Recently, the synthetic utility of 1,3,5-triazinanes has attracted significant attention. Further contributing to this field, we developed a new method for the synthesis of novel tetrahydropyrimidines using a cycloaddition of beta-aminocrotononitrile and 1,3,5-triazinanes under microwave irradiation. In this reaction, 1,3,5-triazinanes contributed to the tetrahydropyrimidine ring construction by playing the role of triatomic C-N-C synthons. The cycloaddition was found to be rather general, tolerating diverse aromatic, heterocyclic, and aliphatic substituents at the triazinane nitrogen atoms. Single-crystal X-ray crystallography on 6-methyl-3-(p-tolyl)-1,2,3,4tetrahydropyrimidine-5-carbonitrile confirmed the spectroscopic assignments and showed the tetrahydropyrimidine ring to adopt an envelope conformation with the tertiary amine being the flap atom, with the attached ptolyl group occupying an axial position. In the crystal, molecules form flat supramolecular layers composed of orthogonal chains of molecules connected via N-H & sdot;& sdot;& sdot;pi(p-tolyl) interactions along the c-axis and methyleneC-H & sdot;& sdot;& sdot;N(nitrile) interactions along the b-axis.

This study investigated the antioxidant and anti-inflammatory properties of Helichrysum italicum flower and leaf extracts using High-Performance Thin-Layer Chromatography coupled with Effect-Directed Analysis (HPTLC-EDA), employing microchemical derivatization and in situ bioassays. The goal was to enhance antioxidant and anti-inflammatory activity through spontaneous fermentation. Although fermentation increased the flavonoid content and enhanced antioxidant activity of the flower extracts, it reduced the total phenolic content and did not improve their anti-inflammatory properties. While fermented ethyl acetate and ethanol leaf extracts showed increased anti-inflammatory activity compared to their non-fermented extracts, it was still lower than that of the non-fermented flower extracts. Notably, the ethyl acetate flower extract showed strong COX-1 inhibition (IC₅₀ = 42.42 µg/band), with a much lower IC50 than salicylic acid (IC50 = 557.58 µg/band) under these assay conditions. Spectroscopic analysis (FTIR, NMR, LC-MS) of bioactive zones isolated via preparative TLC identified triterpenoid acids and santinols, rather than flavonoids, as the primary contributors to anti-inflammatory activity.

A new method for the microwave-assisted synthesis of 6,N2-disubstituted-1,3,5-triazine-2,4-diamines was developed. The method is based on the cycloaddition of N-aryl-substituted cyanoguanidines and nitriles in the presence of potassium hydroxide. The reaction tolerated different N-aryl-substituted cyanoguanidines and various aliphatic, aromatic, and heterocyclic nitriles, expanding the chemical diversity of 6,N2-disubstituted-1,3,5-triazine-2,4-diamines. The biological activity screening of the prepared compounds identified N2-phenyl-6-(2-thienyl)-1,3,5-triazine-2,4-diamine as a promising antiproliferative agent against triple-negative breast cancer MDA-MB-231 cells with a GI50 value of 0.07 µM.

A new series of indoleninyl-pyrazolo[1,5-a]pyrimidines 3a-q was synthesized as biological inhibitors against colorectal cancer (CRC) cells. Structural identity of compounds was elucidated by spectroscopic techniques of NMR (1H, 13C, 19F) and elemental analysis. X-ray crystallography on representative species, 3a and 3k (isolated as a 0.125 hydrate), revealed two similar conformations with each molecule exhibiting twists between the central pyrazolo[1,5-a]pyrimidinyl group and the outer substituents. The central residue exhibits substantial delocalization of π-electron density over both rings, and evidence for the same is noted for much of the pyrrolyl ring. In silico ADMET calculations suggested that compounds 3a-c, 3e, 3g, and 3l possess favorable oral bioavailability and non-toxicity. The MTT assay results show that compounds 3e and 3g exhibited selective cytotoxicity towards colorectal carcinoma HCT 116 cells, whereas 3l was cytotoxic towards HCT 116, colorectal adenocarcinoma HT-29, and normal mouse fibroblast 3T3-LI. The putative molecular anticancer target of the cytotoxic compounds 3e, 3g, and 3l is epidermal growth factor receptor (EGFR), which was calculated using the developed KNIME-based machine learning (Random Forest) models. Further analysis using molecular docking simulations predicted that the three active compounds preferably bind to the extracellular domain of EGFR (PDB: 1IVO) rather than its tyrosine kinase domain (PDB: 2GS6). Molecular dynamics simulations validated the docking results, confirming that the 3l-1IVO complex exhibits the highest structural stability and thermodynamic favorability. Overall, this study highlights a new series of indoleninyl-pyrazolo[1,5-a]pyrimidine-based compounds and provides new insights into their potential mechanism of action through an integrated computational and experimental framework, supporting their development as promising chemotherapeutics for the treatment of CRC.

The isoxazole ring transformation was effectively applied for the synthesis of diverse pyrimidines by using a three-component reaction of 5-aminoisoxazole-4-carbonitrile with primary amines and orthoesters. The one-pot rearrangement of the products further expands the structural diversity that can be accessed via this methodology. The method is efficient on the gram scale, can be performed under microwave and conventional heating, and requires no chromatography.

Marine algae or seaweed are among the ocean's most valuable sources of bioactive compounds. They grow abundantly in harsh marine environments of high salinity, high oxygen concentrations and extreme sunlight. The lack of oxidative damage in their structural components indicates the presence of highly effective antioxidants and anti-inflammatory compounds. This study examines the effect of microbial fermentation on the phytochemical composition and bioactivity in different solvent extracts from marine algae via HPTLC microchemical derivatization and HPTLC bioautography. Microchemical derivatization with anisaldehyde/sulfuric acid was used to assess the extract complexity, DPPH free radical assay to estimate and detect antioxidant activity, and enzymatic bioassay to detect and estimate antiinflammatory activity via COX-1 enzyme inhibition. The red alga sample was selected for further characterisation due to higher amounts of bioactive compounds. The potency of the extract with the highest COX-1 inhibition was evaluated, with the high-maximal inhibitory concentrations (IC50) determined by an HPTLC-based experimental procedure developed in our lab. The IC50 values for COX-1 enzyme inhibition from both fermented and nonfermented extracts were significantly lower compared to the IC50 for salicylic acid as a reference standard. Six chromatographic zones exhibited bioactivity: 1,3,4, 6-8 zones with antioxidant activity and 4, 6-8 zones with anti-inflammatory activity. Compounds from bioactive zones were isolated using preparative TLC. They were further characterised using Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and liquid chromatography-mass spectrometry (LC-MS). The main constituents identified as responsible for antioxidant activity were polypeptides (zone 1), hydrolysed lignin (zone 3), carotenoids (zone 4), macrocyclic 4-pyrones (zone 6), fatty acids (zones 6 and 7) and their diglycerides (zone 8).

This paper explores the use of high-performance thin-layer chromatography (HPTLC) silica gel plates as a reaction medium for on-surface, solvent-free organic synthesis. New applications of HPTLC that go beyond its traditional role as a separation method are presented. By leveraging the catalytic activity of silica gel, the concept of derivatization on TLC silica gel plates is extended to on-surface organic syntheses of target molecules. The possibilities of using (HP)TLC plates not only as a stationary phase but also as a catalyst and dehydrating agent in organic synthesis, as effective platforms for modifying organic compounds and for full synthesis are explored. Special attention is given to on-surface synthesis of compound libraries hyphenated with in situ biological detection and targeted bioactivity screening of activity via bioassays. The integration of biological testing directly on the plates streamlines the workflow, making it a powerful tool for discovering new biologically active molecules. Additionally, the paper highlights the potential applications in pharmaceutical analysis, particularly for quality control and study of possible impurities, markers, and reference compounds.

The substituted 1,3,5-triazine-2,4-diamine motif is a well-recognised scaffold for the construction of bioactive compounds. To improve the synthetic accessibility of these compounds and expand their molecular diversity, a convenient one-pot, two-step method for the synthesis of 6,N2,N4-trisubstituted 1,3,5-triazine-2,4-diamines was developed. The three-component acid-catalysed reaction of arylaldehydes, amines, and N-arylcyanoguanidines under microwave irradiation resulted in the dihydrotriazine ring closure. The subsequent microwave irradiation of the reaction mixture after treatment with a base afforded fully aromatic 6,N2,N4-trisubstituted 1,3,5-triazine2,4-diamines as products of dehydrogenative aromatisation. The method was rather general, tolerated structural variations of all reactants and afforded a high chemical diversity of products. The molecular structure and intermolecular interactions in the crystal of N2-phenyl-4-morpholino-6-(4-methylphenyl)-1,3,5-triazine-2-amine as a representative example were studied using X-ray crystallography and molecular Hirshfeld surface analysis. The crystal packing was stabilised by two one-dimensional motifs: hydrogen bonding between the secondary amino group and morpholine moiety oxygen and pi & sdot;& sdot;& sdot; pi stacking interactions, common for the electron-deficient 1,3,5-triazine ring.

Hyperuricemia is characterised by high blood levels of uric acid, and it can degenerate into gout when monosodium urate crystals precipitate in joints and other tissues. Uric acid is produced during the catabolism of xanthine by the enzyme xanthine oxidase (XO), which is the primary therapeutic target in gout treatment. Current XO inhibitors approved to treat gout, such as allopurinol and febuxostat, suffer from serious adverse effects, creating the need for new drug molecules. Three libraries comprising 75 purine analogues were designed using a 1,2,4-triazolo[1,5-a]pyrimidine scaffold, synthesised and tested in vitro as potential XO inhibitors. The screening identified that 23 compounds exhibited better inhibitory activity than allopurinol, with 2-(4-isopropoxyphenyl)-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid being 23 times more potent. Enzyme kinetics studies and molecular docking simulations were performed on the most active compounds to identify the mechanism of action and intermolecular interactions between the active site of XO and the inhibitors. The most potent compounds exhibited a mix-type inhibition mechanism and were predicted to interact with the same amino acid residues as allopurinol. These novel purine analogues are promising hits for further new lead development among purine-like drug XO inhibitors with therapeutic potential in the treatment of hyperuricemia and associated diseases.

The goal of preparative chromatography is to isolate suitable amounts of compound(s) at the required purity in the most cost-effective way. This study analyses the power of High-performance thin-layer chromatography (HPTLC) guided preparative flash chromatography to separate and isolate bioactive compounds from an olive flower extract for their further characterisation via spectroscopy. The structure and purity of isolated bioactive compounds were assessed using Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. Flash chromatography of the olive flower extract successfully isolated pure oleanolic and maslinic acids. Moreover, the flash chromatography of the extract allowed isolation and phytochemical analysis of the most lipophilic fraction of the extract, which was found to contain n-eicosane and n-(Z)-eicos-5-ene, that has not been isolated previously with preparative TLC.

New potent and selective antileukemic agents were identified in the screening of 94 compounds prepared using a convenient one-pot three-component approach.

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.

1,3,5-Triazine scaffold has garnered considerable interest due to its wide-ranging pharmacological properties, particularly in the field of cancer research. Breast cancer is the most commonly diagnosed cancer among women. Approximately one in eight women will receive a diagnosis of invasive breast cancer during their lifetime. The five-year survival rate for invasive breast cancer is less than 30 %, indicating a need to develop a more effective therapeutic agent targeting breast cancer. This review discusses bioactive 1,3,5-triazines targeting breast cancer cells by the inhibition of different enzymes, which include PI3K, mTOR, EGFR, VEGFR, FAK, CDK, DHFR, DNA topoisomerase, ubiquitin-conjugating enzyme, carbonic anhydrase, and matrix metalloproteinase. The anticancer agent search in some drug discovery programs is based on compound screening for antiproliferative activity. Often, multiple targets contribute to the anticancer effect of 1,3,5-triazines and this approach allows identification of active molecules prior to identification of their targets.

Chapter 6 Synthesis of Heterocyclic Compounds Under Microwave Irradiation Using Name Reactions Sheryn Wong, Sheryn Wong Monash University Malaysia, School of Pharmacy, Jalan Lagoon Selatan, Bandar Sunway, Selangor, 46150 MalaysiaSearch for more papers by this authorAnton V. Dolzhenko, Anton V. Dolzhenko Monash University Malaysia, School of Pharmacy, Jalan Lagoon Selatan, Bandar Sunway, Selangor, 46150 Malaysia Curtin University, Curtin Health Innovation Research Institute, Curtin Medical School, GPO Box U1987, Perth, Western Australia 6845 AustraliaSearch for more papers by this author Sheryn Wong, Sheryn Wong Monash University Malaysia, School of Pharmacy, Jalan Lagoon Selatan, Bandar Sunway, Selangor, 46150 MalaysiaSearch for more papers by this authorAnton V. Dolzhenko, Anton V. Dolzhenko Monash University Malaysia, School of Pharmacy, Jalan Lagoon Selatan, Bandar Sunway, Selangor, 46150 Malaysia Curtin University, Curtin Health Innovation Research Institute, Curtin Medical School, GPO Box U1987, Perth, Western Australia 6845 AustraliaSearch for more papers by this author Book Editor(s):Dakeshwar Kumar Verma, Dakeshwar Kumar Verma Govt. Digvijay Autonomous Postgraduate College, Department of Chemistry, Rajnandgaon, 491441 Chhattisgarh, IndiaSearch for more papers by this authorChandrabhan Verma, Chandrabhan Verma Khalifa University of Science and Technology, Department of Chemical Engineering, P.O. Box, Abu Dhabi, 127788 United Arab EmiratesSearch for more papers by this authorPaz Otero Fuertes, Paz Otero Fuertes University of Vigo Faculty of Food Science and Technology, Analytical and Food Chemistry Department, Ourense, 32004 SpainSearch for more papers by this author First published: 28 March 2024 https://doi.org/10.1002/9783527844494.ch6 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary Microwave irradiation has found its niche in organic synthesis and has been actively used for the green synthesis of heterocycles. This chapter demonstrates the utility of microwave irradiation in promoting classical name reactions and the benefits of such an approach compared to the reactions under conventional heating. 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The crystal and molecular structures of N2-(4-chlorophenyl)-6-(3,4,5-trimethoxyphenyl)-1,3,5-triazine-2,4diamine (1) and its 1:1 ethanol solvate (1.EtOH) are reported. The triazine molecule is substituted by amino, 3,4,5-trimethoxyphenyl and 4-chlorophenylamino groups. The experimental molecular structures are like each other and similar to the calculated gas-phase structure. The molecular packing is distinct in that a twisted supramolecular tape is formed in 1 featuring amino-N-H & sdot;& sdot;& sdot;N (triazine) hydrogen bonds. Similar hydrogen-bonding is evident in 1.EtOH but occurs between centrosymmetrically related molecules. The solvent ethanol molecule plays a pivotal role in the packing by participating amino-N-H & sdot;& sdot;& sdot;O (ethanol) and ethanol-O-H & sdot;& sdot;& sdot;O (methoxy) hydrogen bonds within a jagged supramolecular tape. Many additional non-covalent interactions between the tapes are noted in the three-dimensional molecular packing. These and the conventional hydrogen-bonding interactions have been evaluated by a variety of computational chemistry techniques. The greater crystal lattice energy calculated for 1.EtOH is ascribed to the stability afforded by the additional hydrogen-bonding involving the ethanol molecule and the considerably greater role of pi & sdot;& sdot;& sdot;pi stacking interactions in the molecular packing.

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.

Extracts of two Salvia species, Salvia apiana (white sage) and Salvia officinalis (common sage) were screened for phytoconstituents with the ability to act as antidiabetic, cognitive enhancing, or antimicrobial agents, by hyphenation of high-performance thin-layer chromatography with enzymatic and microbial effect directed assays. Two bioactive zones with α-amylase inhibition (zone 1 and zone 2), 3 zones for acetylcholinesterase inhibition (zones 3, 4 and 5), and two zones for antimicrobial activity (zones 4 and 5) were detected. The compounds from the five bioactive zones were initially identified by coelution with standards and comparing the RF values of standards to the bioautograms. Identity was confirmed with ATR-FTIR spectra of the isolated compounds from the bioactive zones. A significantly higher α-amylase and acetylcholinesterase inhibition of S. apiana leaf extract was associated with a higher flavonoid and diterpenoid content. Fermented S. officinalis extract exhibited a significantly higher ability to inhibit α-amylase compared to other non-fermented extracts from this species, due to increased extraction of flavonoids. The ATR-FTIR spectra of 2 zones with α-amylase inhibition, indicated that flavonoids and phenolic acids were responsible for α-amylase inhibition. Multiple zones of acetylcholinesterase inhibition were related to the presence of phenolic abietane diterpenoids and triterpenoid acids. The presence of abietane diterpenoids and triterpenoid acids was also found responsible for the mild antimicrobial activity. Flash chromatography was used to isolate sufficient amounts of bioactive compounds for further characterisation via NMR and MS spectroscopy. Five compounds were assigned to the zones where bioactivity was observed: cirsimaritin (zone 1), a caffeic acid polymer (zone 2), 16-hydroxyrosmanol (zone 3), 16-hydroxycarnosic acid (zone 4), oleanolic and ursolic acids (zone 5).

Two monoclinic (P21/c; Z′ = 1) polymorphs, α (from methanol) and β (from ethanol, n-propanol and iso-propanol), of a bioactive pyrazolo[3,4-d]pyrimidine derivative have been isolated and characterised by X-ray crystallography as well as by a range of computational chemistry techniques. The different conformations observed for the molecules in the crystals are due to the dictates of molecular packing as revealed by geometry-optimisation calculations. The crucial difference in the molecular packing pertains to the formation of phenylamino-N–H···N(pyrazolyl) hydrogen bonding within supramolecular chains with either helical (α-form; 21-screw symmetry) or zigzag (β-form; glide symmetry). As a consequence, the molecular packing is quite distinct in the polymorphs. Lattice energy calculations indicate the β-form is more stable by 11 kJ/mol than the α-form.

The polymorphic form results from an interplay between global molecular packing and stability of molecular conformation.