The novel heterocyclization of 5-(2-aminophenyl)-1H-tetrazole with potassium ethylxanthogenate or carbon disulfide was proposed. The potassium salt of the tetrazolo[1,5-c]quinazoline-5-thione was subsequently modified by alkylation with proper halogen derivatives to (tetrazolo[1,5-c]quinazolin-5-ylthio)alkyls, N,N-dialkylethylamines, 1-aryl-2-ethanones, 1-(alkyl)aryl-2-ethanols, carboxylic acids, and esters. The structures of all newly synthesized compounds were confirmed by FT-IR, UV-vis, LC-MS, (1)H, (13)C NMR, and elemental analysis data. The substances were screened for antibacterial and antifungal activities (100 μg) against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes, Entrococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans. Preliminary bioluminescence inhibition tests against Photobacterium leiognathi Sh1 showed that substances 5.2-5.4, 6.1, 7.1 with ethanone or carboxylic acid substituents showed toxicity against bacteria cells. The substances chosen by the US National Cancer Institute (NCI) were screened for their ability to inhibit 60 different human tumor cell lines, where 2-(tetrazolo[1,5-c]quinazolin-5-ylthio)-1-(4-tolyl)ethanone (5.2), 3-(tetrazolo[1,5-c]quinazolin-5-ylthio)propanoic and related 3-metyl-butanoic acids (6.2, 6.3), and ethyl tetrazolo[1,5-c]quinazolin-5-ylthio)acetate (7.2) showed lethal antitumor activity (1.0 μM) against the acute lymphoblastic leukemia cell line (CCRF-CEM), and substances 5.2 and 6.3 exhibited moderate anticancer properties inhibiting growth of the leukemia MOLT-4 and HL06-(TB) cell lines. The moderate antitumor activity was demonstrated in 1-(2,5-dimethoxyphenyl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)ethanone (5.4) against the CNS cancer cell line SNB-75. Comparing the docking mode of the Gefitinib and synthesised substances on the ATP binding site of EGFR, it could be assumed that these compounds might act in the same way. The results of the investigation could be considered as a useful base for future development of potent antimicrobials and antitumor agents among tetrazolo[1,5-c]quinazoline-5-thione S-derivatives.

The death rate from cancer and infectious diseases is still very high, therefore research in this area is extremely important and promising as in medical, so in economic point of view. Thus, potassium salt of tetrazolo[1,5-c]quinazolin-5-thion was modified per alkylation by N-aryl(benzyl,heteryl)acetamides with proper confirmation of newly synthesized compounds’ structures by FT-IR, LC–MS, 1H NMR and elemental analysis data. The substances were tested for bioluminescence inhibition against Photobacterium leiognathi Sh1 (5–50μg/mL) to check their cytotoxicity. Then they were screened for antibacterial and antifungal activities (100μg) against Escherichia coli, Staphylococcus aureus, Enterobacter aerogenes and Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae and Candida albicans. It was found that compounds 1.1, 1.5, 1.10, 1.31, 1.33 possessed light activity against K. pneumonia. The US National Cancer Institute (NCI) has chosen 19 compounds and screened them for ability to inhibit in 10μM concentration 60 different human tumor cell lines. The LOX IMVI cell line of melanoma appeared to be the most sensitive one, and N-(6-methylbenzo[d]thiazol-2-yl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)acetamide (1.31) and N-(3-fluorobenzyl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)acetamide (1.19) exhibited high growth inhibition rate, and N-(6-methoxybenzo[d]thiazol-2-yl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)acetamide (1.32) showed lethal antitumor activity against it. The latter compound 1.32 showed the best anticancer results, also inhibiting growth of leukemia SR cell line, NCI-H460 of non-small cell lung cancer, KM12 of colon cancer and SF-295 of CNS cancer. The in silico molecular docking studies have predicted the affinity of the synthesized substances to the epidermal growth factor receptor (EGFR)

Several novel 6-thio-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-based com-pounds containing an ω-(dialkylamino(heterocyclyl)]alkyl fragment were synthe-sized to examine their anticancer activity. Some of the 6-{[ω-(hetero-cyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (3.1–3.10) were obtained by the nucleophilic substitution of 6-[ω-halogenalkyl]thio-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (2.1–2.8) with azaheterocycles. Alter-natively, compounds 3.1–3.22 were synthesized by alkylation of 3-R-6-thio-2Н-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts (1.1–1.4) with (2-chloro-ethyl)-N,N-dialkylamine hydrochlorides or 1-(2-chloroethyl)heterocycle hydro-chlorides. The structures of compounds were elucidated by 1H, 13C NMR, LC–MS and EI-MS analysis. Then anticancer and antibacterial, biolumi-nescence inhibition of Photobacterium leiognathi Sh1 activities of the sub-stances were tested in vitro. It was found that compound 3.18 possessed a wide range of anticancer activity against 27 cell lines of cancer: non-small cell lung, сolon, CNS, ovarian, renal, prostate, breast, melanoma and leukemia (log GI50 < −5.65). The “structure-activity” relationship was discussed. COMPARE analysis for synthesized anticancer active compounds was performed.

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, (1)H 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 (GI(50) at 0.41-0.69 μM), melanoma (GI(50) 0.48-13.50 μM), and ovarian cancer (GI(50) 0.25-5.01 μM). The structure-activity relationship (SAR-analysis) was discussed.