5-Aza-adenine Derivatives for Crop-Protection: Multicomponent Synthesis, Experimental and Theoretical Structural Analysis.

A microwave-assisted synthesis of 7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazine-2-propanamides was developed using a three-component, catalyst-free reaction of cyanamide and trimethyl orthoformate with 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (3). The reaction tolerated structurally diverse substrates and proceeded chemo- and regio-selectively, affording the target compounds in high purity in 5-10 minutes. The convenient chromatography-free isolation and purification of the products add practicality to this method. The structural features of the prepared compounds were investigated using dynamic NMR spectroscopy, X-ray crystallography and computational chemistry calculations. X-ray crystallography performed on a representative compound, 3-(7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazin-2-yl)-N-(4-benzyl)propanamide (4 l), showed the overall molecular conformation to adopt the shape of the letter C. Notable localisation of π-electron density is found within the 1,2,4-triazolo[1,5-a][1,3,5]triazine system; a relatively short C-NH2 bond is consistent with restricted rotation about this bond. This study also presents a detailed analysis of the molecular interactions in 4 l using DFT and QTAIM methods with a focus on the hydrogen-bonding and π-stacking interactions that influence the molecular packing of 4 l. The findings reveal the significant roles of N-H⋅O, N-H⋅N and C-H⋅N interactions, along with electrostatically enhanced π⋅π contacts. A broad screening for insecticidal, fungicidal and herbicidal properties identified several compounds with potent herbicidal activity against Matricaria inodora.

3,4-Diaminopyrazolo[3,4-d]pyrimidines: a new three-component microwave-assisted synthesis and anti-leukemic properties.

A convenient method for the synthesis of N3,N4-disubstituted 3,4-diaminopyrazolo[3,4-d]pyrimidines was developed using a three-component reaction of 3,5-diaminopyrazole-4-carbonitriles with primary amines and orthoesters. The preparation of 116 examples demonstrated the good scope of the reaction, which tolerated variations in the substrate structure and was particularly efficient under microwave irradiation. The short reaction time and chromatography-free product isolation add practicality to this method. The anti-leukemic activity was assessed in vitro using K562 and Jurkat T cells, and the selectivity of the most active compounds was evaluated using non-cancerous MRC5 cells. The most promising compound inhibited Jurkat T cells with a GI50 value of 0.5 µM and a selectivity index of 65.

Novel Aurora A and Protein Kinase C (α, ß1, ß2, and θ) Multitarget Inhibitors: Impact of Selenium Atoms on the Potency and Selectivity.

Aurora kinases and protein kinase C (PKC) have been shown to be involved in different aspects of cancer progression. To date, no dual Aurora/PKC inhibitor with clinical efficacy and low toxicity is available. Here, we report the identification of compound 2e as a potent small molecule capable of selectively inhibiting Aurora A kinase and PKC isoforms α, ß1, ß2 and θ. Compound 2e demonstrated significant inhibition of the colony forming ability of metastatic breast cancer cells in vitro and metastasis development in vivo. In vitro kinase screening and molecular modeling studies revealed the critical role of the selenium-containing side chains within 2e, where selenium atoms were shown to significantly improve its selectivity and potency by forming additional interactions and modulating the protein dynamics. In comparison to other H-bonding heteroatoms such as sulfur, our studies suggested that these selenium atoms also confer more favorable PK properties.

6,N 2-Diaryl-1,3,5-triazine-2,4-diamines: synthesis, antiproliferative activity and 3D-QSAR modeling.

A library of 126 compounds with a 6,N 2-diaryl-1,3,5-triazine-2,4-diamine scaffold was prepared using a one-pot, microwave-assisted method from readily available cyanoguanidine, aromatic aldehydes and arylamines. The three-component condensation of these reagents in the presence of hydrochloric acid was followed by the treatment with a base, which promoted a rearrangement of the dihydrotriazine ring and its dehydrogenative aromatization. The antiproliferative properties of the prepared compounds were evaluated using three breast cancer cell lines. The most promising results were obtained in the growth inhibition of the triple negative MDA-MB231 breast cancer cells. The active compounds were also selective against cancer cells and did not affect growth of the non-cancerous MCF-10A breast cell line. Analyzing the structure-activity relationship within the series, we built a 3D-QSAR model for the further design of more potent anticancer compounds.

Design, synthesis, and biological evaluation of new 6,N 2-diaryl-1,3,5-triazine-2,4-diamines as anticancer agents selectively targeting triple negative breast cancer cells.

New 6,N 2-diaryl-1,3,5-triazine-2,4-diamines were designed using the 3D-QSAR model developed earlier. These compounds were prepared and their antiproliferative activity was evaluated against three breast cancer cell lines (MDA-MB231, SKBR-3 and MCF-7) and non-cancerous MCF-10A epithelial breast cells. The synthesized compounds demonstrated selective antiproliferative activity against triple negative MDA-MB231 breast cancer cells. The most active compound in the series inhibited MDA-MB231 breast cancer cell growth with a GI50 value of 1 nM. None of the tested compounds significantly affected the growth of the normal breast cells. The time-dependent cytotoxic effect, observed when cytotoxicity was assessed at different time intervals after the treatment, and morphological features, observed in the fluorescence microscopy and live cell imaging experiments, suggested apoptosis as the main pathway for the antiproliferative activity of these compounds against MDA-MB231 cells.

New One-Pot Synthesis of 1,3,5-Triazines: Three-Component Condensation, Dimroth Rearrangement, and Dehydrogenative Aromatization.

A new, effective one-pot synthesis of the 6, N2-diaryl-1,3,5-triazine-2,4-diamines under microwave irradiation was developed. The method involved an initial three-component condensation of cyanoguanidine, aromatic aldehydes, and arylamines in the presence of hydrochloric acid. Without isolation, the resulting 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-diamines were treated with a base to initiate Dimroth rearrangement and spontaneous dehydrogenative aromatization, affording the desired compounds. The developed method was found to be sufficiently general in scope, tolerating various aromatic aldehydes and amines; by using their combinations in the first step, a representative library of 110 compounds was successfully prepared and screened for anticancer properties.

Fused Heterocyclic Systems with an s-Triazine Ring. 34. Development of a Practical Approach for the Synthesis of 5-Aza-isoguanines.

Purine isosteres present excellent opportunities in drug design and development. Using isosteres of natural purines as scaffolds for the construction of new therapeutic agents has been a valid strategy of medicinal chemistry. Inspired by the similarity to isoguanine, we attempted to develop a practical method for the preparation of 5-aza-isoguanines. Several synthetic approaches were explored to establish a robust general protocol for the preparation of these compounds. The significant difference in the reactivity of the C-5 and C-7 electrophilic centers of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) towards nucleophiles was demonstrated. The most practical and general method for the preparation of 5-aza-isoguanines involved a regioselective reaction of ethoxycarbonyl isothiocyanate with a 5-aminotriazole. The intramolecular ring closure of the resulted product followed by the S-methylation afforded 7-methylthio-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-one, which could be effectively aminated with various amines. The resulted 5-aza-isoguanines resemble a known purine nucleoside phosphorylase inhibitor and could be interesting for further investigations as potential anticancer agents.

Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism.

Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5) were proposed and successfully realized in the synthesis of 20 representative examples. These methods use the same types of starting materials viz. succinic anhydride, aminoguanidine hydrochloride, and a variety of amines. The choice of the pathway and sequence of the introduction of reagents to the reaction depended on the amine nucleophilicity. The first pathway started with the preparation of N-guanidinosuccinimide, which then reacted with amines under microwave irradiation to afford 5. The desired products were successfully obtained in the reaction with aliphatic amines (primary and secondary) via a nucleophilic opening of the succinimide ring and the subsequent recyclization of the 1,2,4-triazole ring. This approach however failed when less nucleophilic aromatic amines were used. Therefore, an alternative pathway, with the initial preparation of N-arylsuccinimides and their subsequent reaction with aminoguanidine hydrochloride under microwave irradiation, was applied. The annular prototropic tautomerism in the prepared 1,2,4-triazoles 5 was studied using NMR spectroscopy and X-ray crystallography.

A one-pot, multicomponent reaction for the synthesis of novel 2-alkyl substituted 4-aminoimidazo[1,2-a][1,3,5]triazines.

A highly selective, one-pot, three-component synthesis of novel 2-alkyl-substituted 4-aminoimidazo[1,2-a][1,3,5]triazines has been developed. The scope of the method was explored in two dimensions, varying the structures of trialkyl orthoesters and 2-aminoimidazoles in their reactions with cyanamide. Conveniently performed under microwave irradiation, this method was also proved to be efficient under conventional heating. A library of 24 novel compounds was prepared in high purity using this multicomponent approach. Molecular and crystal structures of representative molecules were studied using X-ray crystallography.

1,3,5-Triazine-based analogues of purine: from isosteres to privileged scaffolds in medicinal chemistry.

Purines can be considered as the most ubiquitous and functional N-heterocyclic compounds in nature. Structural modifications of natural purines, particularly using isosteric ring systems, have been in the focus of many drug discovery programs. Fusion of 1,3,5-triazine ring with pyrrole, pyrazole, imidazole, 1,2,3-triazole or 1,2,4-triazole results in seven bicyclic heterocyclic systems isosteric to purine. Application of the isosterism concept for the development of new compounds with therapeutic potential in areas involving purinergic regulation or purine metabolism led to significant advances in medicinal chemistry of the azolo[1,3,5]triazines. These 1,3,5-triazine-based purine-like scaffolds significantly increase level of molecular diversity and allow covering chemical space in the important areas of medicinal chemistry. Some of these azolo[1,3,5]triazine systems have become privileged scaffolds in the development of inhibitors of various kinases, phosphodiesterase, xanthine oxidase, and thymidine phosphorylase, antagonists of adenosine and corticotropin-releasing hormone receptors, anticancer and antiviral agents.