Substituted Pyrimidine Derivatives Research Articles

The Synthesis, Characterization and Antimicrobial Evaluation of Triazole Substituted Pyrimidine Derivatives

The Synthesis, Characterization and Antimicrobial Evaluation of Triazole Substituted Pyrimidine Derivatives

Synthesis of Heterocyclic Compounds with Pyrimidine-4-carbaldehydes as Key Intermediates

AbstractWith the motivation to expand the compound library of specifically substituted pyrimidine derivatives, we prepared several pyrimidine-4-carbaldehydes. In most cases, the chemoselective oxidation of 4-hydroxymethyl-substituted pyrimidine derivatives could be achieved in good yields to provide the desired compounds. Alternatively, the aldehydes were prepared by Riley oxidation with selenium dioxide from the corresponding 4-methylpyrimidines. The formyl group of these compounds was employed as handle to generate alkynyl, cyano, oxazol-5-yl or β-ketoester substituents. Furthermore, two methods were found to prepare furo[3,2-d]pyrimidines. A serendipitously discovered reaction to a 6-(pyrimidin-4-yl)furo[3,2-d]pyrimidin-7-ol derivative involves a mechanistically interestingly ‘dimerization’ process with a benzoin addition as key step. Other compounds in this series contain amino, azido, or 1,2,3-triazol-1-yl groups. All these transformations to highly substituted pyrimidine derivatives demonstrate the synthetic versatility of pyrimidine-4-carbaldehydes and similar compounds.

Novel Substituted Pyrimidine Derivatives as Potential Anti-Alzheimer's Agents: Synthesis, Biological, and Molecular Docking Studies.

The most frequent type of age-related dementia is Alzheimer's disease. To discover novel therapeutic agents for Alzheimer's disease, a series of substituted pyrimidine derivatives were synthesized and evaluated for anti-Alzheimer's activity. All the synthesized compounds were validated by 1HNMR, 13CNMR, and HRMS to assess the structural conformance of the newly synthesized compounds. The synthesized compounds were then evaluated for their in vivo acute toxicity study. Evaluation of acute toxicity showed that none of the synthesized compounds showed toxicity up to 1000 mg/kg. After in vivo acute toxicity studies, the compounds were subjected to behavioral and biochemical studies. Compound N4-(4-chlorophenyl)-N2-(2-(piperidin-1-yl)ethyl)pyrimidine-2,4-diamine 5b (SP-2) displayed an excellent anti-Alzheimer's profile, while the rest of the compounds showed satisfactory results in comparison to donepezil. Docking studies confirmed the results obtained through in vivo experiments and showed that 5b (SP-2) showed a similar interaction to that of donepezil. Further, in silico molecular property predictions showed that 5b (SP-2) possesses favorable drug-likeness and ADME properties for CNS activity. These results implied that 5b could serve as an appropriate lead molecule for the development of anti-Alzheimer's agent.

Design, synthesis and antitumor activity of 4-arylamine substituted pyrimidine derivatives as noncovalent EGFR inhibitors overcoming C797S mutation

Clinical researches have shown that epidermal growth factor receptor (EGFR) is a key target for treatment of non-small cell lung cancer (NSCLC). Many EGFR inhibitors were successfully developed as ani-tumor drugs to treat NSCLC patients. Unfortunately, drug resistances were found in clinic. To overcome C797S mutation in EGFR, a novel series of 4-arylamine substituted pyrimidine derivatives were designed and synthesized under the principle of structure-based drug design. Interestingly, compounds 6e and 9i demonstrated the best anti-proliferative activity against A549, NCI–H1975, and HCC827 cells. In particular, the IC50 values against HCC827 cells reached to 24.6 nM and 31.6 nM, which were much lower than human normal cells 2BS and LO2. Furthermore, compounds 6e and 9i showed extraordinary activity against EGFR19del/T790M/C797S (IC50 = 16.06 nM and 37.95 nM) and EGFRL858R/T790M/C797S (IC50 = 11.81 nM and 26.68 nM), which were potent than Osimertinib (IC50 = 52.28 nM and 157.60 nM). Further studies have shown that compounds 6e and 9i could pertain inhibition of HCC827 colony formation, and arrest HCC827 cells at G2/M phase. Moreover, the most promising compound 6e could inhibit the migration of HCC827 cells, induce HCC827 cells apoptosis, and significantly inhibit the phosphorylation of EGFR, AKT and Erk1/2. In vivo xenograft mouse model with HCC827 cells, compound 6e resulted in remarkable tumor regression without obvious toxicity. In addition, molecular docking studies suggested that compound 6e could firmly combine with T790M-mutant, T790 M/C797S-mutant, and L858R/T790 M/C797S-mutant EGFR kinases as ATP-competitive inhibitor.

Diverse Pharmacological Potential of Various Substituted Pyrimidine Derivatives

Abstract: In many significant bioactive heterocyclic compounds, the six-membered ring pyrimidines play a major role as bioactive components. There is a lot of room for innovation in the fields of medicinal chemistry and the chemical industries because of the numerous pyrimidine synthesis methods and their varied reactions. The pharmacological effects of pyrimidine derivatives include anticonvulsant, antibacterial, antifungal, antiviral, antitubercular, anticancer, antimicrobial, antihypertensive, antiulcer, anti-inflammatory, antimalarial, antioxidant, analgesic, sedative, anti-depressive, antipyretic properties, etc. The synthetic adaptability of pyrimidine has made it possible to create a wide range of structurally different analogs, including analogs from substitution on the pyrimidine ring at various places, which has aided the design of a wide variety of therapeutic targets. This review's goal is to examine the pharmacological effects of numerous pyrimidine derivatives. This review provides an overview of pyrimidine compounds for biological activities and examines the novel pharmacological molecules containing pyrimidine rings in the future.

Access to polysubstituted pyrimidine derivatives via the aza-Diels–Alder reaction of 1,2,3-triazine derivatives and amidines

The synthesis of highly substituted pyrimidine derivatives by the aza-Diels–Alder reaction of 1,2,3-triazines with amidine derivatives is described. This reaction provided direct access to a wide range of 6-aryl-2-substituted pyrimidine-4-carboxylates in good yields with good functional group compatibility. A broad substrate scope, and the operationally simple, metal-free, and neutral reaction conditions are the prominent features of this method.

Structure-based design, drug-likeness, and pharmacokinetic studies of novel substituted pyrimidine derivatives as potent HCV NS3/A4 protease inhibitors

Hepatitis C virus (HCV) infection promotes death rates all over the world. HCV infection is considered a drastic health problem over the world, affecting up to 3% of the population each year. Since NS3/A4 helicase is crucial for HCV replication, this protein was selected as the target for in-silico screening for the design of novel viral entry inhibitors. The finding of valuable information that will aid in the discovery of unique active molecules that may be used to cure HCV infection and subsequently give medically effective therapy is undoubtedly a top global health priority. The PubChem drug repository of publicly available compounds was tested in silico using the enzyme-established RNA binding pronged, yielding 51 substances that were then evaluated for drug likeness, ADMET profile, and synthetic accessibility. Compound 15 was selected as the best hit for designing novel potent HCV NS3/A4 protease inhibitors by structural modification. Most of the molecules designed were proven to disrupt the enzyme by entirely occupying the binding sites of the receptor. The proposed molecule 15f outperformed Voxilaprevir, the FDA-approved NS3/A4 protease inhibitor, with a binding energy of −37.84 kcal/mol compared to −31.86 kcal/mol for Voxilaprevir. Moreover, the ADMET analysis of the proposed molecule (15f) shows higher overall quality with a drug score of 0.57, especially in comparison to Voxilaprevir, which has a drug score of 0.06.

Microwave synthesis and antimalarial screening of novel 4-amino benzoic acid (PABA)-substituted pyrimidine derivatives as Plasmodium falciparum dihydrofolate reductase inhibitors.

The online version contains supplementary material available at 10.1007/s13205-022-03236-w.

Design, synthesis and evaluation of 4-phenyl-1,2,3-triazole substituted pyrimidine derivatives as antiproliferative and tubulin polymerization inhibitors

Ligands binding to the colchicine domain of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in G2/M phase. A series of 4-Phenyl-1,2,3-triazole substituted pyrimidine derivatives have been synthesized and evaluated for antiproliferative and antitubulin activities. In the series, AV-6 and AV-14 were found to be active against the three tested cancer cell lines wherein AV-6 displayed IC50 values of 1.2 µM, 5.5 µM, and 1.9 µM while AV-14 displayed IC50 values of 4.7 µM, 1.7 µM, and 1.4 µM against HCT-116, MCF-7 and HT-29 cell lines, respectively. These compounds were found to be non toxic to the normal cells (HEK-293). In the cell cycle analysis and JC-1 studies, these compounds induce mitocondria mediated apoptosis. In the tubulin polymerization inhibition studies, AV-6 displayed significant tubulin polymerization inhibition potential. In the molecular docking and simulation studies, these compounds fit well in the active site of colchicine.

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents

Development of Fused and Substituted Pyrimidine Derivatives as Potent Anticancer Agents (A Review)

The pyrimidine scaffold is a versatile lead heterocycle in pharmaceutical development. It has diverse chemical reactivity, accessibility and a wide range of biological activities. In the past few years, the pyrimidine derivatives have been developed drastically as potent anticancer agents. This review highlights the current status of pyrimidine molecules in cancer therapy. The in vivo models have been enumerated for the specific types of cancer. The structure – activity relationship (SAR) of fused and substituted pyrimidine derivatives for anticancer activity is discussed. Electron withdrawing groups on aryl moiety attached to both substituted and fused pyrimidine influenced positively, and enhanced potency of novel small molecules as anticancer agents. Electron donating groups reduced the antiproliferative activity. Thus, scientists and researchers of medicinal chemistry discipline could design small molecules with a pyrimidine scaffold possessing more promising anticancer potential.

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents

Microwave Assisted Synthesis of Some Novel Pyrimidine Derivative and Screening for their Biological Activity

A substituted pyrimidine derivatives were synthesized from chalcone of 3-acetyl-2,5-dimethyl thiophene with corresponding active aldehyde in microwave oven. The newly synthesized compounds were characterized by TLC, IR, 1H NMR, 13C NMR spectral analysis. Pyrimidine derivative were screened for their antibacterial activity in vitro by the disk diffusion assay against two Gram-positive and two Gram-negative bacteria and then the minimum inhibitory concentration (MIC) was carried with the reference of standard drugs amoxicillin, ampicillin and ciprofloxacin. The pyrimidine derivatives shows better inhibiting action against both types of bacteria (Gram-positive and Gram-negative) compared to amoxicillin, ampicillin and ciprofloxacin standard drugs.

Palladium-catalyzed synthesis of pyrimidine substituted diaryl ethers through Suzuki Miyaura coupling reactions: Experimental and DFT studies

Aryl and hetero-aryl substituted pyrimidine derivatives demonstrate widespread applications in nonlinear optics (NLO), agrochemical and therapeutic drugs. Therefore, 2-(4-phenoxyphenyl)pyrimidine (2-PPP) and 5-(4-phenoxyphenyl) pyrimidine (5-PPP) were synthesized by palladium-catalyzed Suzuki coupling approach. The structure elucidation of synthesized products was done by 1H-NMR, 13C-NMR, and UV–vis spectroscopic analyses. The natural bond orbital (NBO) analysis was performed using density functional theory (DFT) assisted M06/6-311G** functional, which confirmed the existence of delocalization process and the hyper-conjugative interaction with representative transitions as π(C10-N16)→π*(C14-N17) and π(C26-N30)→π*(C9-N31) having stabilization energies of 36.30 and 36.55 kcal/mol for 2-PPP and 5-PPP, respectively. The small energy ΔE LUMO HOMO gap as 5.330 eV in 2-PPP and 4.975 eV in 5-PPP was evident from the frontier molecular orbital (FMO) analysis, computed at TD-DFT/M06/6-311G** level, Both the NBO and the FMO analysis predicted promising NLO molecular response. Furthermore, HF, LC-BLYP, CAM-B3LYP, M06-2X, and M06 methods, along with the 6-311G** basis set, were utilized to acquire the NLO findings of 2-PPP and 5-PPP. M06 and HF methods indicated the largest and lowest values of average polarizability ⟨α⟩ and first hyperpolarizability (βtot), respectively for both the compounds 2-PPP and 5-PPP. The ⟨α⟩ and βtot values of 2-PPP and 5-PPP were observed as 7.0 and 7.3 times and 15 and 36 times higher than the urea molecule, respectively. Both compounds hold fine NLO characteristics, thus recommended for future NLO applications.

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents.

The rationale behind drug design is the strategic utilization of heterocyclic fragments with specific physicochemical properties to form molecular targeted agents. Among the heterocyclic molecules, pyrimidine has proved to be a privileged pharmacophore for various biological cancer targets. The anti-cancer potential of small molecules with fused and substituted pyrimidines can be enhanced through bioisosteric replacements and altering their ADME parameters. Although several small molecules are used in cancer chemotherapy, oncology therapeutics has various limitations, especially in their routes of administration and their concurrent side effects. Such pernicious effects may be overcome, via selective biological targeting. In this review, the biological targets, to inhibit cancer, have been discussed. The structural activity relationship of fused and substituted pyrimidines was studied. Eco-friendly synthetic approaches for pyrimidine derivatives have also been discussed. This review will give an insight to scientists and researchers of medicinal chemistry discipline to design small molecules having a pyrimidine scaffold with high anti-cancer potential.

Microwave assisted synthesis and antimicrobial evaluation of novel substituted thiosemicarbazide derivatives of pyrimidine

AbstractA new series of antimicrobial thiosemicarbazide substituted pyrimidine derivatives were synthesized by using thiosemicarbazide and ethyl 2‐((2‐amino‐5‐carbamoyl‐6‐[substituted benzyl] pyrimidin‐4‐yl)oxy)acetate derivatives and subsequent addition of acetaldehyde and acetone. The designed compounds were screened for Antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumonia in comparison with the standard drugs Ciprofloxacin and antifungal effect against Aspergillus niger and Aspergillus fumigates in comparison with the standard drug Ketoconazole reveal the potency of synthesized derivatives. In accordance with the data obtained from antimicrobial activity, all the synthesized derivatives have shown good activity against the tested microbes. Among them, compound bearing 2‐hydroxy and 3‐chloro derivatives of thiosemicarbazide substituted pyrimidine has shown good activity against all the tested organisms.

Fluorine substituted thiomethyl pyrimidine derivatives as efficient inhibitors for mild steel corrosion in hydrochloric acid solution: Thermodynamic, electrochemical and DFT studies

Three new 5-fluoro-2- methylthio substituted pyrimidine derivatives have been synthesized and characterized by 1H NMR spectroscopy and Mass spectrometry. Corrosion inhibition characteristics of the synthesized pyrimidine derivatives have been studied on mild steel (MS) in 0.5 M hydrochloric acid solution at various temperatures (303−333 K) using mass loss and electrochemical techniques. The obtained weight loss, electrochemical impedance and potentiodynamic polarization data indicate that the corrosion inhibition efficiency is directly proportional to concentration of the inhibitors. The Adsorption process on MS surface obeyed Langmuir isotherm model. Scanning electron microscopy (SEM) was used to characterize surface morphology of the MS specimen in absence and presence of pyrimidine derivatives. Density functional theory (DFT) calculations using B3LYP functional with 6-311+G (d,p) level was used to establish the relationship between molecular structure and corrosion inhibition efficiency. Electrochemical analysis indicated that pyrimidine derivatives inhibit the corrosion by adsorbing on the metal surface. Mixed-type of corrosion inhibition activity with anodic predominance was proposed by polarization studies.

A simple and facile synthesis of novel 1,2,3‐triazole substituted pyrimidine derivatives

AbstractA series of novel indole and pyrimidine scaffolds bearing 1,2,3‐triazoles have been designed and synthesized using click chemistry reaction conditions. Target compounds 9a‐j were synthesized in the multi‐step process. In the first step 5‐substituted‐1‐methyl‐1H‐indole‐3‐carbaldehyde 2a‐b reacted with ethyl cyanoacetate 3 and guanidine hydrochloride 4 in presence of L‐Proline in ethanol undergoes cyclisation to form 5a‐b. Further, 5a‐b condensed with various benzaldehydes to form Schiff's base 6a‐f, which further proporgylated with propargyl bromide to form 7a‐f. Finally, 7a‐f was subjected to click‐chemistry with various azides in the presence of CuSO4.5H2O + sodium ascorbate mixture in Dimethylformamide at room temperature to obtain 2 + 3 cycloaddition products 9a‐j in high yield. All these synthetic methods are mostly green and inexpensive with excellent yields.

Green and Facile Synthesis of Pyrimidine Derivatives Using Choline Chloride-urea Mixture as a Deep Eutectic Solvent or Cerium (IV) Ammonium Nitrate

An efficient and facile synthesis of substituted pyrimidine derivatives through Biginelli type reaction was achieved in high yields via one-pot reaction of aromatic aldehydes, active methylene compounds and urea or thiourea in the presence of choline chloride- urea mixture as a deep eutectic solvent or cerium (IV) ammonium nitrate (CAN) as a catalyst at different conditions. The reaction was carried out using different ratio of CAN in different solvents to determine the optimum conditions. In addition, 2-mercapto-6-oxo- 4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile was employed in the synthesis of pyrimidinylhydrazide and its corresponding hydrazone. The structural formula of all derivatives was confirmed and characterized by their elemental analyses and spectral data (IR, MS, 1H NMR, 13C NMR).

In vitro Activity of the Novel Pyrimidines and Their Condensed Derivatives Against Poliovirus

Background: Substituted pyrimidine derivatives (non-nucleoside) are found to be associated with various biological activities. The various substituted pyrimidines are also having significant in vitro activity against different DNA and RNA viruses. The present study focuses on the anti-PV activity of new pyrimidines and their condensed derivatives. Methods: A series of novel pyrimidines and their condensed derivatives were synthesized and their structures were confirmed by spectral data. Their antiviral activities against poliovirus type 3 (PV-3) were evaluated in vitro. In cell culture, morphological changes observed in cells infected with polioviruses, including cell rounding and detachment from the substrate, are generally termed cytopathic effects (CPE). The effects of synthetic pyrimidines on PV amplification in a culture of the heteroploid cell line, Vero 76 (African green monkey kidney cells) were investigated. Results: Bioassays in vitro showed that one of seven synthesized compounds, 7-(Benzenesulfonyl)-5- benzyl-N-(prop-2-en-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine, has potent antiviral activity against PV-3 (EC50 = 0.75 μM). The selectivity index of this compound is similar to that of pirodavir. Conclusion: The need for antiviral agents to treat PV-associated diseases remains great, but few options currently exist. Here we show that substituted pyrimidine derivatives are a promising structure class of chemical compounds for the development of antiviral drugs against PV infections.