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Worldwide, colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related deaths. Thymidylate synthase (TS) is a crucial component of DNA biosynthesis and has drawn interest as an essential target for cancer treatment. In the current work, we have designed and synthesized twenty-eight new diaryl-based pyrido[2,3-d]pyrimidine/alkyl-substituted pyrido[2,3-d]pyrimidine derivatives and evaluated their anticancer activity against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines cell lines. Additionally, we have carried out TS inhibitory activity and in silico studies for compounds 1n and 2j. All the synthesized compounds exhibited good anticancer activity, but among them, compounds 1n and 2j showed excellent anticancer activity, having IC50 values of 1.98 ± 0.69, 2.18 ± 0.93, 4.04 ± 1.06, and 4.18 ± 1.87 µM; and 1.48 ± 0.86, 3.18 ± 0.79, 3.44 ± 1.51, and 5.18 ± 1.85 µM, against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines respectively with control raltitrexed (IC50 1.07 ± 1.08, 1.98 ± 0.72, 1.34 ± 1.0, and 3.09 ± 0.96 µM, respectively) and hTS inhibitory activity with IC50 values of 20.47 ± 1.09 and 13.48 ± 0.96 nM with control raltitrexed (IC50 14.95 ± 1.01 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 1n and 2j to the catalytic site of TS with docking scores of -10.6 and − 9.5 kcal/mol, respectively, with reference raltitrexed (-9.4 kcal/mol). Additionally, the assessment of physicochemical, biochemical, structural, and toxicological characteristics were also in the acceptable range for these compounds. Based on the anticancer activity of compounds, SAR was also performed for lead optimization. [ABSTRACT FROM AUTHOR]

The design, synthesis, and biological screening of novel 4-aryl-6-[6-(2,4-dichlorophenyl)-2-methyl-pyridin-3-yl]-3,4-dihydropyrimidine-2(1H)-thiones and 2′-amino-6′-aryl-6-(2,4-dichlorophenyl)-2-methyl[3,4′-bipyridine]-3′-carbonitriles are described. The reaction involves Claisen–Schmidt condensation to afford the target compounds in up to 93% yield. The synthesized compounds were characterized by using FT-IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis and were screened for their antibacterial activity against both gram-negative and gram-positive bacterial strains. Methoxy-, hydroxy-, and halogen-substituted deriva-tives showed good inhibitory effect against the tested microorganisms. Also, some of the compounds showed better anti-inflammatory activity when compared to the standards. The electron-donor properties of the novel pyrimidine derivatives were confirmed by quantum chemical studies. [ABSTRACT FROM AUTHOR]

–Objective: In this paper, a series of piperazine pyrimidines and morpholine pyrimidines have been synthesized effectively, and their biological activities have been evaluated. Methods: We examined the cytotoxicity tests of the compounds against two human tumor cells (HCT-116, HeLa), as well as one human normal cells (L02), in order to determine their anticancer activity. Results: The compound (IV) outperformed the others, and flow cytometry was used to further examine how it works against cancer. Additionally, the (IV) molecule showed strong anticancer efficacy but was marginally less effective in apoptosis assays than the control 5-FU. Discussion: The compound (IV) chemical treated HCT-116 cells and HeLa cells in the cell cycle research had a larger percentage of cells in the G1 phase. The induction of apoptosis by interfering with the cell cycle may be the anticancer mechanism of this substance. Additionally, molecular docking investigated potential interactions between the substances and the Topo II active site. Conclusions: The groundwork for the creation and structural modification of new pyrimidine medications is laid out in this study. [ABSTRACT FROM AUTHOR]

Objective: To synthesize new dihydropyrazolo[1,5-a]pyrimidine derivatives and screen for the antibacterial and antifungal screening. Methods: We have synthesized a new series of 7-(1,3-diphenyl-1-H-pyrazol4-yl)-2-(methylthio)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile compounds and screened compounds for antibacterial and antifungal activity. Gram-positive (Bacillus megaterium, Micrococcus spp.) and Gram-negative bacteria were tested for antibacterial activity (E.coli, S. typhi). Antifungal activity was tested on Ganoderma spp., A. niger, A. flavus, and Penicillium spp.Results: Some compounds have shown significant antimicrobial activity. Discussion: As per the results the compound possesses good biological activity due to presence of core pyrazolo[1,5-a]pyrimidine moiety. Conclusions: The synthesis of new 7-(1,3-diphenyl-1-Hpyrazol-4-yl)-2-(methylthio)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile compounds was successfully completed and characterized by relevant techniques. Compounds are screened for the biological activities with moderate to good results. The MIC of the synthesized compound is compared to marketed available standard drugs. [ABSTRACT FROM AUTHOR]

A series of novel (Z)-N′-(1-(aryl)ethylidene)-6-cyano-5-imino-3-methyl-7-(methylthio)-5Hthiazolo[3,2-a]pyrimidine-2-carbohydrazide derivatives was synthesized. All the synthesized compounds were investigated for antimalarial efficacy against Plasmodium falciparum parasite. It was found that, of all tested compound with 4-Cl and 2,4-Cl substituents in aromatic ring exhibited an excellent activity. Molecular docking analysis of the significantly active compounds was performed using PfDHFR enzyme. Compound with 4-Cl substituent demonstrates a binding energy of –9.0 kcal/mol, while that with 2,4-Cl substituent exhibits a binding energy of –9.3 kcal/mol. An analysis of their physicochemical and pharmacokinetics properties related to ADMET was also carried out for all the synthesized molecules. [ABSTRACT FROM AUTHOR]

Imidazo[1,2-a]pyrimidine derivatives are a class of biologically active parent nucleus structures containing both imidazole and pyrimidine rings, which are important intermediates for the synthesis of a variety of drugs. This class of structures has attracted a lot of attention of researchers, and more and more synthetic strategies have been developed and reported. Currently, the main synthetic strategies are one-pot multi-component methods, microwave radiation, ultrasonic irradiation and other auxiliary Knoevenagel condensation and Michael addition methods to obtain these compounds, with the aim of achieving high yields, low time consumption and environmental friendliness. This review comprehensively summarizes the various synthetic methods as well as mechanism recently reported for the construction of this remarkable backbone structure and further used for the development of new chemical synthesis strategies and drug development as it has a wide range of applications in medicinal chemistry. In order to provide some impetus to the research of synthetic methods for this structure. [ABSTRACT FROM AUTHOR]

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 μM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 μM, 2.3 ± 5.91 μM and 5.65 ± 2.33 μM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted. [ABSTRACT FROM AUTHOR]

A method was developed for the synthesis of new fused 3-alkyl-substituted derivatives of thieno[3,2-d]pyrimidin-4(3H)-ones based on 11-(2-furyl)-8,8-dimethyl-7,10-dihydro-8H-pyrano[3′′,4′′:5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidin-4(3H)-one via nucleophilic substitution in the pyrimidine ring. A series of fused 4-amino-substituted 11-furylthieno[3,2-d]pyrimidine derivatives was also synthesized from the corresponding 4-chloro derivative. [ABSTRACT FROM AUTHOR]

Substituted prop-2-en-1-ones were obtained by the condensation reaction of 1-biphenyl-4-yl-ethanone with aromatic aldehydes in the presence of sodium hydroxide in an aqueous ethanol solution. Subsequent cyclization of the latter with hydrazine hydrate, phenylhydrazine, and thiosemicarbazide in an acidic medium leads to the corresponding pyrazolines. The reaction of amidine hydrochlorides with chalcones in a KOH–ethanol system leads to 2,4,6-trisubstituted pyrimidines. The luminescent and antibacterial properties of the resulting systems were studied. [ABSTRACT FROM AUTHOR]

The current study involves the design and synthesis of a newly synthesized pyrrolo[2,3-d]pyrimidine derivatives to contain chlorine atoms in positions 4 and 6 and trichloromethyl group in position 2 using microwave technique as a new and robust approach for preparation of this type of pyrrolo[2,3-d]pyrimidine derivatives. The chemical structure of the synthesized pyrrolo[2,3-d]pyrimidine derivatives 3–19 was well-characterized using spectral and elemental analyses as well as single-crystal X-ray diffraction. All compounds were tested in vitro against seven selected human cancer cell lines, namely, MCF7, A549, HCT116, PC3, HePG2, PACA2 and BJ1 using MTT assay. It was found that compounds 14a, 16b and 18b were the most active toward MCF7 with IC50 (1.7, 5.7, and 3.4 μg/ml, respectively) relative to doxorubicin (Dox.) (26.1 μg/ml). Additionally, compound 17 exerted promising cytotoxic effects against HePG2 and PACA2 with IC50 (8.7 and 6.4 μg/ml, respectively) relative to Dox. (21.6 and 28.3 μg/ml, respectively). The molecular docking study confirmed our ELISA result which showed the promising binding affinities of compounds 14a and 17 against Bcl2 anti-apoptotic protein. At the gene expression level, P53, BAX, DR4 and DR5 were up-regulated, while Bcl2, Il-8, and CDK4 were down-regulated in 14a, 14b and 18b treated MCF7 cells. At the protein level, compound 14b increased the activity of Caspase 8 and BAX (18.263 and 14.25 pg/ml) relative to Dox. (3.99 and 4.92 pg/ml, respectively), while the activity of Bcl2 was greatly decreased in 14a treated MCF7 (2.4 pg/ml) compared with Dox. (14.37 pg/ml). Compounds 14a and 14b caused cell cycle arrest at the G1/S phase in MCF7. Compounds 16b and 18b induced the apoptotic death of MCF7 cells. In addition, the percentage of fragmented DNA was increased significantly in 14a treated MCF7 cells. [ABSTRACT FROM AUTHOR]

In this work, the surface of Fe3O4 nanoparticles was functionalized with the glycine, furfural, and cobalt (II) nitrate hexahydrate to synthesize a novel support nanocatalyst (Fe3O4@gly@Furfural@Co(NO3)2). The characteristics of the nanocatalyst were confirmed by various techniques, such as energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectrometer, EDX mapping, scanning electron microscopy, X-ray diffraction, thermal gravimetric/derivative thermal gravimetric, vibrating sample magnetometer, and TEM. Finally, the performance of the nanocatalyst was investigated for the one-pot multicomponent synthesis of benzo[b]pyran and pyrano[2,3-d] pyrimidine derivatives. The good–excellent yield of the products was achieved in a green solvent under mild conditions at short reaction time. In addition, the green heterogeneous catalyst has features, such as environmental friendliness, easy separation from the reaction mixture by an external magnet, high catalytic activity, and reusability up to 6 stages without significant reduction of its catalytic activity. [ABSTRACT FROM AUTHOR]

In this work, the surface of Fe3O4 nanoparticles was functionalized with the glycine, furfural, and cobalt (II) nitrate hexahydrate to synthesize a novel support nanocatalyst (Fe3O4@gly@Furfural@Co(NO3)2). The characteristics of the nanocatalyst were confirmed by various techniques, such as energy-dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectrometer, EDX mapping, scanning electron microscopy, X-ray diffraction, thermal gravimetric/derivative thermal gravimetric, vibrating sample magnetometer, and TEM. Finally, the performance of the nanocatalyst was investigated for the one-pot multicomponent synthesis of benzo[b]pyran and pyrano[2,3-d] pyrimidine derivatives. The good–excellent yield of the products was achieved in a green solvent under mild conditions at short reaction time. In addition, the green heterogeneous catalyst has features, such as environmental friendliness, easy separation from the reaction mixture by an external magnet, high catalytic activity, and reusability up to 6 stages without significant reduction of its catalytic activity. [ABSTRACT FROM AUTHOR]

Novel 1,3,4-oxadiazole-functionalized pyrido[2,3-d]pyrimidine derivatives were prepared starting from 2-amino-6-(thiophen-2-yl)-4-(trifluoromethyl)nicotinonitrile, which was reacted with trifluoroacetic acid in the presence of conc. H2SO4 and further with bromoethyl acetate to obtain ethyl 2-{4-oxo-7-(thiophen-2-yl)-2,5-bis(trifluoromethyl)pyrido[2,3-d]pyrimidin-3(4H)-yl}acetate. The reaction of the latter products with hydrazine hydrate gave 2-{4-oxo-7-(thiophen-2-yl)-2,5-bis(trifluoromethyl)pyrido[2,3-d]pyrimidin-3(4H)-yl}acetohydrazide. The subsequent treatment of the products with a series of aromatic acids resulted in the synthesis of 3-[(5-aryl-1,3,4-oxadiazol-2-yl)methyl]-7-(thiophen-2-yl)-2,5-bis(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-ones and 2-aryl-5-({[7-(thiophen-2-yl)-2,5-bis(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-yl]oxy}methyl)-1,3,4-oxadiazoles. All the synthesized final products were tested for anticancer activity against 4 human cancer cell lines: such as A549-Lung cancer (CCL-185), MCF7-Breast cancer (HTB-22), DU145-Prostate cancer (HTB-81), and HeLa-Cervical cancer (CCL-2). Some of the tested compounds showed promising anticancer activity. [ABSTRACT FROM AUTHOR]

One-pot efficient copper-catalyzed approach for the synthesis of tetracyclic chromeno[4',3':4,5]pyrimido[1,2-b]indazolone and chromeno[4,3-d]-[1,2,4]triazolo[4,3-a]pyrimidine derivatives as a class of pharmacologically interesting compounds through the intramolecular domino condensation–aza-Diels–Alder reaction of aminoazoles and o-propargylated salicylaldehydes under reflux conditions has been described. [ABSTRACT FROM AUTHOR]

A new Fe3O4/Mo-MOF (metal–organic framework) magnetic nano polymer was synthesized in one step and Ultrasound assisted. Fe3O4/Mo-MOF magnetic nano polymer was characterized by XRD, SEM, EDX mapping BET, VSM, and FT-IR. The results of the structure confirmation revealed that the ultrasonic method had created unique properties in the Fe3O4/Mo-MOF magnetic nano polymer, and its biological and catalytic applications were investigated. A new pyrano[2,3-d]pyrimidines derivative was synthesized using the catalytic activity of Fe3O4/Mo-MOF magnetic nano polymer in a three-component reaction involving malononitrile, aldehyde derivatives, and barbituric acid derivatives with Fe3O4/Mo-MOF magnetic nano polymer as a magnetic catalyst. In the antimicrobial activity of Fe3O4/Mo-MOF magnetic nano polymer: Antimicrobial properties on gram-positive, gram-negative, and fungal strains based on MIC, MBC, and MFC value. The results of catalytic and biological studies proved that nanoparticles have unique properties attributed to their structure and synthesis method. [ABSTRACT FROM AUTHOR]

Design and synthesis of two series of trifluoromethyl-containing polysubstituted pyrimidine derivatives in order to seek more effective anti-tumor drugs, and the antiproliferative activity of these compounds against four human tumor cell lines (PC-3, MGC-803, MCF-7, HGC-27) was evaluated by MTT method. Most of the compounds have moderate anti-proliferative activities, among which compounds (XXId) and (XXIe) have good selectivity for PC-3 cells. The IC50 (concentration required to achieve 50% inhibition of the tumor cell proliferation) values of compounds (XXId) and (XXIe) for PC-3 cell were 4.42 ± 0.46 μmol L–1 and 4.85 ± 0.59 μmol L–1, respectively, and their anti-proliferative activities were significantly better than that of the positive control 5-fluorouracil (6.39 ± 0.71 μmol L–1). Molecular docking results indicated that compounds (XXId) and (XXIe) were likely to be well integrated in the hydrophobic pocket of ubiquitin-specific protease 7 (USP7), which has the value of further research and development. [ABSTRACT FROM AUTHOR]

A series of 3-amino-4-substituted phenyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-d]pyrimidin-6-imines was synthesized. In vitro antibacterial and antifungal screening indicated that some compounds show good inhibition in comparison with standard drugs amoxycillin, chloramphenicol, ciprofloxacin, norfloxacin, griseofulvin, and nystatin. [ABSTRACT FROM AUTHOR]

Based on the molecular docking simulation and structure of larotrectinib, some larotrectinib derivatives as antitumor compounds were designed and synthesized. The antitumor activities of the synthesized compounds were tested by A549 and H1975 cell lines with larotrectinib as the positive control drugs. The molecular docking of the selected compounds with protein was carried out to further explain the binding modes and the ADME data of the compounds were predicted, which showed that the compounds had good physicochemical property and biological characteristics. The results showed that the selected compounds had further research potential. [ABSTRACT FROM AUTHOR]

Pyrimidine ring is an integral constituent of many natural biological systems, and pyrimidine derivatives have numerous synthetic and biological applications; therefore, there is great interest in the synthesis of pyrimidines for commercial purposes from pharmaceutical industry. In this work, a simple, efficient, and convenient methodology was developed for the synthesis of two series of bis-pyrimidine derivatives by the reaction of bis-chalcones with guanidine hydrochloride or thiourea under basic conditions. The synthesized compounds were evaluated for their antimicrobial and DNA photocleavage activity, and compounds of both series showed excellent potencies, especially those containing sulfur. It was also found that the antimicrobial activity strongly depended on the size and orientation of the olefinic/aromatic linker. The synthesized com-pounds showed excellent DNA photocleavage activity under UV light, which makes them promising from the viewpoint of anticancer drug discovery. [ABSTRACT FROM AUTHOR]

The present study describes an efficient access to enantioenriched pyrimidines' derivatives from readily available Boc-AA-NH2 and β-enaminones. This strategy allows the synthesis of a large variety of chiral pyrimidines (18 examples) with good yields from the chiral pool. In the case of peptide isosteres, this procedure proved to be highly stereoretentive and paves the way to the construction of C-terminal modified peptidomimetics as illustrated in the synthesis of two original pyrimidines containing pseudo-dipeptides. [ABSTRACT FROM AUTHOR]

A highly efficient synthetic methodology for the preparation of 2-thioxocytosine was achieved by the nucleophilic addition of thiourea to α-cyanocinnamonitrile followed by intramolecular cyclization. The reaction smoothly proceeds in the presence of K2CO3-NPs as mild basic catalyst with yield 85%. The product was annulated to new imidazo[1,2-c]pyrimidine derivatives. Besides, Schiff base and acylated pyrimidine derivatives were synthesized via condensation or acylation with triethyl orthoformate, formic acid, maleic anhydride, benzoyl chloride or acetic anhydride. [ABSTRACT FROM AUTHOR]

Ribociclib and palbociclib, two typical selective CDK4/6 inhibitors, which have been employed in clinic for the treatment of estrogen receptor positive (ER+) breast cancer, possess an active fragment of pyrrolo[2,3-d]pyrimidine and pyrido[2,3-d]pyrimidine, respectively. Herein, 25 novel pyrrolo(pyrido)[2,3-d]pyrimidine derivatives have been designed and synthesized based on molecular diversity. Their antiproliferative activity was evaluated against ER+ (T47D) and triple-negative (MDA-MB-436) breast cancer cell lines. The obtained results demonstrated that dihydroartemisinin-pyrrolo[2,3-d]pyrimidine and dihydroartemisinin-pyrido[2,3-d]pyrimidine derivatives are characterized by significant antiproliferative effects on both cell lines and have higher anticancer activity against triple-negative breast cancer cells compared to ribociclib. [ABSTRACT FROM AUTHOR]

Pyrimidine compounds have proven to be effective and efficient additives capable of protecting mild steel in acidic media. This class of organic compounds often functions as adsorption-type inhibitors of corrosion by forming a protective layer on the metallic substrate. The present study reports a computational study of forty pyrimidine compounds that have been investigated as sustainable inhibitors of mild steel corrosion in molar HCl solution. Quantitative structure property relationship was conducted using linear (multiple linear regression) and nonlinear (artificial neural network) models. Standardization method was employed in variable selection yielding five top chemical descriptors utilized for model development along with the inhibitor concentration. Multiple linear regression model yielded a fair predictive model. Artificial neural network model developed using k-fold cross-validation method provided a comprehensive insight into the corrosion protection mechanism of studied pyrimidine-based corrosion inhibitors. Using a multilayer perceptron with Levenberg–Marquardt algorithm, the study obtained the optimal model having a MSE of 8.479, RMSE of 2.912, MAD of 1.791, and MAPE of 2.648. The optimal neural network model was further utilized to forecast the protection capacities of nine non-synthesized pyrimidine derivatives. The predicted inhibition efficiencies ranged from 89 to 98%, revealing the significance of the considered chemical descriptors, the predictive capacity of the developed model, and the potency of the theoretical inhibitors. [ABSTRACT FROM AUTHOR]

This study aimed to synthesize a new pyrimidine derivative with a good synthesis yield of 87% to act as a new cancer marker after radiolabeling with Tc-99m in a high radiochemical yield of 92.3%. In-vivo study in tumor-bearing Swiss albino mice model revealed promising data with high uptake in cancer. Docking study showed good binding interactions of the radiosynthesized complex at the binding site. In conclusion, this novel complex could be a potential probe for cancer targeting. [ABSTRACT FROM AUTHOR]

The protein ATP-binding cassette subfamily G member 2 (ABCG2) is one of the major factors behind multidrug resistance (MDR) in breast cancer. We performed three-dimensional quantitative structure–activity relationship (3D-QSAR) modelling, docking, and molecular dynamics (MD) simulation to design pyrimidine-based ABCG2 antagonists. The developed QSAR model (r2 = 0.92, q2 = 0.82, and good cross-validated r2 = 0.73) dictate requirement of electrostatic, and hydrophobic fields for modulating bioactivity. Based on this rationale, we designed and screened 1010 new compounds, among them 2 (ND-510 and ND-500) exhibit excellent drug-like features. Comparative molecular docking, MM/GBSA and ADMET profiles were determined to understand the interactive poses, affinity, and drug-likeness of the designed compounds. Furthermore, MD simulations were performed with the ABCG2 receptor, and the results were compared with the two earlier synthesized active compounds. The outcomes of the study will help researchers to develop new antagonists for treatment of MDR breast cancer. [ABSTRACT FROM AUTHOR]

Antimalarial drug resistance is a major threat due to the emerging resistance to all the available drugs in the market. In an approach to develop alternative drugs, a novel class of Pf-DHFR inhibitors was developed using pyrimidine as the core nucleus and substituting the 4- and 6- positions with amines and 4-amino benzoic acid (PABA) to avoid the problem of drug resistance. The resultant compounds 3(a–j) after primary in silico screening and filtering were synthesized using microwave efficiently in high yield and reduced time period compared to conventional synthesis. The antimalarial assay was performed in vitro, against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum using chloroquine as a reference standard. The IC50 values were in the range of 5.26–106.76 µg/ml for 3D7 and in Dd2 the value ranges from 4.71 to 112.98 µg/ml. Compounds 3d, 3e, 3f and 3h showed significant antimalarial activity against both the strains of P. falciparum with no cytotoxicity against fibroblast cell line and 3f was found to be the most potent among them. The hemolysis assay of all the compounds in fresh erythrocytes showed insignificant hemolysis below 5% at a higher dose level. Hence, the present study suggests the possible utility of PABA-substituted pyrimidine scaffold for further development of new Pf-DHFR inhibitors. [ABSTRACT FROM AUTHOR]

Cyclization of previously synthesized ethyl 2-amino-4-(1,4-benzodioxan-2-yl)thiophene-3-carbox-ylate with formamide gave 5-(1,4-benzodioxan-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one which was treated with phosphoryl chloride in pyridine to obtain the corresponding 4-chloro derivative. The latter reacted with various primary and secondary amines to produce a series of new thieno[2,3-d]pyrimidines containing a pharmacophoric fragment at the 4-position. The reaction of 5-(1,4-benzodioxan-2-yl)-4-chlorothieno[2,3-d]pyrimidine with hydrazine hydrate afforded the corresponding 4-hydrazinyl derivative which was cyclized with formic acid to thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivative. Antihypoxic properties of the synthesized compounds were studied. [ABSTRACT FROM AUTHOR]

Herein, the biological activities including antibacterial, antifungal, and in-vitro cytotoxicity for some novel substituted pyrazolo[3,4-d]pyrimidinone, benzylidene dihydropyrimidine, pyrano[2,3-d]pyrimidine, hexahydropyrimido[4, 5-d]pyrimidinone, tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile, and pyrido[2, 3-d:6,5-d'] dipyrimidinone derivatives were investigated. The synthesized novel compounds were achieved through the incorporation of the active moieties such as halo compound, pyrazolo, pyrano, pyrimido, pyrido-derivatives with active methylene group in thiobarbituric acid derivatives at C-5. Structures of all synthesized compounds were characterized by spectral techniques including IR, 1H-NMR, MS, and 13C-NMR. All synthesized compounds were screened for their antibacterial and antifungal activity, while the most promising compounds were selected to investigate their in-vitro cytotoxic efficacy against normal Vero cells and cancerous Caco-2 cells. Data showed that the biological activities were concentration-dependent. All novel pyrimidine derivatives exhibited broad-spectrum antimicrobial activity with a varied zone of inhibition ranging between 11.3 ± 0.6 and 25.3 ± 0.6 mm. The MIC values are different according to a pathogenic organism (ranging between 3.91 and 500 µg mL−1), whereas the MBC/MFC were 2 × to 4 × MIC value. Data of in-vitro cytotoxicity confirm the efficiency of selected novel pyrimidine derivatives to target Caco-2 cancerous cells at low concentrations more Vero normal cells. Four selected compounds 4, 7b, 10, and 12 displayed IC50 values of 286.73 ± 4.54, 138.07 ± 8.21, 332.48 ± 18.75, and 241.18 ± 15.60 µg mL−1, respectively, for normal Vero cell line, whereas it was 271.55 ± 3.68, 65.94 ± 2.36, 121.16 ± 4.96, and 82.28 ± 4.08 µg mL−1, respectively, for Caco-2 cancerous cell line. [ABSTRACT FROM AUTHOR]

A new series of 4-(1H-imidazol-4-yl)-2-(substituted phenyl)-1,4-dihydrobenzo[4,5]imidazo[1,2-a]-pyrimidines have been synthesized via a one-pot reaction using PEG-400 as a green solvent in the first step and butan-1-ol in the second step. The structures of the synthesized compounds have been confirmed by spectral data, including IR, 1H and 13C NMR and mass spectra, and their in vitro antimicrobial and antitubercular activities have been evaluated. [ABSTRACT FROM AUTHOR]

Based on tyrosinase inhibition science, two pyrimidine derivatives were designed and studied. Docking of 2-dibenzylamine-5-hydroxy pyrimidine (dba5HP) and 2-benzylamino-5-hydroxy pyrimidine (ba5HP) on mushroom tyrosinase (MT) showed that the former could not occupy MT active site pocket, while ba5HP could do so (Moldock score = − 63.95). MD simulation revealed that the complex of ba5HP-MT reached stability < 30 ns. In silico biocompatibility examinations predicted high permeability, good bioavailability, low toxicity, and synthetic accessibility of 1.59 for ba5HP with high probability for CYP-mediated metabolism. Subsequently, both compounds were synthesized in good yields. Kinetics studies proved that, unlike dba5HP, ba5HP could strongly inhibit MT competitively (IC50 = 32.28, Ki = 11.32 μM). Considering the facile synthesis, potential for structural modifications, and passing most of the lead-likeness filters, it seems likely that ba5HP plays key roles in the syntheses of novel depigmentation medicines as well as more specific inhibitors for various tyrosinases and polyphenol oxidases. [ABSTRACT FROM AUTHOR]

Urease is a dinickel enzyme that is responsible for the hydrolysis of urea to ammonia and carbon dioxide. A series of bacteria like Helicobacter pylori produce urease in order to release ammonia via urea hydrolysis and survive in acidic environments. Urease inhibitors are often used as a part of the medical treatment of infections by ureolytic bacteria. In this work, a series of diaryl pyrimidine derivatives (compounds 6a–6i) have been synthesized as urease inhibitors, their inhibitory activities against Jack bean urease have been investigated in vitro, and the obtained values of IC50 showed potent urease inhibitory activity. Cytotoxic activity of the synthesized compounds was evaluated against four cell lines (HT-29, MCF-7, T47D, and NIH3T3). Many of the tested compounds did not show significant cytotoxicity, and compounds 6d, 6g, and 6i did not show any cytotoxic activity against these cell lines. Among these, compound 6d showed the most pronounced urease inhibitory activity (IC50 = 780 ± 50nM), being over 28-fold more potent than thiourea (IC50 = 22.01 ± 0.08 ìM) and 128-fold more potent than hydroxyurea (IC50 = 100.00 ± 0.08 ìM) as standard inhibitors, respectively. The results of molecular docking studies showed that compound 6b had the best binding energy and exhibited proper interaction with the active site of urease. [ABSTRACT FROM AUTHOR]

Twenty compounds of pyrazolo[1,5-a]pyrimidines 14a–j and pyrazole derivatives as Schiff bases 16a–j have been synthesized by the reaction of 5-amino-pyrazole derivatives 9a, b with 2-(arylidene)malononitriles 10a–e or various aldehydes 15a–e, respectively. The biological activity of the pyrazolo[1,5-a]pyrimidines 14a–j and pyrazole derivatives 16a–j was evaluated and showed a variation in antimicrobial inhibitory activity. In particular, the three pyrazolo[1,5-a]pyrimidines (14b, 14e, and 14j) and four pyrazole Schiff bases (16c, 16d, 16 h, and 16i) have possessed a broad spectrum of activity with the inhibition zone range from 15 to 20 mm. Also, the structure–activity relationship study was done. Furthermore, physicochemical properties, drug-likeness model score, bioactivity scores, ADME, and toxicity properties were predicted in silico and some products possessed acceptable and a good results. Finally, the molecular docking studies performed inside the active site of DNA gyrase (PDB: 2XCT), the secreted aspartic protease from C. albicans (PDB: 1ZAP), and exhibited lower binding energy with different types of binding mode. Besides, the electrostatic potential maps were generated to determine the charge distribution around a molecule and therefore determine the regions that could form hydrogen bonding donors and acceptors that confirmed the binding mode in the docking study. The results suggested that these derivatives could act as antimicrobial agents. [ABSTRACT FROM AUTHOR]

A series of new pyrazolo[3,4-d]pyrimidine derivatives were designed, synthesized and evaluated against leukemia cell lines. All the compounds showed good in vitro anti-proliferative activities and some of them were 8–10 times more potent than BTK inhibitor ibrutinib. The IC50 values of promising compounds (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-2-bromoprop-2-en-1-one (IIc), (R,Z)-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-enenitrile (IIk), (R,E)-4-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) piperidin-1-yl)-4-oxobut-2-enenitrile (III) were observed in the range of 0.84–2.9 μM against L1210, K562 and HL-60 cell lines. [ABSTRACT FROM AUTHOR]

A series of novel N-pyridine substituted 2-chloro-thieno[2,3-d]pyrimidin-4-amine derivatives has been synthesized and characterized by 1H and 13C NMR spectrometry. All the compounds have been docked against acetyl-CoA carboxylase enzyme and also tested for their in vitro antimicrobial activity on Gram-positive (Micrococcus luteus, staphylococcus aureus) and Gram-negative bacteria (Salmonella typhi, klebsiella pneumoniae), and anti-fungal activity on aspergillus niger and fusarium oxysporum. All synthesized compounds have demonstrated moderate activity, and two products have exhibited good antibacterial and antifungal activity. [ABSTRACT FROM AUTHOR]

We studied the reaction of enaminone 3 with some nitrogen nucleophiles to afford the corresponding pyrazole 4, isoxazole 5, and pyrimidine 6 derivatives, and the reactivity of enaminone 3 with heterocyclic amines to afford the corresponding fused pyrrolo[1,2-a]pyrimidine 9a, imidazo[1,2-a]pyrimidine 9b, phenylpyrrolo[1,2-a]pyrimidine 9c, and benzo[4,5]imidazo[1,2-a]pyrimidine 11 derivatives. Additionally, the electrophilic azo-coupling reaction of enaminone 3 with aromatic diazonium salts in pyridine afforded the corresponding intermediate hydrazines 13a–d, which cyclized to pyrazolo[5,1-c][1,2,4]triazine derivatives 14a–d. Moreover, addition of (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one (3) with hydrazonoyl chloride derivatives 15a,b gave novel pyrazole derivatives 17a,b. Almost all of the synthesized heterocyclic compounds exhibited antimicrobial and in vitro anticancer activity (HepG2 and MCF-7 cell lines). Furthermore, the molecular docking of the most effective compound, i.e., 7-(4-fluorophenyl)pyrazolo[5,1-c][1,2,4]triazin-3-yl)(2-hydroxyphenyl)methanone (14c), was studied against (PDB ID: 3t88), (PDB ID: 2wje), (PDB ID: 4ynt), and (PDB ID: 1tgh) to investigate its antimicrobial activity when attached to different proteins with short bond length. Compound 14a docked with (PDB ID: 4hdq) and (PDB ID: 3pxe) with energy affinity of −9.946 and −10.55 kcal/mol, with the pyrazolo[5,1-c][1,2,4]triazine derivative involved in the pockets of the proteins. Moreover; the theoretical and investigational studies of compounds 14a,c were compatible with spectral data obtained at HF/6-31G(d) and DFT/B3LYP/6-31G(d) level. [ABSTRACT FROM AUTHOR]

The current study focused on effective and straightforward routes for preparing a new series of thieno[2,3-d]pyrimidine derivatives in addition to their acyclo nucleosides analogue. The chemical structures of the synthesized products have been elucidated through diverse spectroscopy analyses such as (IR, NMR, MS, and elemental analyses). Some selected thienopyrimidine derivatives were investigated for their anticancer activity against two human cancer cell lines (HepG-2 and MCF-7). The results revealed that compounds 3-ethyl-2-hydrazineyl-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-oneand3-ethyl-2-(2-glucozylidenehydrazineyl)-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one showed the most potent anticancer activity. [ABSTRACT FROM AUTHOR]

The alkaloid 4-O-methylsinomenine was modified by introducing pyrimidine substituents at the C-1 position of the backbone. Two methods were used to synthesize these hybrid molecules. The first method involves the preparation of 1-ethynyl-4-O-methylsinomenine and a sequence of cross-coupling reactions with benzoic acid chlorides and cyclocondensation with amidines. The second method is based on palladium-catalyzed carbonylation–cross coupling of 1-iodo-4-O-methylsinomenine with phenylacetylene in the presence of Mo(CO)6 as a source of CO in MeCN and subsequent cyclocondensation of alkynyl ketone with amidines. The carbonylation–crosscoupling reaction proceeded selectively in the presence of the PdCl2/(1-Ad)2PBn catalytic system. [ABSTRACT FROM AUTHOR]

A new method for the synthesis of quinazolines based on the annulation of the benzene ring to 5-acetyl-6 methylpyrimidin-2-one(thione) derivatives has been proposed. Condensation of the latter at the methyl group with dimethylformamide dimethyl acetal in boiling PhH leads to the formation of 5-acetyl-6-[2-(dimethylamino)vinyl]pyrimidin-2-ones(thiones), which, when boiled with MeONa in MeOH, cyclize to 5-hydroxyquinazolin-2-ones(thiones). Similarly, 5-acetyl-6-methyl-4-(trifluoromethyl)pyrimidine was converted to 5-hydroxy-4-(trifluoromethyl)quinazoline. Quinazolines are not formed from 5-acetyl-6-methylpyrimidines condensed with dimethylformamide dimethyl acetal at the acetyl group, but 5-acetyl-6-methylpyrimidines can be used to obtain pyrido[2,3-d] pyrimidine derivatives. [ABSTRACT FROM AUTHOR]

Herein, synthesis of a new series of pyrano[2,3-d]pyrimidine scaffolds is presented. Ethyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate has been reacted with formamide, formic acid, urea, thiourea, semicarbazide, and thiosemicarbazide to give six new pyrano[2,3-d]pyrimidine derivatives in moderate to high yields (48–78%). Acylation and intramolecular cyclization of pyran with carbon disulfide, ethyl cyanoacetate, acetic anhydride, or chloroacetyl chloride has resulted in formation of the corresponding desired bicyclic pyrimidine derivatives. The chloromethyl derivative was subjected to nucleophilic substitution by its reaction with morpholine, piperidine or aniline resulting in the corresponding 2-substituted pyrimidine derivatives in good yields. [ABSTRACT FROM AUTHOR]

New derivatives of imidazo[1,5-a]pyrimidine have been synthesized by cyclization of in situ generated 1H-imidazol-4(5)-amine with 1,3-diketones or malondialdehyde derivatives. Utilization of asymmetrical 1,3-diketones leads to the formation of a mixture of regioisomers. The discovered conversion of imidazo[1,5-a]pyrimidine core into 3H-imidazo[4,5-b]pyridine that takes place only under acidic conditions can be considered as a new version of Dimroth rearrangement involving cleavage of C–N bond and formation of C–C bond. [ABSTRACT FROM AUTHOR]

A series of new pyrrolo[2,3-d]pyrimidine derivatives were prepared in good yields via the reaction of 6-aryl-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones with 1-chloropropan-2-ol, 3-chloropropane-1,2-diol, and 2-(2-chloroethoxy)ethanol. Some 6-aryl-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones were converted to 2-(6-aryl-4-oxo-7-phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-3-yl)acetohydrazides through intermediate esters, and the corresponding hydrazones were synthesized by the condensation with monosaccharides such as arabinose, glucose, and fructose. The structure of the newly synthesized compounds was elucidated by microanalytical and spectroscopic measurements. Some of the new compounds were shown to have promising antimicrobial (compared to Gentamicin) and antiviral activities (compared to Ribavirin), including the activity against Newcastle disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A series of new benzo[d][1,2,3]triazol-1-yl-pyrazole-based dihydro-[1,2,4]triazolo[4,3-a]pyrimidine derivatives 4a-p were synthesized and well characterized by using IR, 1H, 13C NMR and mass spectral data. Finally, the structure of the compound 4l was solved unambiguously by single-crystal X-ray diffraction (SXRD) which confirms all the structures 4a–p. The in vitro α-glucosidase inhibition, anticancer (A549 and MCF-7 cell lines) and antioxidant studies of the title compounds 4a–p were screened. Among all the compounds, 4g, 4h and 4n exhibited significant α-glucosidase inhibition activity with the IC50 values 20.12 ± 0.19 µM, 21.55 ± 0.46 µM and 24.92 ± 0.98 µM. Similarly, the compounds 4h, 4d and 4e showed potent anticancer activity against A549 (human lung carcinoma) cell line with IC50 values 3.64 µM, 4.73 µM and 4.56 µM, respectively, whereas the compounds 4c and 4o displayed potent anticancer activity against human breast cancer (MCF-7) cell line with IC50 values of 2.66 µM and 2.11 µM. In addition, the antioxidant activity revealed that the compounds 4e and 4h exhibited potent antioxidant activity (IC50: 4.25 µM and 5.40 µM). To determine the safety profile of the most active compounds 4c, 4d, 4e, 4g, 4h, 4n and 4o were tested against non-cancer HEK293 cell line (human embryonic kidney 293), results in the lower toxicity of these compounds. New benzo[d][1,2,3]triazol-1-yl-pyrazole-based dihydro-[1,2,4]triazolo[4,3-a]pyrimidines were synthesized. The target compounds were showed significant α-glucosidase inhibition, anticancer and antioxidant activities. [ABSTRACT FROM AUTHOR]

Difficultly accessible pyrimidine, thiazolopyrimidine, triazolopyrimidine, and thiazinopyrimidine derivatives containing an oleyl residue were synthesized via alkylation of 6-oleyl-2-thiouracil. The structure of the synthesized compounds was established on the basis of their spectral data, elemental analyses, and chemical behavior. The in vitro cytotoxicity of selected compounds was screened against two human cancer cell lines, MCF-7 breast cancer and HepG2 liver cancer cell lines. 8-[(8Z)-Heptadec-8-en-1-yl)-3-hydroxy-3,4-dihydropyrimido[2,1-b][1,3]thiazin-6(2H)-one turned out to be the most potent with IC50 values of 12.5 and 20 μg/mL against MCF-7 and HepG2 cancer cell lines, respectively. The structure–activity relationship for this compound was interpreted in terms of molecular docking and molecular dynamics studies. [ABSTRACT FROM AUTHOR]

The mechanism of a multicomponent reaction between aminoazoles, 1-morpholino-2-nitroalkenes, and benzaldehyde was studied in acidic medium. Performing the reaction in acetic acid led to the formation of 6-nitro-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidines, which subsequently underwent a rearrangement. Reaction conditions were proposed for a multicomponent synthesis with trioxane, and the alkylation reactions of 4,7-dihydroazolo[1,5-a]pyrimidine nitro derivatives were optimized. [ABSTRACT FROM AUTHOR]

In the present paper we synthesized 10 unique pyrimidine scaffolds (Lanso Aminopyrimidines) derived from 4-(2,2,2-trifluoroethoxy)-2-(chloromethyl)-3-methylpyridine as a core molecule, which can be used for the design of more potent and effective anticancer agents. The in vitro anticancer activities of the synthesized new pyrimidine derivatives were screened at the National Cancer Institute, USA, against a full NCI 60 cell lines. Most of the compounds exhibited remarkable growth inhibition at a single dose (10 µM) in Leukaemia cancer cell. 4-(4-{3-Methyl-4-[(2,2,2-trifluoroethoxy)pyridin-2-yl]methylamino}phenyl)-6-phenyl-1,6-dihydropyrimidin-2-amine which showed high activity against RPMI-8226 leukaemia cancer cells (GI50 35.50 µM) and can be considered as a candidate lead compound for developing new promising anticancer agents. [ABSTRACT FROM AUTHOR]

"Double" derivatives of the drug Xymedon (1,2-dihydro-4,6-dimethyl-1-N-(hydroxyethyl)pyrimidone-2), hereafter referred to as pyrimidine (I), in which the pyrimidine (I) molecules are joined by an alkyl(xylylenyl)dionate bridge have been synthesized. Primary data on the hepatoprotective activity of five "double" pyrimidine (I) derivatives with different numbers of methylene groups and a meta-xylylene fragment in the ester bridge have been obtained on normal human hepatocytes of the Chang Liver cell line. The cytotoxicity and the cytoprotective properties of the new compounds against the background of exposure to d-galactosamine at a concentration of 150 mmol/L have been determined, their effect on the cell cycle compared with that of the initial pyrimidine (I) has been studied, and the dependence of the biological properties of the derivatives on their structure has been established. [ABSTRACT FROM AUTHOR]

2-Oxo-2,5,6,7-tetrahydro-3-cyano-1H-cyclopenta[b]pyridine was used as the starting point to develop an accessible synthesis of condensed cyclopentanopyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives. The neurotropic activity of these compounds was studied, and a number of them showed anticonvulsant activity as antagonism to corasol. Compound II, like diazepam, had anti-anxiety and activating effects, while the other compounds had sedative activity. [ABSTRACT FROM AUTHOR]

A number of new pyrazole and pyrimidine derivatives containing an allylmorpholine fragment were obtained by reactions of chromone-containing allylmorpholines with 1,2- and 1,3-binucleophiles (hydrazine, guanidine, acetamidine). The syntheses were carried out under mild conditions (ethanol, room temperature), and the target products were isolated with high yields. The obtained compounds are of interest as potential cholinesterase inhibitors. [ABSTRACT FROM AUTHOR]

Novel scaffold of 1,3,4-thiadiazolo-(3,2-α)-pyrimidine-6-carbonitrile derivatives was designed based on SAR of known inhibitors of STAT3 and synthesised using optimized reaction condition. These compounds were subjected to in silico studies using Discovery studio software and evaluated for their anticancer activity. A docking study of the newly synthesized compounds was performed; the results showed good binding mode in the active site of STAT3 enzyme. Among the synthesized compounds, compounds B4 and B5 show binding similar to standard drug static. The cellular evaluation indicates that the anticancer activity of compounds B4, B5 (IC50 = 54.51 ± 2.02 µg/mL and 45.43 ± 1.05 µg/mL, respectively) is active against MDA-MB-232 cell line and compounds B5, B7 (IC50 = 40.21 ± 3.01 µg/mL, 56.77 ± 2.96 µg/mL, respectively) are most active against MCF-7 cell lines. From in vitro result, compound B5 subjected to acute oral toxicity studies by OECD 423 guidelines and in vivo anti-cancer studies carried out using DMBA-induced model. [ABSTRACT FROM AUTHOR]