Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines

Abstract

The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds’ structures were established by 1H, 13C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N′-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI50 level (MG_MID, GI50 is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI50=0.34), CNS (SF-295, GI50=0.95), ovarian (OVCAR-3, GI50=0.33), prostate (PC-3, GI50=0.56), and breast cancer (MCF7, GI50=0.52), leukemia (K-562, GI50=0.41; SR, GI50=0.29), and melanoma (MDA-MB-435, GI50=0.31; SK-MEL-5, GI50=0.74; UACC-62, GI50=0.32). SAR-analysis is also discussed.

2‐Heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones and Their S‐Substituted Derivatives: Synthesis, Spectroscopic Data, and Biological Activity

“…In addition, compounds 3 were characterized by the functional substituent signals at position 2, which, depending on the structure, had classical magnetic shifts and the corresponding multiplicity. [15][16][17][18] In the spectra of compounds 6 and 7, the triazoloquinazoline fragment of molecules formed a characteristic subspectrum of two one-proton doublets: H-10 at d = 8.48-8.35 ppm and H-7 at d = 7.97-7.83 ppm, and two one-proton triplets: H-8 at d = 7.85-7.60 ppm and H-9 at d = 7.67-7.60 ppm. The data indicated that the chemical shifts of these protons differed from those of the parent compounds 3 and, as expected, they significantly affected the nature of the substituent at position 5.…”

5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolines. Message 4. Spirocompounds with [1,2,4]triazolo[1,5-c]quinazolines moieties. The synthesis and spectral

“…(4) of the triazole ring and resulted in formation of ions with m/z 234 (7.6%) and 221 (15.3%). It should be noted that the direction of fragmentation significantly differed from the 2-R- [1,2,4]triazolo [1,5-c]quinazoline systems previously described [14]. In the systems mentioned fragmention of [M] +• was carried out by the cleavage of С(10b)-N(1) and N(3)-N(4) with formation of the amidine moiety and the fragmentary ion with the mass corresponding to quinazoline (m/z 129).…”

2-([1,2,4]triazolo[1,5-c]quinazolin-2-yl-)alkyl-(alkaryl-, aryl-)-amines and their derivatives. (3Н-quinazolin-4-yliden)hydrazides (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)alkyl-(alkaryl-, aryl-)carboxylic acids: features of synthesis, modification and ant

“…(Fig.1). 1 H NMR spectra show the formation of structures 3.1-3.9 which is characterized by the signal of proton H-5, which is observed as a singlet in 9.50-9.27 ppm [5,10,11,18]. In this case after the reaction of intramolecular heterocyclization of [1,2,4]triazolo [4,3-c] quinazoline, the last turn into corresponding [1,5-c]-series due to recyclization isomerization according to the Dimroth's rearrangement type [20].…”

“…3). It is important, that the triazine[1,5-c]-quinazoline proton signal H-10 also undergo signifi cant deshielded impact and appear at 8.59-8.34 ppm, which also show the formation of the corresponding heterosystems [5,11,18].…”

“…Moreover, aminoacids are actively involved in metabolic processes and are the precursors of bioregulators and have a signifi cant amount of binding centers in organism [17]. In addition, (3H-quinazoline-4-ylidene)hydrazide aminocarbonic acids can serve as an effective reagents for the construction of new functionally substituted heterocycles such as 2-aminosubstituted [1,2,4]triazine [1,5-c]quinazolines [5,10,11,18]. Thus, combination of different "pharmacophore" components in one structure connected via "linker" functional groups is a major and a reasonable approach to obtain new biologically active substances.…”