Substituted 2-[(2-Oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]acetamides with Thiazole and Thiadiazole Fragments: Synthesis, Physicochemical Properties, Cytotoxicity, and Anticancer Activity

Abstract

The series of novel N-R-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]acetamides with thiazole and thiadiazole fragments in a molecule were obtained by alkylation of potassium salts 1.1–1.4 by N-hetaryl-2-chloroacetamides and by aminolysis of activated acids 2.1–2.4 with N,N’-carbonyldiimidazole (CDI). The structures of compounds were determined by IR, 1H NMR, MS, and EI-MS analysis. The results of cytotoxicity evaluated by the bioluminescence inhibition of bacterium Photobacterium leiognathi, Sh1 showed that the compounds have considerable cytotoxicity. The synthesized compounds were tested for anticancer activity in NCI against 60 cell lines. Among the highly active compounds 3.1, 3.2, and 6.5, 2-[(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]-N-(1,3-thiazol-2-yl)acetamide (3.1) was found to be the most active anticancer agent against the cell lines of colon cancer (GI50 at 0.41–0.69 μM), melanoma (GI50 0.48–13.50 μM), and ovarian cancer (GI50 0.25–5.01 μM). The structure-activity relationship (SAR-analysis) was discussed.

Methodology for prediction of anticancer action of (2-oxo-2H-[1,2,4]¬triazino[2,3-c]-quinazolin-6-yl)thiones via QSAR and docking studies

“…I t is well known, that derivatives of quinazoline have signifi cant anticancer potential, that has been proved by our previous articles [2,10,11], and also by many other researchers. What is even more persuasive, that based on quinazoline skeleton a set of anticancer drugs is being used as an inhibitor of the tyrosine kinase activity associated with EGFR (epidermal growth factor receptor), HER2/neu (Human EGFR type 2), vascular endothelial growth factor receptor (VEGFR) and the RET-tyrosine kinase, (Erlotinib, Lapatinib, Vandetanib) [1,[4][5][6].…”

“…Main skeleton with radicals chosen for this work, to built QSAR models is displayed in fi g. 1. The detailed description of the synthesis and structure elucidation is presented in our previous papers [2,10,11].…”

An insight into the therapeutic potential of quinazoline derivatives as anticancer agents

“…Next, a series of novel N-R-2-[(3-R-2-oxo-2H-[1,2,4]triazinoij2,3c]quinazolin-6-yl)thio]acetamides were prepared by introducing thiazole and thiadiazole fragments. 97 Thirteen of the synthesized compounds were evaluated for anticancer activity (Fig. 9), which exhibited the maximum anticancer activity against the cell lines of colon, melanoma, and ovarian cancer cells with GI 50 in the micromolar range.…”

Synthesis and Antimicrobial Activity of 6-Thioxo-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-one Derivatives

“…Recent publications describe the synthesis and biological activity of the [ 1 , 2 , 4 ]triazino[ 2 , 3 - c ]-quinazoline series [ 5 – 13 ]. It is known that the introduction of a thio-group in position 6 of the [ 1 , 2 , 4 ]triazino[ 2 , 3 - c ]quinazoline system allows the obtainment of compounds with significant cytotoxic action against Photobacterium leiognathi [ 9 , 11 – 13 ] and antimicrobial action against Staphyloccocus aureus and Aspergillus niger [ 8 – 13 ]. The following structure modification of 6-thio-3-R-2 H -[ 1 , 2 , 4 ]triazino[ 2 , 3 - c ]quinazoline-2-ones by synthesis of S-substituted derivatives enabled the obtainment of compounds with anticancer action [ 9 , – 13 ].…”