Pyrimidine Derivatives Research Articles

Aza-Povarov Reaction. A Method for the Synthesis of Fused Tetracyclic Chromeno[4,3-d]pyrido[1,2-a]pyrimidines.

A cornerstone in drug discovery is the development of strategies to provide privileged small molecules with specific structural and stereochemical complexity, allowing access to new potential therapeutic entities. In this work, a new strategy based on the [4 + 2] Povarov reaction involving 1,3-diazadiene was developed. This approach is applied for a straightforward procedure in the preparation of chromeno[4,3-d]pyrido[1,2-a]pyrimidine derivatives, with accessible substrates, 2-aminopyridine and unsaturated aldehydes, and excellent atom economy to obtain four fused ring heterocycles, in a regio- and diastereoselective way.

Development of new thieno[2,3-d]pyrimidines as dual EGFR and STAT3 inhibitors endowed with anticancer and pro-apoptotic activities

In part due to the resilience of cellular feedback pathways that develop therapeutic resistance to targeting the EGFR alone, using EGFR inhibitors alone was demonstrated to be unsuccessful in clinical trials. The over-activation of the signal transducer/activator of transcription 3 (STAT3) during the administration of an EGFR inhibitor is expected to play a substantial part in the failure and resistance of EGFR inhibitor treatment. Therein, we proposed a hypothesis that induced STAT3-mediated resistance to EGFR inhibition therapy could be addressed by a dual inhibition of EGFR and STAT3 method. To this end, we tried to discover new thieno[2,3-d]pyrimidine derivatives “5a-o”. Results from the screening on A549 and MCF7 cancer cell lines revealed that compounds 5j and 5k showed two-digit nanomolar with appropriate safety towards the WI-38 cell line. The best molecules, 5j and 5k, were subjected to γ-radiation, and their cytotoxic efficacy didn’t change after irradiation, demonstrating that not having to use it avoided its side effects. Compounds 5j and 5k demonstrated the highest inhibition when their potency was tested as dual inhibitors on EGFR 67 and 41 nM, respectively, and STAT3 5.52 and 3.34 nM, respectively, proved with in silico molecular docking and dynamic simulation. In light of the results presented above, the capacity of both powerful compounds to alter the cell cycle and initiate the apoptotic process in breast cancer MCF7 cells was investigated. Caspase-8, Bcl-2, Bax and Caspase-9 apoptotic indicators were studied.

Ruthenium-catalysed direct C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidines with acyl/phosphoryl azides.

A ruthenium-catalysed arene ortho C-H amidation of 4-aryl-pyrrolo[2,3-d]pyrimidine derivatives with acyl azides or phosphoryl azides as the nitrogen sources toward C-N bond formation was developed. This protocol could offer a novel and direct approach to access a series of amidated and phosphoramidated pyrrolo[2,3-d]pyrimidine derivatives in moderate to good yields, thereby evading the general Curtius rearrangement. The protocol features significant functional group tolerance and a single-step process, with the release of only innocuous molecular nitrogen as the byproduct.

In vitro biological studies and computational prediction-based analyses of pyrazolo[1,5-a]pyrimidine derivatives.

There is a need for new pharmaceutical discoveries from bioactive nitrogenous derivatives due to the emergence of scourges, numerous pandemics, and diverse health problems. In this context, pyrazolo[1,5-a]pyrimidine derivatives 12a and 12b were synthesized and screened to evaluate their biological potentials in vitro as antioxidants, anti-diabetics, anti-Alzheimer's, anti-arthritics, and anti-cancer agents. Additionally, the computational pharmacokinetic and toxicity properties of the two pyrazolo[1,5-a]pyrimidines 12a and 12b were calculated and analyzed. The preliminary studies and results of this work represent the initial steps toward more advanced studies and define the bioactive chemical structure of pyrazolo[1,5-a]pyrimidine derivatives with the goal of exploring new drugs to address numerous health problems.

New pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors: design, green synthesis, potential anti-proliferative activity and P-glycoprotein inhibition.

In this study, four series of new pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized with both green and conventional methods. All the synthesized candidates were chemically confirmed using spectroscopic methods, and the DFT of the reaction mechanism was illustrated. The anti-proliferative activity of the synthesized compounds was evaluated against NCI 60 cancer cell lines. Two compounds (15 & 16) exhibited excellent broad-spectrum cytotoxic activity in NCI 5-log dose assays against the full 60-cell panel with GI50 values ranging from 0.018 to 9.98 μM. Moreover, the enzymatic assessment of the most active derivatives 4, 15, and 16 against EGFR tyrosine kinase showed significant inhibitory activities with IC50 of 0.054, 0.135, and 0.034 μM, respectively. The quantitative real-time PCR for the P-glycoprotein effect of compounds 15 and 16 was examined and illustrated the ability to inhibit the P-glycoprotein by 0.301 and 0.449 fold in comparison to the control. Mechanistic study using reversal activity in MDA-MB-468 cell line revealed the effect of both compounds 15 and 16 cytotoxicity against DOX/MDA-MB-468 with IC50 = 0.267 and 0.844 μM, respectively. Additionally, compound 16 was found to induce cell cycle arrest at the S phase with a subsequent increase in pre-G cell population in MDA-MB-468 cell line. It also increased the percentage of apoptotic cells in a time-dependent manner. Moreover, a molecular docking study was carried out to explain the target compounds' potent inhibitory activity within the EGFR binding site.

Design, synthesis, pharmacological evaluation, and in silico studies of the activity of novel spiro pyrrolo[3,4-d]pyrimidine derivatives.

In the present study, spiro compounds are shown to have distinctive characteristics because of their interesting conformations and their structural impacts on biological systems. A new family of functionalized spiro pyrrolo[3,4-d]pyrimidines is prepared via the one-pot condensation reaction of amino cyclohexane derivatives with benzaldehyde to prepare fused azaspiroundecanedione and azaspirodecenone/thione derivatives. A series of synthesized spiro compounds were scanned against DPPH and evaluated for their ability to inhibit COX-1 and COX-2. All compounds exhibit significant antiinflammatory activity, and they inhibited both COX-1 and COX-2 enzymes with a selectivity index higher than celecoxib as a reference drug. The most powerful and selective COX-2 inhibitor compounds were 11 and 6, with selectivity indices of 175 and 129.21 in comparison to 31.52 of the standard celecoxib. However, candidate 14 showed a very promising antiinflammatory activity with an IC50 of 6.00, while celecoxib had an IC50 of 14.50. Our findings are promising in the area of medicinal chemistry for further optimization of the newly designed and synthesized compounds regarding the discussed structure-activity relationship study (SAR), in order to obtain a superior antioxidant lead compound in the near future. All chemical structures of the novel synthesized candidates were unequivocally elucidated and confirmed utilizing spectroscopic and elemental investigations.

Review: Pyrimidine Derivatives as Anticancer Agents

Review: Pyrimidine Derivatives as Anticancer Agents

Design, synthesis and biological evaluation of quinazoline and pyrrolo[3,2-d]pyrimidine derivatives as TLR7 agonists for antiviral agents.

Pattern recognition receptors (PRRs) play a critical role in the innate immune response, and toll-like receptor 7 (TLR7) is an important member of PRRs. Although several TLR7 agonists are available, most of them are being tested clinically, with only one available on the market. Thus, it is imperative to develop new TLR7 agonists. In this study, we designed and synthesized three kinds of quinazoline derivatives and five kinds of pyrrolo[3,2-d]pyrimidine derivatives targeting TLR7. The antiviral efficacy of these compounds was evaluated in vitro and in vivo. Our findings indicated that four kinds of compounds showed exceptional antiviral activity. Furthermore, molecular docking studies confirmed that compound 11 successfully positioned itself in the pocket of the TLR7 guanosine loading site with a binding energy of -4.45 kcal mol-1. These results suggested that these compounds might be potential antiviral agents.

CCC pincer Ru complex-catalyzed C-H vinylation/6π-E-cyclization of aldimines for constructing 4H-pyrido[1,2-a]pyrimidines.

An unusual cascade C-H activation, vinylation and 6π-electrocyclization of 2-pyridyl aldimines with vinyl bromides/triflates was achieved using catalysis with a unique CCC pincer NHC-Ru(iii) complex (Cat B). This reaction was found to enable a rapid and diverse synthesis of polycyclic 4H-pyrido[1,2-a]pyrimidine derivatives in mostly good to high yields, and with a broad substrate scope. A mechanistic study suggested the formation of a semi-opened Ru(iii) intermediate chelating/activating the aldimine, and the occurrence of single-electron transfer (SET) to generate a vinyl radical, followed by vinylation and then an intramolecular 6π-electrocyclization of 1N,3N-hexatrene to form the product. This protocol provides a convenient approach for preparing and seeking new drug candidates.

ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-a]ПИРИМИДИНА И ИХ БИОЛОГИЧЕСКАЯ АКТИВНОСТЬ

The pyrazolo[1,5-a]pyrimidine scaffold is a promising target in the field of heterocyclic chemistry due to its unique structure and wide potential for application in medical chemistry. The ability to chemically modify both the pyrazole and pyrimidine rings provides a platform for the preparation of a variety of derivatives with variable properties. The review examines pyrazolo[1,5-a]pyrimidine derivatives that have antitumor, anti-inflammatory, antidiabetic and antiviral activity.

Design, synthesis and biological evaluation of novel pyrimidine derivatives as bone anabolic agents promoting osteogenesis via the BMP2/SMAD1 signaling pathway.

Anti-resorptive inhibitors such as bisphosphonates are widely used but they have limited efficacy and serious side effects. Though subcutaneous injection of teriparatide [PTH (1-34)] is an effective anabolic therapy, long-term repeated subcutaneous administration is not recommended. Henceforth, orally bio-available small-molecule-based novel therapeutics are unmet medical needs to improve the treatment. In this study, we designed, synthesized, and carried out a biological evaluation of 31 pyrimidine derivatives as potent bone anabolic agents. A series of in vitro experiments confirmed N-(5-bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-yl)hexanamide (18a) as the most efficacious anabolic agent at 1 pM. It promoted osteogenesis by upregulating the expression of osteogenic genes (RUNX2 and type 1 col) via activation of the BMP2/SMAD1 signaling pathway. In vitro osteogenic potential was further validated using an in vivo fracture defect model where compound 18a promoted the bone formation rate at 5 mg kg-1. We also established the structure-activity relationship and pharmacokinetic studies of 18a.

Synthesis of novel bioactive pyrido[2,3-d]pyrimidine derivatives with potent cytotoxicity through apoptosis as PIM-1 kinase inhibitors.

Direct synthesis and cytotoxicity activity of new series of pyrido[2,3-d]pyrimidine was described. Nicotinamide 2 was synthesized via cyclization of N-cyclohexyl derivative with cyanoacetamide. The o-aminonicotinonitrile 2 was subjected to acylation or thio acylation process followed by intramolecular heterocyclization to afford the desired pyrido[2,3-d]pyrimidine (3-10) and pyrido triazine 11. Compounds 4 and 11 exhibited remarkable cytotoxicity against MCF-7 cells with IC50 values of 0.57 μM and 1.31 μM and IC50 values of 1.13 μM and 0.99 μM against HepG2 cells. Interestingly, compounds 4 and 10 had potent PIM-1 kinase inhibition with IC50 values of 11.4 and 17.2 nM, respectively, with inhibition of 97.8% and 94.6% compared to staurosporine (IC50 = 16.7 nM, with 95.6% inhibition). Moreover, compound 4 significantly activated apoptosis in MCF-7 cells, increasing the cell apoptosis by 58.29-fold by having 36.14% total apoptosis in treated cells compared to 0.62% for control. Moreover, it arrested the cell cycle at the G1 phase. PIM-1 kinase inhibition was virtually elucidated by the molecular docking study, highlighting binding interactions of the lead compound 4 towards the PIM-1 protein. Accordingly, compound 4 was validated as a promising PIM-1 targeted chemotherapeutic agent to treat breast cancer.

A Quinquennial Review of Potent LSD1 Inhibitors Explored for the Treatment of Different Cancers, with Special Focus on SAR Studies.

Cancer bears a significant share of global mortality. The enzyme Lysine Specific Demethylase 1 (LSD1, also known as KDM1A), since its discovery in 2004, has captured the attention of cancer researchers due to its overexpression in several cancers like acute myeloid leukaemia (AML), solid tumours, etc</i>. The Lysine Specific Demethylase (LSD1) downregulation is reported to have an effect on cancer proliferation, migration, and invasion. Therefore, research to discover safer and more potent LSD1 inhibitors can pave the way for the development of better cancer therapeutics. These efforts have resulted in the synthesis of many types of derivatives containing diverse structural nuclei. The present manuscript describes the role of Lysine Specific Demethylase 1 (LSD1) in carcinogenesis, reviews the LSD1 inhibitors explored in the past five years and discusses their comprehensive structural activity characteristics apart from the thorough description of LSD1. Besides, the potential challenges, opportunities, and future perspectives in the development of LSD1 inhibitors are also discussed. The review suggests that tranylcypromine derivatives are the most promising potent LSD1 inhibitors, followed by triazole and pyrimidine derivatives with IC₅₀ values in the nanomolar and sub-micromolar range. A number of potent LSD1 inhibitors derived from natural sources like resveratrol, protoberberine alkaloids, curcumin, etc</i>. are also discussed. The structural-activity relationships discussed in the manuscript can be exploited to design potent and relatively safer LSD1 inhibitors as anticancer agents.

Ligand-centred phenotype-driven development of potent kinase inhibitors against oesophageal cancer.

Oesophageal cancer (OC) is one of the leading causes of cancer-related deaths worldwide. Due in part to its high heterogeneity, OC prognosis remains poor despite the introduction of targeted and immunotherapy drugs. Although numerous kinases play a significant role in the oncogenesis and progression of OC, targeting kinases have shown so far limited therapeutic success. Based on our understanding of the pharmacological properties of the pyrazolo[3,4-d]pyrimidine scaffold and the complex biology of OC, we implemented a ligand-centred strategy combined with phenotypic screening to develop novel antiproliferative inhibitors against OC. This approach is specifically designed to accelerate the discovery of lead compounds in cancers of high molecular heterogeneity such as OC. In an iterative process driven by structure-antiproliferative activity relationships (SAARs), we synthesised and tested 54 novel pyrazolo[3,4-d]pyrimidine derivatives against OC cell lines. The lead compound 2D7 (a.k.a. eCCA352) induces pan-OC activity and cell cycle arrest in the submicromolar range and was determined to inhibit Aurora kinase A, providing a new starting point to develop anticancer targeted agents against OC.

QSAR and molecular docking studies on pyrimidine and pyrrolidine derivatives as potent inhibitors of influenza virus neuraminidase

QSAR and molecular docking studies on pyrimidine and pyrrolidine derivatives as potent inhibitors of influenza virus neuraminidase

A review on potential heterocycles for the treatment of glioblastoma targeting receptor tyrosine kinases.

Glioblastoma, the most aggressive form of brain tumor, poses significant challenges in terms of treatment success and patient survival. Current treatment modalities for glioblastoma include radiation therapy, surgical intervention, and chemotherapy. Unfortunately, the median survival rate remains dishearteningly low at 12-15 months. One of the major obstacles in treating glioblastoma is the recurrence of tumors, making chemotherapy the primary approach for secondary glioma patients. However, the efficacy of drugs is hampered by the presence of the blood-brain barrier and multidrug resistance mechanisms. Consequently, considerable research efforts have been directed toward understanding the underlying signaling pathways involved in glioma and developing targeted drugs. To tackle glioma, numerous studies have examined kinase-downstream signaling pathways such as RAS-RAF-MEK-ERK-MPAK. By targeting specific signaling pathways, heterocyclic compounds have demonstrated efficacy in glioma therapeutics. Additionally, key kinases including phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase, cytoplasmic tyrosine kinase (CTK), receptor tyrosine kinase (RTK) and lipid kinase (LK) have been considered for investigation. These pathways play crucial roles in drug effectiveness in glioma treatment. Heterocyclic compounds, encompassing pyrimidine, thiazole, quinazoline, imidazole, indole, acridone, triazine, and other derivatives, have shown promising results in targeting these pathways. As part of this review, we propose exploring novel structures with low toxicity and high potency for glioma treatment. The development of these compounds should strive to overcome multidrug resistance mechanisms and efficiently penetrate the blood-brain barrier. By optimizing the chemical properties and designing compounds with enhanced drug-like characteristics, we can maximize their therapeutic value and minimize adverse effects. Considering the complex nature of glioblastoma, these novel structures should be rigorously tested and evaluated for their efficacy and safety profiles.

Novel tetranuclear grid-like Zn(II) complexes derived from dihydrazone pyrimidine derivatives as antitumor agents.

Due to the antitumor properties, Zn(II) complexes have attracted more and more attention. Herein, three novel tetranuclear Zn(II) complexes 1-3 based on dihydrazone pyrimidine derivatives H2L1-H2L3 were synthesized and characterized using IR spectroscopy, 1H NMR spectroscopy, single crystal X-ray diffraction analysis, XRD, TG and elemental analysis. Single crystal X-ray diffraction analysis revealed that 1-3 all displayed a [2 × 2] grid-like topology. The stability in solution, lipophilicity, confocal imaging and antitumor activities were investigated. Complexes 1-3 displayed high structural stability, membrane permeability and different lipophilicities. They can target mitochondria due to the cation charge. The MTT assay indicated that all of them exhibited stronger antiproliferative activity than the corresponding derivatives H2L1-H2L3 and the well-known cisplatin against all the selected tumor cells (BGC-823, BEL-7402, MCF-7 and A549), with IC50 values ranging from 2.83 μM to 7.97 μM. AO/EB double staining, flow cytometry and ROS detection suggested that complexes 1 and 2 could induce BGC-823 apoptosis in a dose-dependent manner. UV-Vis spectra, CD spectra, viscosity analysis and molecular docking revealed that complexes 1 and 2 interact with DNA mainly via partial intercalation and groove binding. Tetranuclear [2 × 2] grid-like Zn(II) complexes have the potential to be promising antitumor agents in the future.

Breaking boundaries in diabetic nephropathy treatment: design and synthesis of novel steroidal SGLT2 inhibitors.

The activity of sodium glucose co-transporter 2 (SGLT2) has always been an important parameter influencing chronic kidney disease in type-2 diabetic patients. Herein, we have meticulously designed, synthesized, and evaluated several novel steroidal pyrimidine molecules that possess the capability to successfully bind to the SGLT2 protein and inhibit its activity, thereby remedying kidney-related ailments in diabetic patients. The lead steroidal pyrimidine compounds were selected after virtually screening from a library of probable N-heterocyclic steroidal scaffolds. A nano-catalyzed synthetic route was also explored for the synthesis of the steroidal pyrimidine analogs demonstrating an environmentally benign protocol. Extensive in vitro investigations encompassing SGLT2 screening assays and cell viability assessments were conducted on the synthesized compounds. Among the steroidal pyrimidine derivatives evaluated, compound 9a exhibited the highest SGLT2 inhibition activity and underwent further scrutiny. Western blot analysis was employed to determine the impact of 9a on inflammatory and fibrotic proteins, aiming to elucidate its mechanism of action. Additionally, in silico analyses were performed to illuminate the structural dynamics and molecular interaction mechanism of 9a. The overall investigation is crucial for advancing the development of the next generation of anti-diabetic drugs.

Sulfonamide based pyrimidine derivatives combating Plasmodium parasite by inhibiting falcipains-2 and falcipains-3 as antimalarial agents.

In this report, we present the design and synthesis of a novel series of pyrimidine-tethered spirochromane-based sulfonamide derivatives aimed at combating drug resistance in malaria. The antimalarial effectiveness of these compounds was assessed in vitro. Structural validation of the synthesized compounds was conducted using mass spectrometry and NMR spectroscopy. Strong antimalarial activity against CQ-sensitive (3D7) and CQ-resistant (W2) strains of Plasmodium falciparum was demonstrated by the majority of the compounds. Notably, compounds SZ14 and SZ9 demonstrated particularly potent effects, with compound SZ14 showing IC50 values of 2.84 μM and SZ9 3.22 μM, indicating single-digit micromolar activity. The compounds exhibiting strong antimalarial activity were assessed through enzymatic tests against the cysteine protease enzymes of P. falciparum, falcipain-2 and falcipain-3. The results indicated that SZ14 and SZ9 inhibited PfFP-2 (IC50 values: 4.1 and 5.4 μM, respectively), and PfFP-3 (IC50 values: 4.9 and 6.3 μM, respectively). To confirm the compounds' specificity towards the parasite, we investigated their cytotoxicity against Vero cell lines, revealing strong selectivity indices and no significant cytotoxic effects. Additionally, in vitro hemolysis testing showed these compounds to be non-toxic to normal human blood cells. Moreover, predicted in silico ADME parameters and physiochemical characteristics demonstrated the drug-likeness of the synthetic compounds. These collective findings suggest that sulfonamide derivatives based on pyrimidine-tethered oxospirochromane could serve as templates for the future development of potential antimalarial drugs.

Study the effect of Cu(II) on the biological efficiency of pyrimidine derivatives in the presence of 1,10-phenanthroline and 2,2\-bipyridin

Study the effect of Cu(II) on the biological efficiency of pyrimidine derivatives in the presence of 1,10-phenanthroline and 2,2\-bipyridin