molecules Article Design, Synthesis and Anticancer Activity of New Polycyclic: Imidazole, Thiazine, Oxathiine, Pyrrolo-Quinoxaline and Thienotriazolopyrimidine Derivatives Ameen Ali Abu-Hashem 1,2,* , Sami A. Al-Hussain 3 and Magdi E. A. Zaki 1,3 1 Heterocyclic Unit, National Research Centre, Photochemistry Department, Dokki, Giza 12622, Egypt; [email protected] or [email protected] 2 Chemistry Department, Faculty of Science, Jazan University, Jazan 45142, Saudi Arabia 3 Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +20-012-2521-1700 or +966-591-363-915; Fax: +20-2-3337-0931 Abstract: In this article, we showed the synthesis of new polycyclic aromatic compounds, such as thienotriazolopyrimidinones, N-(thienotriazolopyrimidine) acetamide, 2-mercapto-thienotriazolo- pyrimidinones, 2-(((thieno-triazolopyrimidine) methyl) thio) thieno-triazolopyrimidines, thieno- pyrimidotriazolo-thiazines, pyrrolo-triazolo-thienopyrimidines, thienopyrimido-triazolopyrrolo- quinoxalines, thienopyrimido-triazolo-pyrrolo-oxathiino-quinoxalinones, 1,4-oxathiino-pyrrolo- tri- azolothienopyrimidinones, imidazopyrrolotriazolothienopyrimidines and 1,2,4-triazoloimidazo- pyrrolotriazolothienopyrimidindiones, based on the starting material 2,3-diamino-6-benzoyl-5- Citation: Abu-Hashem, A.A.; methylthieno[2,3-d]pyrimidin-4(3H)-one (3). The chemical structures were confirmed using many Al-Hussain, S.A.; Zaki, M.E.A. spectroscopic ways (IR, 1H, 13C, −NMR and MS) and elemental analyses. A series of thiazine, Design, Synthesis and Anticancer Activity of New Polycyclic: imidazole, pyrrole, thienotriazolopyrimidine derivatives were synthesized and evaluated for their Imidazole, Thiazine, Oxathiine, antiproliferative activity against four human cancer cell lines, i.e., CNE2 (nasopharyngeal), KB (oral), Pyrrolo-Quinoxaline and MCF-7 (breast) and MGC-803 (gastric) carcinoma cells. The compounds 20, 19, 17, 16 and 11 showed Thienotriazolopyrimidine significant cytotoxicity against types of human cancer cell lines. Derivatives. Molecules 2021, 26, 2031. https://doi.org/10.3390/ Keywords: thienopyrimidinone; thienotriazolopyrimidinone; 1,2,4-triazole; thiazine; pyrrole; molecules26072031 oxathiinoquinoxaline; imidazole; imidazopyrrolotriazole; anticancer activity Academic Editor: Brullo Chiara Received: 6 March 2021 1. Introduction Accepted: 23 March 2021 Published: 2 April 2021 Cancer is one of the most recent serious diseases that afflict humans and ultimately leads to their death. From here, researchers began to develop and discover much ef- Publisher’s Note: MDPI stays neutral fective anticancer therapeutics, such as treatment of cancer using chemotherapy [1] and with regard to jurisdictional claims in heterocyclic compounds, such as thienopyrimidine, triazolopyrimidine, quinoxaline and published maps and institutional affil- imidazole derivatives containing anticancer drugs [2], as follows: Azathioprine, Pimonida- iations. zole, Dacarbazine, Misonidazole, Fadrozole, Tipifarnib, Bendamustine, Indimitecan and Nilotinib. Therefore, the chemical studies of each of thiophene, pyrimidine, triazole, thiazine, pyrrole, quinoxaline and imidazole nucleus play a significant role in the syn- thesis of a diversity of fused heterocyclic compounds having a wide range of biologi- cal and pharmacological activities. Accordingly, previous scientific studies confirmed Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. that thienopyrimidine derivatives have various biological and pharmacological activi- This article is an open access article ties, such as antibiotics [3], antimicrobial [4,5], anticonvulsants [6], antiviral [7], antiox- distributed under the terms and idant and antitumor agents [8], anticancer [9] and mitotic arrest of breast cancer [10], conditions of the Creative Commons anti-inflammatory and analgesic activities [11,12], antiglaucoma agents [13], platelet ag- Attribution (CC BY) license (https:// gregation inhibitors [14], anti-hyperlipidemia [15], antidepressant, anti-inflammatory and creativecommons.org/licenses/by/ antimicrobial activities [16]. In addition, the thiazolopyrimidine, 1,2,4-triazolopy- rim- 4.0/). idine and thienotriazolopyrimidinone derivatives possess such biological activities as Molecules 2021, 26, 2031. https://doi.org/10.3390/molecules26072031 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 21 Molecules 2021,[14],26, 2031 anti-hyperlipidemia [15], antidepressant, anti-inflammatory and antimicrobial activ- 2 of 20 ities [16]. In addition, the thiazolopyrimidine, 1, 2, 4-triazolopy- rimidine and thienotria- zolopyrimidinone derivatives possess such biological activities as anti-inflammatory and analgesic activityanti-inflammatory [17,18], antimicrobial and analgesic [19] an activityd anticancer [17,18 ],activity antimicrobial through [19 ]a andpotential anticancer of activity the enzyme (PARP-1)through inhibition a potential [20]. of the Lately, enzyme in connection (PARP-1) inhibition to continuing [20]. Lately, work in in connection the syn- to contin- thesis and biologicaluing workevaluation in the synthesis of new andpolycyclic biological fused evaluation thienopyrimidine, of new polycyclic purine fused and thienopyrim- 1,2,4-triazole systems,idine, purinepurine and derivatives 1,2,4-triazole are systems,of great purineimportance derivatives and wide are of applications great importance and in many biologicalwide activities, applications such in as many antitumor biological [21] activities, and the such potential as antitumor xanthine [21] oxidase and the potential (XO)-inhibitory activities,xanthine oxidase as well (XO)-inhibitoryas many biological activities, activities as well when as many fused biological with 1,2,4-tria- activities when fused with 1,2,4-triazole ring, shown in Figure1, as the following: 7 β-D-ribofuranosyl- zole ring, shown in Figure 1, as the following: 7β-D-ribofuranosyl-1,2,4-triazolopurines 1,2,4-triazolopurines (A) [22], 1,2,4-triazolopurines (B) [23], thienotriazolopyrimidinones (A) [22], 1,2,4-triazolopurines(C) and 2-sub-thienotriazolopyrimidinones (B) [23], thienotriazolopyrimidinones (D) as a new (C) class and of 2-sub-thieno- the XO inhibitors [24]. triazolopyrimidinonesAdditionally, (D) as Azathioprinea new class of (E) the is an XO anticancer inhibitors drug [24]. that Additionally, possesses considerable Azathio- potential, prine (E) is an anticancerbecause of drug its ability that possesses to interfere considerable with DNA prepared potential, and because then stop of growth its ability and division to interfere with cellsDNA and prepared it is used and for thethen treatment stop growth of metastatic and division malignant cells melanoma and it is andused cell for carcinoma the treatment of ofmetastatic the pancreas malignant [25]. melanoma and cell carcinoma of the pancreas [25]. Figure 1.FigureChemical 1. Chemical structures structures of formerly of synthesized formerly synthesize drugs: triazolopurinesd drugs: triazolopurines and thienotriazolo- and pyrimidinesthienotriazolo- analogues. pyrimidines analogues. The nitrogen atoms containing heterocycles, especially, display a different range of The nitrogenbiological atoms containing activities, due heterocycles to their similarities, especially, with numerous display synthetica different and range natural of molecules with recognized biological activities [26]. The benzimidazole and imidazole rings have biological activities, due to their similarities with numerous synthetic and natural mole- been generally used as the substantial basic structure for the development of therapeutic cules with recognizedmolecules biological of biological activities and pharmaceutical[26]. The benzimidazole activities. Anand example imidazole of five-memberedrings have been generallyheterocycles used as is the imidazole, substantial which basic is spread structure between for the the significant development biological of thera- building blocks. peutic moleculesThus, of biological many drugs and contain pharmaceutical imidazole, suchactivities. as the following:An example Sertaconazole of five-mem- is used as an bered heterocyclesantifungal is imidazole, agent [ 27which]. Omeprazole is spread is between antiulcer andthe controlssignificant the acidbiological secretion build- in the stomach ing blocks. Thus,and many it is drugs considered contain clinically imidazole, superior such to Has2-receptor the following: antagonists Sertaconazole [28,29]. Mizolastine is is used as an antifungalan antihistaminic agent [27]. andOmeprazole potent antagonist is antiulcer at H 1andreceptor controls sites the for theacid treatment secretion of allergic rhinoconjunctivitis and urticarial [30]. Candesartan is used as a receptor antagonist, because in the stomach and it is considered clinically superior to H2-receptor antagonists [28,29]. it contains a bulky lipophilic group, carboxylic acid, the biphenyl group that is more Mizolastine is an antihistaminic and potent antagonist at H1 receptor sites for the treat- efficient than the tetrazole analogue [31]. Azanidazole is an antiparasitic drug and used ment of allergic rhinoconjunctivitisas an antibacterial and and antiprotozoal urticarial [30]. drug Candesartan [32]. Maribavir is used is an as antiviral a receptor drug, which antagonist, becauseis used it contains in the treatment a bulky and lipop preventionhilic