Design and Evaluation of Novel Antimicrobial and Anticancer Agents Among Tetrazolo[1,5-c]quinazoline-5-thione S-Derivatives

Abstract

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, 1H, 13C 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.

Synthesis, Cytotoxicity and Molecular Docking Studies of the 9-Substituted 5-Styryltetrazolo[1,5-c]quinazoline Derivatives

“…The 4-chloroquinazolines 2a – c were, in turn, subjected to sodium azide in DMF at 45 °C and we isolated after 4 h the corresponding 5-styryltetrazolo[1,5- c ]quinazolines 3a – c by aqueous work-up and recrystallization ( Scheme 1 ). Previous studies on the 5-alkyl and 5-aryl substituted tetrazolo[1,5- c ]quinazolines have revealed that these compounds exist predominantly in the tetrazole form in both the solid state and solution phase [ 10 ]. However, the presence of an electron-withdrawing substituent such as a halogen atom in position 8 or 10 was found to result in spontaneous cleavage of the pyrimidine ring of the formed tetrazolo[1,5- c ]quinazoline into the corresponding N -3/5-halogeno-2-(1 H -tetrazolo-5-yl)phenyl)formamides [ 11 ].…”

Search for Compounds with Hypoglycemic Activity in the Series of 1-(2-(1H-Tetrazol-5-yl)-R1-Phenyl)-3-R2-phenyl(ethyl)ureas and R1-Tetrazolo[1,5-c]quinazolin-5(6H)-ones

“…The R 1 -2-(1 H -tetrazol-5-yl)anilines ( 1.1 – 1.5 ) were used as starting compounds and were obtained by known methods, described elsewhere [ 10 – 15 ]. Treatment of R 1 -2-(1 H -tetrazol-5-yl)-phenylamines with R 2 -phenylisocyanates was carried out under different conditions: heating with reflux in glacial acetic acid or stirring at room temperature also in acetic medium or alternatively in dioxane ( Scheme 1 ).…”

“…Substances 1.1–1.5 were synthesized according to the reported procedures [ 10 , 11 ]. Other starting materials and solvents were obtained from commercially available sources and used without additional purification.…”

Tetrazolium Compounds: Synthesis and Applications in Medicine

“…Introduction of the 4-methoxyphenyl group at the 5 position of tetrazolo[1,5- c ]quinazoline-5-thione ( 46 ) resulted in the best antimicrobial agent among all the investigated substances. It even moderately inhibited the growth of Pseudomonas aeruginosa and Klebsiella pneumoniae [ 48 ]. Other research results showed that N -(4-(2-(2 H -tetrazol-5-yl)ethyl)-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)-benzamide ( 47 ) exhibited antimicrobial activity against Bacillus subtilis with a MIC value of 100 μg/mL compared with penicillin (31 μg/mL), against Pseudomonas aeruginosa with a MIC value of 125 μg/mL compared with penicillin (46 μg/mL), and against Streptomyces species with a MIC value of 125 μg/mL compared with penicillin (33 μg/mL) [ 49 ].…”