Synthesis and Cytotoxicity Studies of Novel [1,2,4]Triazolo[1,5-a]pyrimidine-7-amines

Abstract

941Cancer is a disease of striking significance in the world today. It represents the second leading cause of human mortality after cardiovascular diseases. In order to develop more effective and reliable anticancer agents, a large number of compounds bearing nitrogen-containing fused heterocyclic skeletons, such as 4-anilinoquinazolines, pyrazolopyrimidines, triazolopyrimidines, pyrrolopyrimidines, pyrazolopyridazines and imidazopyrazines, have been discovered particularly and many of them exhibited excellent anticancer activity. [1][2][3][4][5] Recently, [1,2,4]triazolo [1,5-a]pyrimidines have aroused increasing attentions from chemical and biological view points since they were proved to be the promising anticancer agents with a unique mechanism of promoting tubulin polymerization 1,6) as well as the mechanism of cyclin-dependent kinases-2 inhibition.7) It was not until recently that some N-anilino- [1,2,4]triazolo [1,5-a]pyrimidine-7-amine analogs bearing functional groups at C-2 position were reported for their good cytotoxicity, 8,9) which have largely inspired us and directed parallel developments in the chemistry and cytotoxicity studies of these related derivatives.10) With an aim to produce [1,2,4]triazolo[1,5-a]pyrimidine-7-amine derivatives endowed with improved solubility and better biological interactions, a series of new molecules containing nitrogen atoms in the terminal of side chain at C-2 position on the scaffold were designed and synthesized. Further modifications were performed by introducing various alkylaminomethyl functional groups into C-5 position of furan ring in the side chain and substituted anilines into C-7 position in the [1,2,4]triazolo[1,5-a]pyrimidine core.In this paper, we would like to report the synthesis and cytotoxicity of a series of novel N-anilino-5-methyl-2-(3-(5-(alkylaminomethyl) Results and DiscussionChemistry The title [1,2,4]triazolo[1,5-a]pyrimidine-7-amine derivatives 7-24 were synthesized as shown in Chart 1. Commercially available g-butyrolactone was treated with aminoguanidine carbonate in pyridine to give the 5-amino-3-(3-hydroxypropyl)-4H-[1,2,4]-triazole 2 in 40% yield exclusively. As described in literature, 11) cyclization of 2 with ethyl acetoacetate was carried out in acetic acid at reflux to afford the 3Ј-hydroxy acetylized intermediate, which was converted to hydroxylate 3 by further reaction with ammonia in methanol in 88% yield. Subsequent treatment of 3 with excess phosphorus oxychloride afforded chloro derivative 4, a key synthon for further elaboration, in 94% yield. Coupling reaction of 4 with various anilines provided the intermediates 5a-d in 87-93% yields after recrystallization. By etherification of 5a-d with (furan-2-yl)methanethiol in the presence of an excess amount of sodium hydride in dried DMF, the key intermediates 6a-d were obtained.To further investigate the influence on cytotoxicity of polar chains that facilitate the solubility and the biological interactions, we introduced various Mannich bases into the C-5 position of furan ri...

Anti-neuropathic and anticonvulsant activities of various substituted triazoles analogues

“…They are used as optical brightening agents, as antioxidants, as corrosion inhibitors and as additives with a variety of other functions. www.bosaljournals/chemint/ editorci@bosaljournals.com as antimicrobial, analgesic, anti-Inflammatory, anti convulsant, anti-neoplastic, anti-malarial, anti-viral, antiproliferative, and anti-cancer activities (Zhou and Wang, 2012;Ebdrup et al, 2004;Sun et al, 2006;Upadhayaya et al, 2009;Vishnumurthy et al, 2011;Wuest et al, 2009;Zhai et al, 2008;Zhu et al, 2008). The importance of triazole derivatives lies in the field that these have good position in heterocyclic chemistry, due to its various biological activities.…”

An Overview on Synthetic and Medicinal Perspectives of [1,2,4]Triazolo[1,5‐a]pyrimidine Scaffold

“…SAR is briefly represented in Figure 10. [43] In 2012, Huang and co-workers described a simplistic method for the synthesis of novel 7-arylandrostano [17,16-d] [1,2,4]triazolo [1,5-a]pyrimidine analogs and performed in vitro anticancer activity against EC9706 (human esophageal carcinoma), PC-3 (human prostatic carcinoma), and MCF-7 (human breast carcinoma) cell lines. Among the series, compounds 10 and 11 bearing isopropyl group on the phenyl ring of the main scaffold displayed promising activity against all the cell lines.…”

“…From the SAR, it was observed that substitution decoration of the side chain at the C‐2 position and trifluoromethylaniline substitution at the C‐7 position are essential for potent activity. SAR is briefly represented in Figure 10 [43] …”