
In recent years, computational chemistry methods have been brought to bear to determine both the molecular properties and biomolecular interactions that heteroaromatic compounds exhibit. Molecular docking studies of heteroaromatic compounds have identified myriad potential uses in the treatment of a host of illnesses. A number of the articles found in our Special Issue also leverage this important theoretical tool to allow the reader a better understanding of the impact that new molecules bearing heteroaromatic components may have to both the chemical enterprise writ large and the pharmaceutical industry.
This Special Issue brings together contributions from a truly international and diverse array of ninety experts in the fields of heteroaromatic compound synthesis, QSAR studies, computational chemistry and molecular docking, as well as bioactivity studies. Here are some highlights of the original research work and reviews presented in this Special Issue.
Several papers within this collection not only feature the synthesis of new heteroaromatic compounds but also investigate the potential biological applications of those molecules. Xiang's group prepared a series of 8H-indeno[1,2-d]thiazole derivatives and evaluated their inhibitory activities against SARS-CoV-2 3CL pro through a high-throughput screening of their compound collection. One compound was identified as a novel SARS-CoV-2 3CL pro inhibitor and was subjected to molecular docking to predict the binding mode with SARS-CoV-2 3CL pro [4]. Gomha's group synthesized 3-aryl-5-substituted 1,3,4-thiadiazoles, 3phenyl-4-arylthiazoles and the 4-methyl-3-phenyl-5-substituted thiazoles from 1-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-3-phenylthiourea and hydrazonoyl halides, α-haloketones, 3-chloropentane-2,4-dione and ethyl 2-chloro-3-oxobutanoate. The new compounds showed anticancer activity against the cell line of human colon carcinoma (HTC-116) as well as hepatocellular carcinoma (HepG-2). Molecular docking studies of the thiadiazol confirmed a binding site with EGFR TK [8]. Another team under Gomha's direction designed and synthesized novel 3-thiazolhydrazinylcoumarins via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. Molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (an approved medicine). The cytotoxicity of the most active thiazole derivatives was investigated for their efficacy against human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using an MTT assay and Sorafenib as the reference drug. Several compounds were found to have higher anticancer activities than Sorafenib [13]. Yang's group prepared a series of new N-(thiophen-2-yl) nicotinamide derivatives via the nucleophilic acyl substitution of nicotinic acid chlorides and aminothiophenes. The in vivo bioassay results of all the compounds against cucumber downy mildew (CDM; Pseudoperonospora cubensis) indicated that several compounds exhibited fungicidal activities higher than both diflumetorim and flumorph fungicides [11].
This Special Issue also features reviews of topics that are of ongoing interest to the scientific community in the areas of heteroaromatic synthesis and applications. Henary and Tran reviewed the synthesis and applications of antiviral agents derived from various nitrogen-containing heteroaromatic moieties, such as indole, pyrrole, pyrimidine, pyrazole and quinoline, within the last decade. The synthesized scaffolds target HIV, HCV/HBV, VZV/HSV, SARS-CoV, COVID-19 and influenza [3]. Schoffstall and Hoffman examined the current state of synthesis methodologies used to prepare pyrazines and pyridazines fused to 1,2,3-triazoles. The review also details the use of these heterocycles in medicinal chemistry as c-Met inhibitors or GABA A modulators, in materials science as fluorescent probes, and as structural units of polymers [6]. Murai and Hashimoto give a comprehensive accounting of both conventional and green synthetic methodologies used to prepare (3-trifluoromethyl)diazirine-substituted heteroaromatics, including pyrimidines, pyridines, benzimidazoles, pyrazoles, benzoxazoles, benzothiophenes and indoles. The authors also highlight medicinal, polymer and materials science applications for these diazirinesubstituted heteroaromatics [16]. Rogalski and Pietraszuk explore recent advances in the application of the olefin metathesis reaction, particularly the cyclization of dienes and enynes, in synthesis protocols leading to (hetero)aromatic compounds, including pyrroles, furans, indolizines, benzofurans, pyrimidiniums, indoles, pyridoindoles and carbazoles. Several examples of green preparations of these heteroaromatic compounds are described [17]. Asquith's group provided a thorough review of the synthesis methodologies used to prepare 1,2,3-dithiazoles, their reactivity with other substrates, and their medicinal uses as antifungals, herbicides, antibacterials, anticancer agents, antivirals and antifibrotics, and as melanin and Arabidopsis gibberellin 2-oxidase inhibitors [19]. In their review of heteroaromatic hybrid chalcones, Mallia and Sloop outline the recent advances made in the incorporation of heteroaromatic moieties in the synthesis of hybrid chalcones. Examples of environmentally responsible processes employed in the preparation of this important class of organic compound are also highlighted [20].

Conflicts of Interest:
The authors declare no conflict of interest.