General Synthesis of 1-Aryl-6-azaisocytosines and Their Utilization for the Preparation of Related Condensed 1,2,4-Triazines

Abstract

A simple general synthesis of 1-aryl-6-azaisocytosine-5-carbonitriles 4 is described. This method is based on coupling diazonium salts with cyanoacetylcyanamide 2 and then cyclization of the formed 2-arylhydrazono-2-cyanoacetylcyanamides 3. The 6-azaisocytosines 4 were studied with respect to tautomeric equilibrium and the transformation of functional groups, and used in the synthesis of the condensed heterocyclic compounds: Purine isosteric imidazo[2,1-c]-[1,2,4]triazine 8 and the 1,2,4-triazino[2,3-a]quinazolines 9–12.

Application of Simultaneous and Coupled Thermal Analysis Techniques in Studies on the Melting Process, Course of Pyrolysis and Oxidative Decomposition of Fused Triazinylacetohydrazides

“…Fused azaisocytosine-containing congeners with the acetohydrazide functional group (1-4, Figure 1), which is prone to quick oxidation, are an important class of nitrogen-rich heterocycles. All these annelated triazinylacetic acid hydrazides, including the parent compound (1, as an unsubstituted structure) and the remaining para-substituted derivatives (2)(3)(4), have been synthesised formerly, and their spectroscopic data were consistent with the assigned structures shown in Figure 1 [1]. These compounds have previously been subjected to extensive biological assays evaluating their reducing power and antioxidant potential, as a result of which some of them have been disclosed as new, promising antioxidant agents with prospective utility in the treatment of diseases induced by reactive oxygen species and non-radical reactive oxygen metabolites.…”

“…Moreover, the strongest scavenger of hydrogen peroxide proved to be the ethoxy derivative (4), whose effect is better than that of standard antioxidants. For all the molecules bearing the common acetohydrazide pharmacophore (1)(2)(3)(4), the mechanism of their antiradical action (through hydrogen atom transfer to the DPPH  ) has already been established [1]. This makes them promising drug candidates in the preclinical phase of drug development.…”

“…These papers concern 2-(1H-indol-3-yl)acetohydrazide, 2-[(4-bromophenyl)amino]acetohydrazide, 2-(1H-benzotriazol-1-yl)acetohydrazide and 2-(4,6-dimethyl-1H-pyrazolo [3,4-b]pyridine-1-yl)acetohydrazide) [13][14][15][16]. There is a number of known drugs and potential molecular pharmaceutics that contain the privileged scaffold of 1,2,4-triazine or 1,2,4-triazinone [2][3][4][5]. Nevertheless, there are only few scientific reports on the thermal analysis of drugs structurally based on the 1,2,4-triazine system (lamotrigine-used for the treatment of epilepsy and bipolar disorder) [6,7] or with the 1,2,4-triazin-4(3H)-one nucleus incorporated into the bicyclic structure (vardenafil-used for the treatment of erectile dysfunction) [8].…”

Studies on the Thermal Decomposition Course of Nitrogen-Rich Heterocyclic Esters as Potential Drug Candidates and Evaluation of Their Thermal Stability and Properties

“…They were designed as functionalised isosteric isomers of azacytosine. Having the amino nitrogen locked up in an imidazolidine ring, these innovative small molecules may be of biochemical interest as they are suspected to be resistant to enzymatic deamination, unlike short-acting cytosine-or azacytosine-based drugs (such as cytarabine, gemcitabine, or azacytidine, respectively), which are susceptible to inactivation by cytidine deaminase [7][8][9]. Therefore, their development may contribute to the discovery of more effective and metabolically stable azaisocytosine-based drugs for anticancer chemotherapy.…”

Experimental Studies on the Thermal Properties and Decomposition Course of a Novel Class of Heterocyclic Anticancer Drug Candidates

“…A number of bioorganic compounds containing a core structural component of asymmetrical triazine, i.e., 1,2,4-triazine, found utility as molecular pharmaceutics [ 6 , 7 ]. Nevertheless, a literature search revealed that there were only a few scientific reports on the thermal analysis of medicines structurally based on the 1,2,4-triazine system [ 8 , 9 ] as well as those containing the template of 2-methyl-3-sulfanyl-1,2-dihydro-1,2,4-triazine-5,6-dione linked via a methylene bridge with a cephem-based hybrid structure [ 10 ] or the 1,2,4-triazin-4(3 H )-one nucleus incorporated into the structure of diazolo-annelated triazinone [ 11 ].…”