Abstract
Novel 6(3-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (7a–e) were synthesized from different enaminones (6a–e) with 6-hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-dione. 2,6(4-2-Substituted-1,3,5-triazin-1(2H)-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (8a–k) were synthesized from the reaction of 1-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-yl)thiourea, urea, or guanidine (3a–c) with enaminones (6a–e), and a series from 3-substituted-2-imino-1,3,5-triazin-1(2H)-yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-dione (12a–j) were obtained from the reaction of N-(diaminomethylene)-4-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzenesulfonamide (11) with the enaminone (6a–j). The antitumor activity of the synthesized compounds was evaluated against two human cell lines: human colon carcinoma HCT116 and human hepatocellular carcinoma HEP-G2. Some of the tested compounds showed significant potency compared to the reference drug staurosporin.
Highlights
Quinazolines are such interesting scaffolds that cover a wide range of biological activity depending on the nature and position of substituents and are reported to act as an antidepressant, antipsychotic, sedative, analgesic, antibacterial, anti-inflammatory, and others [1]. ere are different classes of quinazolinones depending on the position of substituents: 2-substituted-4(3H)-quinazolinones, 3-substituted-4(3H)quinazolinones, 4-substituted quinazolinones, 2,3disubstituted-4(3H)-quinazolinones, and 2,4-disubstituted4(3H)-quinazolinones
Enaminones (6a–e) (1 mmol) and 1-(2,4-dioxo-3-phenyl-1,2,3,4tetrahydroquinazolin-6-yl)thiourea, urea, or guanidine (3a– c) (1 mmol) were refluxed in ethanol (20 ml) for 24 hours. e reaction was monitored using TLC till termination. e solutions were dried under suction. e obtained precipitates were recrystallized from petroleum ether to obtain products in yields of 92–97%. e following compounds were prepared: 6-(4-(Furan-2-yl)-2-oxo-1,3,5-triazin-1(2H)-yl)-3phenylquinazoline-2,4(1H,3H)-dione ( 8a )
Urea derivative (3a) was characterized by 1H NMR that showed three peaks exchangeable with D2O: one peak was upfield at 3.6 ppm corresponding to two protons of the urea’s NH2 group, and the other was downfield at 9.2 ppm corresponding to one proton of the urea’s NH group. e third peak was at 5.5 ppm corresponding to one proton of NH of the quinazoline ring
Summary
Quinazolines are such interesting scaffolds that cover a wide range of biological activity depending on the nature and position of substituents and are reported to act as an antidepressant, antipsychotic, sedative, analgesic, antibacterial, anti-inflammatory, and others [1]. ere are different classes of quinazolinones depending on the position of substituents: 2-substituted-4(3H)-quinazolinones, 3-substituted-4(3H)quinazolinones, 4-substituted quinazolinones, 2,3disubstituted-4(3H)-quinazolinones, and 2,4-disubstituted4(3H)-quinazolinones. A series of 2[(3-substituted-4(3H)quinazoline-2-yl-thio]N-(3,4,5)trimethoxy phenyl)acetamides were reported to act as antitumor agents against a number of cancer cell lines [4]. A series of 6-methyl-2thioxoquinazoline-4(1H)-ones were reported to act as antitumor candidates through targeting and inhibiting the epidermal growth factor receptor (EGFR) [5]. Erlotinib is an antitumor agent that is used for nonsmall cell lung cancer and pancreatic cancer, and it is reported that it acts through the inhibition of EGFR [8]. Journal of Chemistry agent that acts through inhibiting EGFR as well [9] Both erlotinib and gefitinib (Figure 1) belong to a class of EGFR inhibitors that are 4-anilinoquinazolines [10]. Is class was reported to show potent in vitro antiproliferative activity against different cell lines compared to gefitinib [11]. New compounds of quinazoline-2,4(1H,3H)-diones were designed through introducing substituted N-containing ring systems: triazole or 2oxo-, 2-thia-, 2-imino-triazine moieties at C6, or introduction of 2- imino-triazine through a phenyl sulfonyl linker at N3 of the quinazolinone ring (Figure 2). e antitumor activity of the new derivatives was evaluated via the MTT assay
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