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Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts the cognitive function and memory of a person. Despite the significant research efforts, the ability to completely prevent or effectively treat AD and its related dementias remains limited. Protein kinases are integral to AD pathology and represent promising targets for therapeutic intervention. Methods: A series of pyrimidine-based compounds 4-(4-(arylsulfonyl)piperazin-1-yl)-6-(thiophen-3-yl)pyrimidine derivatives (8 - 14) were synthesized and characterised. ATPase inhibition was carried out against the MARK4 enzyme. Molecular docking and molecular dynamics (MD) simulation at 500 ns was carried out against MARK4 (PDB: 5ES1). The drug-likeness feature and toxicity of the molecules were evaluated using QikProp and other tools. Results: Compounds were synthesized following a multi-step approach and characterized using multi-nuclear magnetic resonance (1H/13C-NMR) and mass spectrometry. ATPase inhibition assay of the compounds against MARK4 showed an IC50 value in the micromolar (μM) range. The results of the docking studies were consistent with the in-vitro experiments and identified (9) and (14) as the candidates with the highest affinity towards MARK4. MD simulation further supported these results, showing that the binding of ligands stabilises the target protein. Conclusion: Using experimental and theoretical approaches, we demonstrated that the reported class of pyrimidine derivatives are an excellent starting point for developing the next-generation anti-AD drugs. [ABSTRACT FROM AUTHOR]

Background: Despite recent breakthroughs in cancer treatment, non-small cell lung cancer (NSCLC) and breast cancer remain major causes of death from all malignancies. The epidermal growth factor receptor (EGFR) is an important mediator of the pathways involved in cell proliferation, apoptosis, and angiogenesis. Thus, its overexpression triggers several types of cancer, including NSCLC and breast cancer. Methods: In the current study, we synthesized new pyrimidine-tethered compounds (chalcone derivative (B-4), pyrazoline–carbothioamide (B-9), and pyrazoline–thiazole hybrids (BH1-7)). These compounds were then tested for cytotoxicity against A549 NSCLC and MCF-7 breast cancer cells. Results: Of these, B-4 displayed significant cytotoxicity against both cells (IC50 = 6.70 ± 1.02 µM for MCF-7; IC50 = 20.49 ± 2.7 µM for A549) compared to the standard agent lapatinib (IC50 = 9.71 ± 1.12 µM for MCF-7; IC50 = 18.21 ± 3.25 µM for A549). The anticancer potential of B-4 between Jurkat leukemic T cells and peripheral blood mononuclear cells (PBMCs) (healthy) was found to be selective. Mechanistically, 11.9% and 10.2% of A549 and MCF-7 cells treated with B-4, respectively, underwent apoptosis and B-4 produced 46% EGFR inhibition at a concentration of 10 μM. The B-4/EGFR complex obtained after induced fit docking was subjected to 300 ns of molecular dynamics simulation, which confirmed the stability of the complex in a mimicked biological environment. On the other hand, B-4 was shown to have drug-like properties by in silico pharmacokinetic estimation. Conclusions: B-4 is an EGFR inhibitor and apoptosis inducer for future NSCLC and breast cancer studies. [ABSTRACT FROM AUTHOR]

The molecular mechanisms by which vaccinia virus (VACV), the prototypical member of the poxviridae family, reprograms host cell metabolism remain largely unexplored. Additionally, cells sense and respond to fluctuating nutrient availability, thereby modulating metabolic pathways to ensure cellular homeostasis. Understanding how VACV modulates metabolic pathways in response to nutrient signals is crucial for understanding viral replication mechanisms, with the potential for developing antiviral therapies. In this study, we establish the importance of de novo pyrimidine synthesis during VACV infection. We report the significance of vaccinia growth factor (VGF), a viral early protein and a homolog of cellular epidermal growth factor (EGF), in enabling VACV to phosphorylate the key enzyme CAD of the de novo pyrimidine pathway at serine 1859, a site known to positively regulate CAD activity. Although nutrient-poor conditions typically inhibit mTORC1 activation, VACV activates CAD via the mTORC1-S6K1 signaling axis in a VGF-dependent manner, especially upon glutamine and asparagine limitation. However, unlike its cellular homolog EGF, the VGF peptide alone, in the absence of VACV infection, has minimal ability to activate CAD. This suggests the involvement of other viral factors yet to be identified. Our research provides a foundation for understanding the regulation of a significant metabolic pathway, de novo pyrimidine synthesis during VACV infection, shedding new light on viral regulation under distinct nutritional environments. This study not only has the potential to contribute to the advancement of antiviral treatments but also improve the development of VACV as an oncolytic agent and vaccine vector. [ABSTRACT FROM AUTHOR]

A series of D-galactose-conjugated substituted 4-formylsydnone thiosemicarbazones 4a-j were designed and synthesized from appropriate substituted 3-aryl-4-formylsydnones 2a-j and tetra-O-acetyl-β-d-galactopyranose 3. These synthesized thioureas exhibited the remarkable inhibitory activity against both selected Gram-(+)- and Gram-(–)-bacteria. Amongst them, thiosemicarbazones 4a,b,c,f,j were the most potent inhibitors against Gram-(+) bacterial strains with MIC values of 0.78–1.56 μg/mL, while compounds 4b,c,g,j had the most inhibitions against Gram-(–) bacterial ones with MIC values of 0.78–1.56 μg/mL. The thiosemicarbazones 4b, 4c, 4 f and that contain simultaneously two methyl or methyl/nitro substituents on benzene ring exhibited the strong inhibition against both Gram-(+), including MRSA bacterium, and Gram-(–) bacterial strains with MIC values of 0.78–1.56 μg/mL. In addition, compound 4j had strongest potent inhibitory activity against S. aureus DNA Gyrase and compound 4b was the strongest inhibitor against S. aureus Topoisomerase IV. Almost all of the most potential compounds had low toxicity to WI-38 normal cell line. The in silico studies, including predictive ADMET and induced fit docking simulations, for the most potential compounds were performed. Molecular dynamics simulations applied for two most potential complexes 4b/URN and 4j/4URO to understand their mechanism of active interaction for these respective enzymes. [ABSTRACT FROM AUTHOR]

Cancer is the world's leading cause of death impacting millions of lives globally. The increasing research over the past several decades has focused on the development of new anticancer drugs, but still cancer continues to be a global health challenge. Thus, several new alternative therapeutic strategies have been tried for the drug design and discovery. Purine and pyrimidine heterocyclic compounds have received attention recently due to their potential in targeting various cancers. It is evident from the recently published data over the last decade that incorporation of the purine and pyrimidine rings in the synthesized derivatives resulted in the development of potent anticancer molecules. This review presents synthetic strategies encompassing several examples of recently developed purine and pyrimidine-containing compounds as anticancer agents. In addition, their structure–activity relationships are represented in the schemes indicating the fragment or groups that are essential for the enhanced anticancer activities. Purine and pyrimidines combined with other heterocyclic compounds have resulted in many novel anticancer molecules that address the challenges of drug resistance. The purine and pyrimidine derivatives showed significantly enhanced anticancer activities against targeted receptor proteins with numerous compounds with an IC50 value in the nanomolar range. The review will support medicinal chemists and contribute in progression and development of synthesis of more potent chemotherapeutic drug candidates to mitigate the burden of this dreadful disease. [ABSTRACT FROM AUTHOR]

Fluorescent drugs and pyrimidine-indole scaffolds have been shown to have advantages in cancer treatment. Fluorescent antitumor drugs BF3-o, m, p-phenylenediamine pyrimidine-indole derivatives (PYB1, PYB2, and PYB3) were synthesized by linking pyrimidine and indole groups with aniline through a simple step and introducing BF3. The drugs exhibit promising antitumor activity and their fluorescent properties make them useful for imaging purposes. The optical properties of the three compounds have been investigated. All of them have fluorescent properties and compound PYB2 has good fluorescent properties. Additionally, the in vitro cytotoxicity of these compounds was evaluated against the human cancer cell line HeLa and the human normal cell line L02. The inhibition rates of HeLa cells treated with PYB1, PYB2, and PYB3 at a concentration of 19.2 μg/mL were 80.91%, 77.72%, and 65.94%, respectively. These results indicate a strong inhibitory effect on cancer cells. Further through the cell imaging experiment, we can see that PYB2 can enter the cell through the cell membrane through the fluorescence scattering diagram, which has good biocompatibility. In addition, the possible interactions between the compounds and Ras protein active sites were analyzed by molecular docking. The three compounds can bind well to Ras protein through hydrogen bonding. This study provides a basis for the development and modification of pyrimidine-indole fluorescent anticancer drugs. Compound PYB2 shows potential as a fluorescent anticancer drug. [ABSTRACT FROM AUTHOR]

In a quest to innovate biologically active molecules, the benzoylation of 4,6-dimethylpyrimidine-2-thiol hydrochloride (1) with benzoyl chloride derivatives was employed to produce a series of pyrimidine benzothioate derivatives (2–5). Subsequent sulfoxidation of these derivatives (2–5) using hydrogen peroxide and glacial acetic acid yielded a diverse array of pyrimidine sulfonyl methanone derivatives (6–9). In parallel, the sulfoxidation of pyrimidine sulfonothioates (10–12) yielded sulfonyl sulfonyl pyrimidines (13–15), originating from the condensation of compound 1 with sulfonyl chloride derivatives. The newly synthesized compounds underwent characterization via FT-IR, NMR, mass spectrometry, and elemental analyses. Biological screenings unveiled interesting properties: compounds 1 and 6 exhibited significant antimicrobial potency against S. epidermidis and S. haemolyticus, whereas compound 11 showed distinct insensitivity. Excitingly, compounds 12 and 6 showcased robust antioxidant activity by efficiently scavenging DPPH• radical, underscoring their potential in oxidative stress mitigation. Notably, compounds 10 and 12 displayed promising anti-tumor effects, with compound 12 demonstrating superior efficacy against the MCF-7 breast cancer cell line compared to compound 10. The study revealed a spectrum of biological activities across the synthesized derivatives, with modifications often resulting in diminished bioactivity compared to the parent compound 1. These findings shed light on the intricate relationship between chemical modifications and biological properties, offering valuable insights for future drug discovery endeavors. [ABSTRACT FROM AUTHOR]

1,2,4-Triazolo[4,3-a]pyrimidines have significant application prospects in various fields of science, especially as biologically active compounds. This review focused on synthetic approaches of these annulated heterocyclic systems. The main trends, their development, and achievements in this field of synthesis of these classes of heterocyclic compounds, advantages and limitations of the approaches used for 1958–2024 are presented. [ABSTRACT FROM AUTHOR]

The total cross-sections for the single electron-impact ionization of pyrimidine (C4H4N2), 2-chloropyrimidine (2-C4H3ClN2), 5-chloropyrimidine (5-C4H3ClN2), 2-bromopyrimidine (2-C4H3BrN2) and 5-bromopyrimidine (5-C4H3BrN2) molecules have been calculated with the binary-encounter-Bethe model from the ionization threshold up to 5 keV. The input data for the BEB calculations concerning electronic structure of the studied targets have been obtained with quantum chemical methods including the Hartree–Fock (H-F) and the outer valence Green function (OVGF) methods. The calculated cross-section for the ionization of the pyrimidine molecules due to electron impact is compared with available experimental and theoretical data. The question of the magnitude the pyrimidine ionization cross-section is also discussed, as is the efficiency of the ionization process of studied halogenated derivatives of pyrimidine. [ABSTRACT FROM AUTHOR]

C1 chemistry has a central role in the efficient utilization of single-carbon molecules, contributing significantly to sustainability, innovation and economic growth across various sectors. In this study, we present an efficient and rapid method for synthesizing a variety of heteroannulated pyrimidones using cyanoacetamide-based multicomponent reaction (MCR) chemistry. By utilizing specific MCR-based scaffolds as precursors and employing the abundant and inexpensive formamide as a C1 feedstock under neat conditions, we were able to efficiently access substituted thieno-, quinolino- and indolopyrimidones without the need of column chromatography. Further, a single-crystal X-ray structure was obtained, revealing certain geometrical features.

In this work, we have developed a method for synthesizing new 8-substituted triazolo[5,1-b]purines using diacetoxyiodobenzene as an oxidizing agent with good yields (59–67%). The advantages of this approach include mild reaction conditions and removing the need to use transition metals. Based on the results obtained, a plausible reaction pathway was proposed. The developed approach opens new possibilities for the preparation of previously inaccessible condensed purine derivatives, which are of interest for the development of biomolecules with a variety of pharmacological applications. The structures of the compounds were confirmed by the data of 1H, 13C NMR spectroscopy, IR spectroscopy, and an elemental analysis.

Abstract A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors as antidiabetic agents. Chemical structure of all new compounds were confirmed by different spectroscopic methods. The designed compounds were evaluated using a MAK 203 kit as DPP4 inhibitors in comparison with Sitagliptin. The biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety of 6-bromo quinazoline ring had promising inhibitory activity with IC50 = 9.25 ± 0.57 µM. The toxicity test of all compounds confirmed safety profile of them. Kinetic studies showed that compound 9i exhibited a competitive-type inhibition with a Ki value of 12.01 µM. Computational approach supported the rationality of our design strategy, as 9i represented appropriate binding interactions with the active sites of DPP4 target. MD simulation outputs validated the stability of ligand 9i at DPP4 active site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, and theoretical IR spectrum was employed to study the reactivity descriptors of 9i and 9a as the most and least potent compounds respectively. Based on the DFT study, compound 9i was softer and, as a result, more reactive than 9a. Taken together, our results showed the potential of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives as promising candidates for developing some novel DPP4 inhibitors for managing of type 2 diabetes.

Nitrogen‐containing heterocyclic molecules feature metal resource‐independence, flexible conjugation structure and fast charge storage kinetics, making them promising to be used as the electrode material in lithium‐ion batteries. However, an insufficiently high capacity (<400 mAh g−1) seriously threatens their practical application. Herein, a novel molecule, viz. 3,6‐bis(2‐pyrimidinyl)‐1,2,4,5‐tetrazine (DPmT), is developed by inserting an electron‐withdrawing π‐bridge unit of s‐tetrazine between two pyrimidine rings, in which a dense assembly of multiple active sites is realized. The DTmP exhibits a remarkable atom economy of 40 g (mol e)−1, which refers to the molecule mass per unit of charge transferred. The cathode material of DPmT yields a high capacity of 653 mAh g−1 and an energy density of 1188 Wh kg−1 at 50 mA g−1 at 70 °C. And 80% capacity retention is achieved after 500 cycles at 500 mA g−1, confirming its superior cyclability. Spectroscopy studies and theoretical calculations are performed to investigate the charge storage process. First, the C═N and N═N are claimed as plausible binding sites for the lithium ions. Second, the introduction of s‐tetrazine significantly enhances molecular planarity, thereby promoting charge delocalization and molecular stability. This work provides a novel strategy for designing atom‐economic multi‐charge electrode materials with high capacity. [ABSTRACT FROM AUTHOR]

A series of novel hybrid bipyrimidine derivatives were designed, synthesized and evaluated for their anticancer activity against the breast cancer cell line MCF-7 and the lung cancer cell line A549. The structures of all the synthesized molecules were confirmed using various spectroscopic techniques. Molecular docking studies were conducted using Maestro software from Schrödinger, targeting the crystal structure of the ErbB4 kinase (PDB ID: 3BBT). Lapatinib and gefitinib were used as reference drugs to compare binding affinities with the ErbB family of receptor tyrosine kinases. Several of the synthesized bipyrimidine derivatives demonstrated promising activity, with IC50 values comparable to the standard drug doxorubicin and gefitinib. Notably, compound PP-10 exhibited equipotent effects when compared to the reference drugs in both breast and lung cancer cell lines. Additionally, compounds PP-07 and PP-09 showed significant potency against the MCF-7 cell line, while compounds PP-02, PP-09, PP-11 and PP-14 were active against the A549 cell line. These novel hybrid bipyrimidine derivatives served as potential lead molecules in the development of novel drug-like molecules for the treatment of breast and lung cancer. [ABSTRACT FROM AUTHOR]

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, serious, and pharmacoresistant epileptic disorder often linked to gain-of-function mutations in the KCNT1 gene. KCNT1 encodes the sodium-activated potassium channel known as SLACK, making small molecule inhibitors of SLACK channels a compelling approach to the treatment of EIMFS and other epilepsies associated with KCNT1 mutations. In this manuscript, we describe a hit optimization effort executed within a series of 2-aryloxy-N-(pyrimidin-5-yl)acetamides that were identified via a high-throughput screen. We systematically prepared analogs in four distinct regions of the scaffold and evaluated their functional activity in a whole-cell, automated patch clamp (APC) assay to establish structure-activity relationships for wild-type (WT) SLACK inhibition. Two selected analogs were also profiled for selectivity versus other members of the Slo family of potassium channels, of which SLACK is a member, and versus a panel of structurally diverse ion channels. The same two analogs were evaluated for activity versus the WT mouse channel as well as two clinically relevant mutant human channels. [ABSTRACT FROM AUTHOR]

A new compound, 2-amino-5-(4-bromophenyl)-5-{5-bromo-2-[(prop-2-en-1-yl)oxy]benzyl}-3,5-dihydro-4H-imidazol-4-one, has been synthesized by the reaction of (2E)-1-(4-bromophenyl)-3-{5-bromo-2-[(prop-2-en-1-yl)oxy]benzyl}prop-2-en-1-one with guanidine in the presence of hydrogen peroxide. The product structure was determined by NMR spectroscopy and X-ray analysis. A probable reaction mechanism has been proposed. [ABSTRACT FROM AUTHOR]

An array of 5-(5-amino-1,3,4-thiadiazole-2-yl)-3,4-dihydro-6-methyl-4-phenyl-pyrimidin-2(1H)-one derivatives (3a–3j) were synthesized. The synthesized chemicals effectively suppressed fungus activities. IR, 1H, 13C NMR, GC-MS, and Elemental analysis techniques were used to analyze the structures of the newly synthesized compounds. The majority of substances, compared to standard Amphotericin-B, have demonstrated promising antifungal activity. [ABSTRACT FROM AUTHOR]

In this study, a series of novel pyrimidine derivatives incorporating amide and 1,3,4-thiadiazole thioether moieties were synthesized and their structures were confirmed using 1H NMR, 13C NMR, and HRMS analyses. Bioassay results demonstrated that compound 2-{[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]thio}-N-[5-(propylthio)-1,3,4-thiadiazol-2-yl]acetamide exhibited superior antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo), with an inhibition rate of 100% at a concentration of 200 μg/mL, compared to thiodiazole copper. Meanwhile, compound 2-[(4,6-dimethylpyrimidin-2-yl)thio]-N-[5-(ethylthio)-1,3,4-thiadiazol-2-yl]acetamide displayed remarkable antifungal activity against Gilbertella persicaria (G. persicaria), with an EC50 value of 6.71 μg/mL, surpassing that of prochloraz. To the best of our knowledge, this study represents the first report on the synthesis and bioactivity evaluation of pyrimidine derivatives incorporating amide and 1,3,4-thiadiazole thioether moieties. [ABSTRACT FROM AUTHOR]

Herein, a novel series of 6-amino-5-cyano-2-thiopyrimidines and condensed pyrimidines analogues were prepared. All the synthesized compounds (1a-c, 2a-c, 3a-c, 4a-r and 5a-c) were evaluated for in vitro anticancer activity by the National Cancer Institute (NCI; MD, USA) against 60 cell lines. Compound 1c showed promising anticancer activity and was selected for the five-dose testing. Results demonstrated that compound 1c possessed broad spectrum anti-cancer activity against the nine cancerous subpanels tested with selectivity ratio ranging from 0.7 to 39 at the GI50 level with high selectivity towards leukaemia. Mechanistic studies showed that Compound 1c showed comparable activity to Duvelisib against PI3Kδ (IC50 = 0.0034 and 0.0025 μM, respectively) and arrested cell cycle at the S phase and displayed significant increase in the early and late apoptosis in HL60 and leukaemia SR cells. The necrosis percentage showed a significant increase from 1.13% to 3.41% in compound 1c treated HL60 cells as well as from 1.51% to 4.72% in compound 1c treated leukaemia SR cells. Also, compound 1c triggered apoptosis by activating caspase 3, Bax, P53 and suppressing Bcl2. Moreover, 1c revealed a good safety profile against human normal lung fibroblast cell line (WI-38 cells). Molecular analysis of Duvelisib and compound 1c in PI3K was performed. Finally, these results suggest that 2-thiopyrimidine derivative 1c might serve as a model for designing novel anticancer drugs in the future. [ABSTRACT FROM AUTHOR]

In this work, we have developed a method for synthesizing new 8-substituted triazolo[5,1-b]purines using diacetoxyiodobenzene as an oxidizing agent with good yields (59–67%). The advantages of this approach include mild reaction conditions and removing the need to use transition metals. Based on the results obtained, a plausible reaction pathway was proposed. The developed approach opens new possibilities for the preparation of previously inaccessible condensed purine derivatives, which are of interest for the development of biomolecules with a variety of pharmacological applications. The structures of the compounds were confirmed by the data of 1H, 13C NMR spectroscopy, IR spectroscopy, and an elemental analysis. [ABSTRACT FROM AUTHOR]

Peptide-based therapeutics have been gaining attention due to their ability to actively target tumor cells. Additionally, several varieties of nucleotide derivatives have been developed to reduce cell proliferation and induce apoptosis of tumor cells. In this work, we have developed novel peptide conjugates with newly designed purine analogs and pyrimidine derivatives and explored the binding interactions with the kinase domain of wild-type EGFR and its mutant EGFR [L858R/ T790M] which are known to be over-expressed in tumor cells. The peptides explored included WNWKV (derived from sea cucumber) and LARFFS, which in previous work was predicted to bind to Domain I of EGFR. Computational studies conducted to explore binding interactions include molecular docking studies, molecular dynamics simulations and MMGBSA to investigate the binding abilities and stability of the complexes. The results indicate that conjugation enhanced binding capabilities, particularly for the WNWKV conjugates. MMGBSA analysis revealed nearly twofold higher binding toward the T790M/L858R double mutant receptor. Several conjugates were shown to have strong and stable binding with both wild-type and mutant EGFR. As a proof of concept, we synthesized pyrimidine conjugates with both peptides and determined the KD values using SPR analysis. The results corroborated with the computational analyses. Additionally, cell viability and apoptosis studies with lung cancer cells expressing the wild-type and double mutant proteins revealed that the WNWKV conjugate showed greater potency than the LARFFS conjugate, while LARFFS peptide alone showed poor binding to the kinase domain. Thus, we have designed peptide conjugates that show potential for further laboratory studies for developing therapeutics for targeting the EGFR receptor and its mutant T790M/L858R. [ABSTRACT FROM AUTHOR]

Synthetic chemists have organized easy and effective ways to achieve perfect synthesis in response to the requirement for scaffolds that are crucial for medical applications. A general strategy was developed for the synthesis of fused [1,2,3]triazolo[4′,5′:3,4]pyrrolo[1,2‐c]pyrimidines using one‐pot CuI‐catalyzed cycloaddition followed by C─C bong coupling. The cancer activity of the synthesized compounds was then tested in vitro against two lung cancer cell lines and some compounds showed potent activity compared to the primary standard, 5‐FU. We also found EGFR properties in the potent compounds and the results showed that compounds 1‐(3,5‐difluorophenyl)‐7‐methyl‐1,4‐dihydro‐6H‐[1,2,3]triazolo[4′,5′:3,4]pyrrolo[1,2‐c]pyrimidine‐6,8(7H)‐dione, and 1‐(3,5‐dichlorophenyl)‐7‐methyl‐1,4‐dihydro‐6H‐[1,2,3]triazolo[4′,5′:3,4]pyrrolo[1,2‐c]pyrimidine‐6,8(7H)‐dione were strong EGFR inhibitors compared to remaining compounds. We also carried out in silico studies to assess the molecular interactions of more potent compounds with EGFR proteins (PDB: 4HJO). Our findings revealed that all potent compounds exhibited more binding interactions than standard erlotinib (‐7.69 K cal/mol) with binding energies from −8.22 to −9.45 K cal/mol. [ABSTRACT FROM AUTHOR]

The photophysical and two‐photon absorption (TPA) properties of five push‐pull pyrimidine derivatives were studied upon protonation with trifluoroacetic acid (TFA). The pyrimidine heterocycles have been used as the protonation sites and electron acceptors while methoxy groups were employed as electron donors. Steady state and fluorescence time‐resolved spectroscopy from femtoseconds to nanoseconds have been used together with the two‐photon excited fluorescence method. Protonation with TFA resulted in red‐shifted absorption and fluorescence spectra as well as to an acceleration of the excited state dynamics. The TPA properties showed a remarkable enhancement upon protonation with a ten‐times increase of the TPA cross sections due to an increased intramolecular charge transfer. Our results demonstrate the potential of pyrimidine chromophores to be used as protonation tunable non‐linear optical chromophores. [ABSTRACT FROM AUTHOR]