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• Novel pyrazolo-pyrano[2,3- d ]-pyrimidine molecular hybrids were reported. • Its structure elucidation was established via different spectroscopic techniques. • Synthesized compounds were evaluated anti-diabetic activity (in vitro) against α-glucosidase and α-amylase enzymatic inhibition. • Compound 7d showed the high potency inhibitory activity for the α-glucosidase, and α-amylase. • Binding interaction was also validated with molecular docking studies. The anti-diabetic potential of newly synthesized pyrazolo-pyrano[2,3- d ]-pyrimidine analogues (7a-j) was evaluated through comparative screening against two enzymatic targets like α-glucosidase and α-amylase. All newly prepared molecules were characterized and confirmed by 1HNMR, 13CNMR, and HR-MS analysis. The in vitro anti-diabetic activity was screened using α-glucosidase and α-amylase enzymatic inhibition using Acarbose as standard. Among these, compound (7d) exhibited the most potent anti-diabetic activity IC 50 value of 1.18 µM, and 21.63 µM for the α-glucosidase, and α-amylase inhibition respectively, surpassing the IC 50 values of 3.26 µM and 32.21 µM for the reference Acarbose. The molecules' structural study revealed that the para-position electron-withdrawing (NO 2) group were crucial to the inhibitory activity. The other hybrid scaffolds 7f, 7c, and 7 h also exhibited good inhibition compared with reference. A molecular docking study were performed for all the molecules, and based on the AutoDock vina program score, and was further considered for molecular dynamics simulations. The investigation included a look at protein stability, APO-protein dynamics, and interactions. Using molecular dynamics simulations, the overall RMSD analysis of APO protein of α-amylase (PDB: 1B2Y), and α-glucosidase (PDB: 5NN8) forms showed a stable interaction and the average RMSD value is 1.93±0.18 Å and 1.62±0.17 Å. These novel pyrazolo-pyrano[2,3- d ]-pyrimidine molecular hybrids have the potential to be useful in the treatment of diabetes. [ABSTRACT FROM AUTHOR]

• Synthesis of substituted ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylates. • Characterization of synthesized compounds by IR, NMR and HRMS. • Anti-tubercular activity against Mycobacterium tuberculosis (Mtb) H37Rv strain. • In-silico molecular modeling studies against DHFR enzyme and MMGBSA analysis. • MD simulations, RMSD and RMSF suggest stable complex and potent inhibitory effect. A small library of substituted ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate was designed and synthesized. All the characterized molecules were screened for their anti-tubercular activity using the H37Rv strain of Mycobacterium tuberculosis (Mtb). The compounds 5c, 5d, 5f, 5h , and 5k showed equipotent activity (MIC 3.12 µg/mL), compounds 5b, 5e, 5g , 5i, and 5j were more potent (MIC 1.6 µg/mL), whereas, 5a and 5l shown moderate activity (MIC 6.25 µg/mL). The potent inhibitory activity of screened compounds was rationalized with in-silico molecular modeling studies against the Mtb- dihydrofolate reductase (DHFR) enzyme. Compound 5i displayed a good docking score of −8.56 Kcal/mole with H-bond and hydrophobic interactions. These interactions revealed the stability of the complex which in turn determined the potent inhibitory effect. To get in-depth mechanistic insight into the inhibitory effect and to assess the stability of the ligand–protein complex, a molecular dynamics (MD) simulation study was performed. The RMSD and RMSF values obtained by the MD simulation study were 2.39 Å and 0.92 Å, respectively. The obtained values suggested that the drug–ligand complex maintained the stability over entire 100 ns run and the molecule did not fluctuate. The H-bond and hydrophobic interactions displayed in molecular docking studies were found to be retained in the MD simulation run. The obtained MD simulation values indicate that the complex was stable and rationalize the potent inhibitory effect. The drug-likeliness properties of potent compounds were calculated and the values thus obtained suggested that the molecule 5i has drug-likeliness properties and complies with Lipinski's rule of five/Ro3. Hence, the identified compounds can be taken into further stages of drug discovery processes. [Display omitted] [ABSTRACT FROM AUTHOR]

• New library of pyrimido[5,4- e ][1,2,4]triazolo[1,5- c ]pyrimidine derivatives was designed and synthesized. • All the newly synthesized compounds were screened for their herbicidal activities by Petri dish assays and pot experiments in a glasshouse. • The inhibitory efficacies of the target compounds against ALS were evaluated, and molecular docking analysis is performed. • The results of bioassay and molecular docking indicated that compound 7 2-((2,4-dichlorophenoxy)methyl)-10-(methylthio)-8-(pentylthio)-5-propyl-5,6-dihydro pyrimido[5,4- e ][1,2,4]triazolo[1,5- c ]pyrimidine showed excellent biological activities and exhibited good affinities for ALS, and could be possibly acted as a lead compound of ALS inhibitor. The development of nitrogen-containing heterocyclic compounds with novel structure and remarkable biological activity is always in demand. Herein, new library of pyrimido[5,4- e ][1,2,4]triazolo[1,5- c ]pyrimidine derivatives (1–98) was designed, synthesized, and characterized by Fourier Transform Infrared Spectoscopy (FT-IR), nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic resonance (13C NMR), high-resolution mass spectroscopy (HRMS), and X-ray single-crystal diffraction. Their herbicidal activities were screened for the first time by Petri dish assay and pot experiment in a glasshouse. The results indicated that some of title compounds (e.g., 1, 4, 5 , and 7–11) exhibited 100 % inhibition rate against the roots and stalks of Cucumis sativus, Raphanus sativus, Sorghum bicolor and Echinochloa crusgalli at a dosage of 100 mg/L, higher than the positive control Flumetsulam, a well-known commercial acetolactate synthase (ALS) inhibiting herbicide. 2-((2,4-Dichlorophenoxy)methyl)-10-(methylthio)-8-(pentylthio)-5-propyl-5,6-dihydropyri- mido[5,4- e ][1,2,4]triazolo[1,5- c ]pyrimidine 7 showed notable postemergence herbicidal activity against Abutilon theophrasti, Amaranthus spinosus, Chenopodium album, Digitaria sanguinalis, Echinochloa crusgalli , and Setaria viridis at a rate of 375 g/ha, and its activities were similar to the positive control Flumetsulam. Enzymatic bioassays revealed that 7, 8 , and 40 displayed good inhibitory potency against ALS with 39.6 %, 39.1 %, and 40.9 % inhibition rate, respectively, comparable to that of Flumetsulam (43.5 % inhibition rate). Moreover, molecular docking analysis was conducted by using ALS protein and target ligand molecule 7. The results of molecular docking were consistent with the bioassay experiments, showing compound 7 with a new structure and excellent herbicidal potency was potent inhibitors of ALS. [Display omitted] [ABSTRACT FROM AUTHOR]

• A series of rhodamine pyrimidine derivatives (RP1,RP2,RP3 and RP4) and rhodamine pyrimidine nido-carborane derivatives (RPB1,RPB2,RPB3 and RPB4) were successfully synthesized. • Compounds RP4 and RPB4 have a good inhibitory effect on tumor cells in cytotoxicity experiments. • According to cell imaging experiments, compounds RP4 and RPB4 can enter tumor cells through the cell membrane and have good cell compatibility. Because of the advantages of fluorescent drugs consisting of fluorescent dyes and compounds with anticancer activity for therapeutic diagnostics and personalized medicine. A series of fluorescent antitumor drugs rhodamine pyrimidine derivatives (RP1, RP2, RP3 and RP4) were synthesized by linking rhodamine B and pyrimidine derivatives through ethylenediamine bridge and then introduced into nido- carborane to form fluorescent salt derivatives (RPB1, RPB2, RPB3, and RPB4). It improves the tumor targeting and imaging ability of pyrimidine derivatives. By CCK8, it was found that the inhibition rates of RP4 and RPB4 at 10 μg/mL on HeLa, PC-3 and L02 cells were 70.4 %, 68.7 %, 86.1 % and 72.5 %, 76.4 %, 81.0 %, respectively. The compound has strong inhibitory effect on cancer cells. The logP values of compounds RP4 and RPB4 were between 0 and 3, which were easily absorbed and transported through the cell membrane. Further cell imaging experiments showed that RP4 could enter tumor cells through cell membrane and had good biocompatibility. The experimental results show that compounds RP4 has good imaging capability and tumor targeting, and is a potential fluorescent anticancer agents. [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesis of novel hybrid Benzo[4,5]imidazo[1,2- a ]pyrimidine derivatives using ionic liquid (DIPEAc) as a reaction media. • In vitro antimalarial screening of synthesized Benzo[4,5]imidazo[1,2- a ]pyrimidine derivatives. • Molecular docking of active compounds at the binding site of DHFR enzyme. • 3D-QSAR analysis and In silico study of Benzo[4,5]imidazo[1,2- a ]pyrimidine derivatives. • ADMET parameter prediction of active compounds, leading to oral bioavailability evaluation. Synthesis of Benzo[4,5]imidazo[1,2- a ]pyrimidine derivatives using an environmentally friendly Biginelli-type reaction in ionic liquid DIPEAc was performed. Remarkably, this ionic liquid exhibits efficient recyclability over five cycles. Synthesized compounds underwent rigorous in vitro antimalarial efficacy screening, complemented by computational and in vitro studies, assessing their potential as Plasmodium falciparum dihydrofolate reductase (Pf -DHFR) inhibitors. A robust 3D-QSAR model was established and validated, elucidating structure-activity relationships. Estimated ADMET descriptors highlighted favorable pharmacokinetics, suggesting their role in new antimalarial drug development. This study exemplifies the synergy of sustainable synthesis, enzyme inhibition, and pharmacokinetic profiling, promising a transformative outlook for antimalarial innovation. [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesis of new cyanoacetamidopyrimidine compounds and their utility as a starting material for the synthesis of more heterocyclic compounds bearing pyrimidine moiety. • The main objective of this work was to study cytotoxicity and antitumor evaluation of the new pyrimidine derivatives. • Study the structure-activity relationship (SAR) of the newly prepared pyrimidine derivatives. • Study the molecular docking of the newly prepared pyrimidine derivatives. The precursor cyanoacetamide derivatives (6) were achieved by the reaction of pyrimidine derivative 5 with cyanoacetic acid catalyzed by acetic anhydride. The reaction of cyanoacetamide derivative 6 with different reagents afforded many heterocyclic systems such as thioacetic acid (9) , dithiolane derivatives (11) and (12) , 1,8-naphthyridine (14) , quinoline derivatives (17) and (18) , pyridine derivatives 20, 22, 24, 26 , and 27 , pyridazine (30) , pyranopyrimidine (32) , and pyrazolopyrimidine (34). All the newly synthesized compounds were characterized with spectroscopic analyses. Compounds were tested for their anticancer activity against three human cancer cell lines: hepatocellular carcinoma (HepG-2), colon cancer (HCT-116), and mammary gland breast cancer (MCF-7). The studied compound's cytotoxic activity ranged from very strong to very weak. The most active compounds were 9, 10, 11, 27 , and 34. The binding disposition of the docked compounds, in particular 9, 10, 11, 27, and 34 , towards the binding site of AKT complexed with co-crystallized ligand was investigated using molecular docking (PDB = 4EJN). A new approach for the synthesis of some new heterocyclic compounds bearing pyrimidine rings as antitumor agents. [Display omitted] [ABSTRACT FROM AUTHOR]

• Facile synthesis of a series of 22 new pyrimidine appended fused pyrazolones. • Structural confirmation by spectral data and single crystal X-ray crystallography. • Anticancer and antimicrobial testing of synthesized fused pyrazolones. • Docking studies of most active compounds 6e & 6j docked with DNA Topoisomerase 1. A series of twenty-two new pyrimidine appended fused pyrazolones 6a‒k and 7a‒k has been efficiently synthesized in good yields. Their structural characterization was achieved by physical and spectral analysis data (FTIR, NMR (1H & 13C), 2D NMR and HRMS) and single-crystal X-ray crystallography. All compounds were assayed for their in vitro anticancer activity against three human cancer cell lines viz. (i) human colorectal carcinoma (HCT116), (ii) human breast carcinoma (MCF7), and (iii) human prostate cancer (PC3) employing sulphorhodamine B assay by taking Camptothecin as a standard reference drug, and were also evaluated for their in vitro antimicrobial activities against two Gram-positive bacterial strains viz. E. faecalis (MTCC 439) and S. aureus (NDRI 110), two Gram-negative bacterial strains viz. E. coli (MTCC 723) and S. Typhi (MTCC 3224), and one fungal strain R. oryzae (MTCC 262) employing a quantitative micro-spectrophotometric assay by taking Tetracycline and Fluconazole as standard reference drugs for the antibacterial and antifungal testing, respectively. Amongst all the newly synthesized pyrazolones, 6e and 6j were found to exhibit maximal inhibitory activity against all the tested cancer cell lines, however, these are well active in comparison to the standard drug Camptothecin. The antimicrobial activity evaluation results revealed that compound 6k showed the highest potency against all the bacterial and fungal strains under study in comparison to the respective standard drugs Tetracycline and Fluconazole. Furthermore, in vitro anticancer activity was supported by docking studies performed on the derivatives 6e and 6j with their binding scores ‒65.842 and ‒64.555, respectively whereas the binding score of co-crystallized Topotecan was ‒65.675. Using X-ray crystal structure of compound 6e, DFT analysis gave energies of HOMO and LUMO as ‒0.2268 a.u.and ‒0.0872 a.u., respectively while the calculated dipole moment was 9.202833 D. The HOMO is mainly concentrated on chlorophenyl and indenopyrazolone nucleus while LUMO showed larger coefficient on dimethylpyrimidine ring which is in accord with binding interaction results of docking studies. [Display omitted] [ABSTRACT FROM AUTHOR]

• A novel series of quinazoline-pyrimidine derivatives (3a - 3i) linked to different aryl substitutions were designed and synthesized as promising anti-cancer candidates. • Compounds 3d and 3f were found to be the most active compounds against the SW480 cell line, with IC 50 = 1.1 and 8 μM, respectively. • Molecular docking, pharmacokinetic profiles, and DFT analysis were performed to investigate the interactions between ligands and EGFR targets and the drug-likeness of the synthesized compounds. • The result of MD simulation revealed that 3d ligand was stable in the active site of EGFR receptor and confirm docking study. A novel series of quinazoline-pyrimidine derivatives (3a - 3i) linked to different aryl substitutions were designed and synthesized as promising anti-cancer candidates. The Chemical structures of the new compounds were confirmed by IR, 1HNMR, 13CNMR, and Mass spectroscopy. Antiproliferative activities of all synthesized compounds were evaluated against MCF-7 and SW480 cell lines by the MTT method. The biological results exhibited IC 50 values in the range of 1.1 to 59.0 μM. Compounds 3d and 3f were found to be the most active compounds against the SW480 cell line, with IC 50 = 1.1 and 8 μM respectively. Furthermore, in silico analyses of the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of the synthesized compounds exhibited that our molecules have acceptable predictive ADMET features. The results of the docking studies were in line with biological outputs, Density functional theory (DFT) studied 3a and 3d 's reactivity descriptors at the B3LYP/6-31G** level of theory. HOMO, LUMO, and electrostatic surface potential energy were also examined. According to DFT calculations, compound 3d exhibits higher reactivity than compound 3a , which is consistent with the experimental observations. Molecular dynamic simulation of the potent synthetic compound (3d) and native ligand (Erlotinib) was performed to validate the docking study and also, RMSD, RMSF, total hydrogen bond, and clusters were analyzed. A novel series of quinazoline-pyrimidine derivatives (3a - 3i) were designed and synthesized as promising anti-cancer agents. The antiproliferative activity of all compounds was investigated against two cancerous cell lines (SW480 and MCF-7) by using an MTT assay. A docking study and MD simulation were performed to validate the biological outputs. Furthermore, in silico analysis of the ADME profile of compounds and DFT analysis was also investigated. [Display omitted] [ABSTRACT FROM AUTHOR]

• Three novel sets of pyrazolo[1,5-a]pyrimidines with expected cytotoxicity and PIM-1 and PIM-2 inhibition potential were designed and synthesized. • Three derivatives 5h, 5j, and 5l exhibited significant anticancer activity against tumor cells presenting IC 50 range of 1.26–3.22 µM. • The 4-hydroxy-3-methoxyphenyl analog 5j has shown the best cytotoxic activity combined with a lower level of toxicity towards normal cells (WI-38 cell line), suggesting an increased level of safety with high selectivity toward cancer cells. • Compound 5j displayed a potent activity against both PIM-1 and PIM-2 having IC 50 0.158 and 0.297 μM; respectively. • Compound 5j promoted apoptosis via elevating the levels of Bax, p53, and caspase-3 and dropping down Bcl-2 level. This study involved designing and synthesizing new derivatives of pyrazolo[1,5- a ]pyrimidine 5a-l, which were prepared via reaction of 4-Arylazo-1 H -pyrazole-3,5-diamines 3a,b with arylidenemalononitriles (4a-f) in refluxing methanol. The structure of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using docking simulation between the target pyrazolo[1,5- a ]pyrimidine 5j and the active binding site of the PIM-1 enzyme. The cytotoxicity of novel derivatives of pyrazolo[1,5- a ]pyrimidine framework was screened on the cancer cell lines: colon (HCT-116), hepatocellular (Hep-G2), and breast (MCF-7). Comparing with doxorubicin, compounds 2,5-diamino-7-(4-ethoxyphenyl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5h, 2,5-diamino-7-(4-hydroxy-3-methoxyphenyl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5j, and 2,5-diamino-7-(furan-2-yl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5l exhibited noteworthy anticancer properties, with half maximal inhibitory concentration (IC 50 range) = 1.26–3.22 μM. In addition, the most potent compound, 5j demonstrated a lower level of toxicity towards normal cells (WI-38 cell line), suggesting an increased level of safety. Compounds 5h, 5j, and 5l were evaluated for their activity against three different PIM kinases (PIM-1, PIM-2, and PIM-3 enzymes) in an effort to elucidate their inhibitory potential on PIM kinases. Additionally, the apoptotic potency of 5j was assessed on MCF-7 cells. Results revealed that compound 5j was potent against both PIM-1 and PIM-2 having IC 50 0.158 and 0.297 μM, respectively, comparing to staurosporine's IC 50 0.294 and 0.477 μM against both enzymes, respectively, while its inhibitory activity against PIM-3 enzyme was moderate. In addition, compound 5j promoted apoptosis via elevating the levels of Bax, p53, and caspase-3 and dropping down Bcl-2 level. G1 phase arrest of cell cycle was also observed. Furthermore, docking analyses of 5j in the PIM-1 binding site was conducted. [Display omitted] [ABSTRACT FROM AUTHOR]

• 1,2,3,4-tetrazole integrated thieno[2,3-d]pyrimidine hybrids synthesis. • Evaluation of anti-microbial activities and fungal pathogens. • Binding affinities of the test molecules against selected protein targets. • Significant MIC values for the best lead compounds. The present study describes synthesis of a novel series of 1,2,3,4-tetrazole integrated thieno[2,3- d ]-pyrimidine hybrid 11a -l. Further, in vitro anti-microbial activities of the synthesized analogues 11a - l were evaluated against Gram-positive bacteria and Gram-negative bacteria, and fungal pathogens respectively. As a result, the analogues 11d and 11l were shown potent anti-bacterial activities 0.09–0.48 µg/mL and 0.07–0.51 µg/mL, respectively against tested pathogens and compared with standard Ciprofloxacin (0.08–0.34 µg/mL). As well, the compounds 11 h and 11l have also shown highest inhibition zones (ZOIs) ranging from 13.20 ± 0.57 to 16.70 ± 0.50 ; and 17.00 ± 0.00 to 17.50 ± 1.04 mm, respectively against nominated fungal pathogens. Subsequently, the conducted molecular docking studies with the active site of DNA gyrase of Staphylococcue aureus and Esterase of Aspergillus niger were shown that all the synthesized derivatives 11a - l exhibited good docking scores of between -9.2 and -8.8 kcal/mol and were better as compared with standard drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

• A novel series of novel Morpholino-1,3,5-triazine-pyrimidine were synthesized. • The molecules were tested for DPP-4, −8, and −9 inhibition. • Compounds selectively inhibit DPP-4, displaying compound 8c as most potent analogue. • Compound 8c was efficiently docked in the catalytic triad of DPP-4. • Compound 8c showed excellent anti-diabetic activity in high-fat low dose streptozotocin (STZ)-induced diabetes in Wistar rats. Due to their favorable safety profile, DPP-4 inhibitors are the suggested option for Type 2 Diabetes Mellitus (T2DM) for therapeutic purposes. In light of this, in this paper, we report the discovery of several novel morpholino-1,3,5-triazine-pyrimidine hybrid compounds. These compounds were synthesized via an inexpensive and simple synthetic method in high yields. The target molecules' structures have been established using FT-IR, 1H NMR, 13C NMR, mass, and elemental analyses. These compounds inhibited DPP-4 more effectively and selectively than DPP-8 and DPP-9. Compound 8c has been identified as the most effective DPP-4 inhibitor with an inhibitory concentration (IC 50) of 2.9 nM. In docking analysis, compound 8c demonstrated good glide energy, and various bonded and non-bonded interactions with key DPP-4 amino acid residues of the S1/S2 site, including Tyr666, Val656, Tyr547, Gly632, Asn710, etc. Furthermore, the effect of compound 8c was also studied on high-fat, low-dose streptozotocin (STZ)-induced diabetes in Wistar rats to determine its anti-diabetic performance. Compound 8c has been shown to considerably improve the insulin level, lipid profile, and anti-oxidant status of diabetic Wistar rats in a dose-dependent manner, with no toxicity. Our findings imply that new morpholino-pyrimidine 1,3,5-triazine hybrid compounds could serve as potential lead for anti-diabetic drug discovery. [Display omitted] [ABSTRACT FROM AUTHOR]

• Modification of the sugar nucleoside analogue. • Substitution of furanose ring with various substituted uracil and synthesis of L-Nucleosides. • The synthesized compounds are assayed by HIV-RT assay. • The docking score shows that the compounds have a good affinity towards reverse transcriptase enzyme. The remarkable activity of 1,3-thiazolidine pyrimidines against a variety of viruses has made them a viable class of antiviral medicines. These compounds exhibit a unique mechanism of action, targeting multiple stages of the viral life cycle, including viral entry, replication, and release. Moreover, their broad-spectrum antiviral activity and low cytotoxicity make them an attractive drug candidate for the treatment of viral infections. In this article, we detailed the synthesis of 1,3-thiazolidine pyrimidine derivatives substituted on the 5th position of the pyrimidine ring with different functional groups. The anti-HIV activity of the synthesized compounds was tested using the HIVRT assay. In comparison to the IC 50 value of standard nevirapine (112.2 nM), the 1,3 thiazolidine pyrimidine compound substituted with Fluoro S4 (21.16 µM) and Bromo S5 (30.52 µM) only has moderate anti-HIV activity. Similarly, compounds S5 and S4 have a high affinity for the active site of HIV-1 reverse transcriptase, as evidenced by their docking scores of -89.5147 and -82.5556 kcal/mol, respectively. [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel 1,2,3-triazolo[4′,5′:3,4]pyrazolo[1,5- a ]pyrimidin-2-ium-1(3)-ides are studied. • Thermal decomposition and oxidative cyclization on diazenyl precursors are applied. • Green emission with large stokes shifts independent of solvent polarity is observed. • TD-DFT calculations are performed and redox analysis conducted by cyclic voltammetry. • Redox processes are mainly influenced by EDG/EWG effects of the aryl substituents. This study reports the unexpected synthesis of eight examples of a new heterocyclic system, which is composed of a charged triazole ring fused to the pyrazolo[1,5 -a ]pyrimidine, named 2,8-(diaryl)-6-(trifluoromethyl)-[1,2,3]triazolo[4′,5′:3,4]pyrazolo[1,5- a ]pyrimidin-2-ium-1(3)-ides (2). Compounds 2 were successfully synthesized from the reactions of E -3-(aryldiazenyl)-7-(trifluoromethyl)-pyrazolo[1,5- a ]pyrimidin-2-amines (1) in yields of up to 85% by employing two different method: thermal azide decomposition and oxidative cyclization. In general, derivatives 2a–h presented absorption bands at the ultraviolet region (250–380 nm) and green emission properties with large Stokes shifts. Moreover, TD-DFT calculations were performed, and redox analysis was conducted by cyclic voltammetry. [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesized first-in-class uracil-barbituric acid-imines using new method. • Observed anti-Tb activity in 6 compounds; compound D16 had an MIC 100 of 6 µM. • Compounds are noncytotoxic to mouse macrophage cell line at 25 µg/mL. • Conducted in silico docking to analyze mechanism of action. • D16 exhibited −9.1 kcal/mol binding affinity with TK. Two series of novel multifunctional pyrimidine–imine hybrids were synthesized and evaluated for their antitubercular and antimicrobial properties. A novel synthetic methodology utilizing water as a green solvent and a catalytic amount of HCl resulted in the isolation of barbituric acid – uracil – imine hybrids in moderate to good yields. The in vitro antitubercular activity of the compounds revealed exceptional activity, with D16 showing MIC 100 at 6 µM, which is comparable to the commercial drug ethambutol with MIC 100 at 7.63 µM. Compounds D7, D12, D18, D19 , and D20 also showed MIC 100 at concentrations ranging from 10.60 µM to 50.86 µM. The compounds were also noncytotoxic in the mouse macrophage cell line (RAW 264.7) at 25 µg/ml concentration. Molecular docking studies were carried out against M.tb thymidylate kinase to gain insights into the binding modes of the compounds and understand the plausible mechanism of action. The compound D16 outperformed all compounds with a MIC 100 of 6 µM, attributed to its strong binding affinity with thymidylate kinase valued at -9.1 kcal/mol. Compounds also showed promising activity against pathogenic bacterial and fungal strains, with the M series being more active. Even though the compounds showed broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria, the inhibitory effect on the growth of Gram-positive bacteria was more significant. This may be due to the structural difference in the cell wall composition of both bacteria. Compound M9 displayed moderate to good activity against bacteria and various species of Candida. This is the first-ever report on the synthesis and biological evaluation of uracil–imine hybrids as antitubercular and antimicrobial agents. [Display omitted] [ABSTRACT FROM AUTHOR]

• PEG-4000-OSO 3 H catalysed microwave-assisted MCRs of spiro-chromeno[2,3- d ]pyrimidines 4a-o. • Single crystal XRD analysis of 4j shows a monoclinic system with a P 2 1 / n space group. • DFT was used to gain insight into molecular geometry and physicochemical properties. • Compounds 4j and 4k exhibit excellent potency against T-47D (breast) and WiDr (colon) cell lines. • The most potent compound is 4j , which exhibits GI 50 values in the range 5.2–11 µM against all cell lines. Herein, we established an environmentally benign green approach for the synthesis of new spirochromeno[2,3- d ]pyrimidines. PEG-4000-OSO 3 H catalysed microwave-assisted multicomponent reaction of sesamol, isatin and barbituric acid enables us to produce spirochromeno[2,3- d ]pyrimidines. This approach is notable for its eco-friendly polymer catalyst, rapid metal-free synthesis, easy workup, higher yield (88–97%), no need for column chromatographic purification and outstanding green credential parameters of the process. The use of harmless solvents, microwave process and reusability of reaction media made the present protocol sustainably effective from a green perspective. The molecular structure of 4j was confirmed by Single crystal XRD analysis and their DFT study was carried out. To gain insight into the molecule's geometry and physicochemical properties, quantum chemical density functional theory was employed at B3LYP/6–31G(d, p) basis set. Furthermore, all compounds were examined for antiproliferative activity against six solid human tumour cell lines. Compounds 4j and 4k exhibit excellent potency against T-47D (breast) and WiDr (colon) cell lines as compared to the standard drug cisplatin (CDDP). The most potent compound is 4j , which exhibits GI 50 values in the range 5.2–11 µM against all cell lines. [Display omitted] [ABSTRACT FROM AUTHOR]

• Biologically active pyridopyrimidine derivative was synthesized. • Characterization is done by various spectroscopic methods. • DFT and Molecular docking studies were performed. • ADMET analysis was done for drug likeness properties. In this work, we report an efficient synthesis of pyrimidine fused novel 4-phenyl-2-thioxo-3,4-dihydro-1H-pyrido[1,2- a ]pyrimido[4,5- d ]pyrimidin-5(2 H)-one. The chemical structure of the title compound was ascertained by spectral techniques including UV–Visible, FT-IR, 1H NMR, 13C NMR and HRMS. The molecule was further subjected to quantum chemical calculations at the level of Density Functional Theory method employing B3LYP (Becke 3-parameter, Lee-Yang-Parr) level with 6–311++ G (d,p) basis set. The computed characteristics of the molecule were investigated and interpreted comparing with the experimental values. Furthermore, Frontier Molecular Orbital (FMO) analysis was used to predict the energy properties and model the possible charge transfer within the molecule. The reactivity sites were identified by mapping the electron density into Molecular Electrostatic Potential (MEP). The stability of the molecule arising from hyper-conjugative interactions and charge delocalization were analyzed using Natural Bond Orbital (NBO) analysis. All the theoretical values were in good agreement with experimental studies. Docking studies was performed to examine binding sites of the title molecule and bioactivity scores indicated that the ligand's pharmacokinetic and pharmacological properties are sufficiently additive and shows the drug-likeness of the synthesized molecule. The study was validated by i) re-docking the N3-peptide inhibitor and superimposing them onto co-crystallized complex and ii) protein ligand complex. Molecular dynamics simulations were performed for 50 ns to assess the conformational stability and fluctuations of protein-ligand complexes during the simulation. [Display omitted] [ABSTRACT FROM AUTHOR]

• Pyrimidine Schiff bases are platelet aggregation inhibitors. • The synthesized complexes adopted varied geometries based on data obtained. • The compounds had enhanced radical scavenging potentials from antioxidant studies. • Cu-L2 had the highest binding affinity with 1WS3 from the fungus Aspergillus flevush. The amino-pyrimidine-based imine-chelators, 1-((pyrimidin-2-ylimino)methyl)naphthalene-2-ol(HL1), 2-(((2-hydroxynaphthalen-1-yl)methylene)amino)pyrimidine-4,6-diol(HL2) and 1-(((4,6-dimethylpyrimidin-2-yl)imino)methyl)naphthalen-2-ol(HL3) have been synthesized by facile reaction of 2‑hydroxyl-1-naphthaldehyde with 2-aminopyrimidine, 2-amino-4,6-dihydroxypyrimidine, and 2-amno-4,6-dimethypyrimidine respectively. The chelators were coordinated with Fe(II) sulfate and Cu(II) acetate to afford the corresponding complexes which were fully characterized. The Cu(II) complex exhibited superlative antimicrobial activity with an inhibitory growth zone reaching 26.5 mm outperforming both the chelators and the Fe(II) complexes. Thus Cu(II) complex has potential significance in new antibacterial drug designs and isolation. The impressive activity was due chelation which increased the lipophilic feature of the Cu(II) complex, thereby favouring its infiltration through the lipid layers of the bacterial membranes. However, compared to other samples, Fe-L2 has the best antifungal performance activity against Aspergillus niger, Aspergillus flevus, and Rhizopus stolonifer with inhibition zone of 29±1.4, 19±2.1 and 22±1 respectively. The C 18 H 12 N 5 O 6 antioxidant result confirmed that Cu-L2 had the highest scavenging ability (99.80%) at 200 μg/mL. Interestingly, Cu-L2 exhibited the highest antioxidant actions both in vitro and in silco evaluations, hence can serve as a potential antioxidant agent. Molecular docking determinations displayed a substantial binding affinity with the drug targets suggesting that the metallic compounds could be exploited for drugs design. [Display omitted] [ABSTRACT FROM AUTHOR]

• Seventeen new pyrazolo[3,4- d ]pyrimidine derivatives were designed and synthesized. • Cytotoxic activities were evaluated against A549, HepG2, MCF-7, and HCT-116. • In vitro VEGFR-2 and EGFRT790M tyrosine kinases inhibition assays were carried out for the most active derivatives. • Molecular docking studies were carried out. Seventeen new pyrazolo[3,4- d ]pyrimidine derivatives have been designed, created and tested as dual VEGFR-2 and EGFR inhibitors for their anticancer special effects against A549, HepG2, MCF-7, and HCT-116. In order to determine how the proposed chemicals might interact to the EGFR and VEGFR-2 receptors, molecular docking was used for these derivatives. The data from the docking studies and the results of the biological screening had excellent correlation. Compounds 14 and 15 displayed the best effects against HepG2, while the derivatives 10d, 15 and 18 showed the greatest anticancer activity against MCF-7. Moreover, compounds 15 and 18 exhibited the greatest anticancer effects against HCT-116 but compound 18 exhibited the greatest anticancer effect against A549. Compound 18 exhibited higher activities than Sorafenib against MCF-7, HCT116 and A549 correspondingly but lower actions versus HepG2. However, this substance showed greater effects than erlotinib against MCF-7 and HCT116 but lesser effects against A549 and HepG2 in that order. Compound 15 shown lower activities versus A549 but higher activity against HepG2, MCF-7, and HCT116 than Sorafenib and Erlotinib. Derivative 18 displayed higher effects as dual VEGFR-2 and EGFRT790M tyrosine kinases inhibitors more than both Sorafenib and Erlotinib respectively. Finally, our derivatives 10d, 15 and 18 demonstrated an excellent ADMET profile when calculated in silico. According to the results, our compounds could serve as a model for future creation, optimization, adaption, and research to create more powerful and selective dual VEGFR-2/EGFRT790M inhibitors with more anticancer potential. [Display omitted] [ABSTRACT FROM AUTHOR]

• Multicomponent reactions helps to swiftly synthesize and evaluate for activity. • This review covers synthesis of dihydropyrimidines and their biological activities. • Novel dihydropyrimidines can be potential anticancer therapeutics. • This review reports all the patented and marketed dihydropyrimidines as drugs. • This review reports future perspectives of dihydropyrimidines in drug discovery. One of the largest classes of organic molecules are dihydropyrimidines and its derivatives. They are widely used in a variety of pharmacological and industrial applications. Their biological and pharmacological activities include antihypertensive, antidiabetic, anti-inflammatory, antibacterial, antifungal, anticancer, and antiviral activities. The presence of pyrimidine and pyrimidine-containing rings in the substructures of therapeutically effective drugs has drawn considerable interest amongst the scientific fraternity. The potential therapeutic use of these heterocycles has prompted medicinal chemists to synthesize drugs that contain these heterocycles. Against this backdrop, this review examines the one-pot multicomponent reaction, that is, the Biginelli reaction and its mechanism. Also, we reviewed various synthetic approaches for the synthesis of dihydropyrimidines and their diverse pharmacological activities reported in the last two decades. We highlight different marketed drugs with dihydropyrimidine as a pharmacophore as well as patented dihydropyrimidines in the recent past. [Display omitted] [ABSTRACT FROM AUTHOR]

• Two novel pyrimidine derivatives (BMPO and BBMP) were synthesized as eco-friendly corrosion inhibitors for mild steel in acidic environment. • BMPO and BBMP have outstanding corrosion inhibition effect with the inhibition efficiencies of 99.28% and 99.69%. • The adsorption of BMPO and BBMP is achieved by the bonding of N, S, and O atoms and the benzene ring to steel surface. • The modification with more benzyl groups in BBMP further improves its corrosion inhibition effect. In the pickling, oil well acidification, and other industrial processes, mild steel would suffer from severe corrosion in the acidic environment. In this work, two novel pyrimidine derivatives, 2-Benzylthio-6-methylpyrimidin-4(3 H)-one (BMPO) and 4-Benzyloxy-2-benzylthio-6-methylpyrimidine (BBMP), were synthesized through nucleophilic substitution reaction, and used as eco-friendly corrosion inhibitors for mild steel in HCl medium. The corrosion inhibition properties of BMPO and BBMP were investigated using electrochemical tests, surface analyses, and theoretical calculations. The experimental results indicate that BMPO and BBMP have superior inhibition effect, with high inhibition efficiency (99.28% and 99.69% at 0.6 mM) and good corrosion inhibition stability. Theoretical calculations reveal that the interface adsorption of BMPO and BBMP is achieved by the bonding of N, S, O atoms and the benzene ring to steel surface. The protonation of BMPO and BBMP molecules could further promote their adsorption. Compared to BMPO, the modification with more benzyl groups lowers the polarity and increases the hydrophobicity of BBMP. Then BBMP molecules could adsorb on steel surface to create a hydrophobic film with a large coverage, which accounts for the better corrosion inhibition effect of BBMP. [Display omitted] [ABSTRACT FROM AUTHOR]

• Microwave irradiation is an important methodology to synthetize chemical compounds. • Chagas disease is a neglected tropical disease which is endemic in latin america. • Heterocyclic nuclei are in the structure of several biologically active compounds. • Conjugated heterocyclic compounds show photophysical properties. Pyrazole derivatives are pharmacologically important agents that possess a wide spectrum of biological activities. Thus, the optimization of their synthetic approaches is of great interest for medicinal and pharmaceutical chemistry. In this work, eleven new 7-aryl-2,3-dihydro-7 H -imidazo[1,2- c ]pyrazolo[4,3- e ]pyrimidines 1(a-k) were synthesized employing microwave irradiation conditions (150 W, 15–45 min). All compounds were completely characterized through Fourier Transform Infrared Spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR), and High-resolution Mass Spectrometry (HRMS) analyses. The in silico prediction of physicochemical properties showed that all analogs do not violate Lipinki's rule with prediction of good oral bioavailability. Analogs showed low activity against T. cruzi. Correlated experimental methods have been applied to investigate the photophysical properties of 1(a-k), describing their absorption properties in function of substituents. The molecular set exhibits a cyan emission, enabling it to investigate the basic fluorescence spectroscopy in solution. [Display omitted] [ABSTRACT FROM AUTHOR]

• A series of new pyrazolo[1,5- a ]pyrimidine derivatives were designed and synthesized. • Compounds 6a and 6b showed their best anticancer potency against MCF-7 breast cell line. • The potent compounds showed more SI values than that of sorafenib. • Compounds 6a and 6b proved to be potent EGFR/HER2 kinase inhibitors. • The experimental results were supported by the molecular docking studies. The pyrazolo[1,5- a ]pyrimidine core framework is a good starting point for the synthesis of drug-like molecules since the biological activity is determined by the kind and position of the substituents on the heterocyclic center. To develop safer and more effective anticancer medications, pyrazolopyrimidine derivatives (6a-o) were designed and developed. The structure and purity of the resulting molecules were confirmed by elemental analysis and various spectroscopic techniques. The human cancer cell lines, including HepG2 (liver), MCF-7 (breast), and HCT116 (colorectal), have been used to test the synthetic compounds' anticancer properties. The most of pyrazolopyrimidine derivatives demonstrated a cytotoxic impact, few compounds exhibit much more potent than doxorubicin and sorafenib. For HepG2, MCF7, and HCT116, respectively, the IC 50 values of compound 6b were 3.26, 3.19, and 5.01μM. To determine their selectivity indices, the potent molecules were assessed for cytotoxicity on the WI-38 cell line, a normal healthy cell line. Inhibition studies for the human epidermal growth factor receptor 2 (HER2) and the epidermal growth factor receptor (EGFR) were also carried out in an effort to determine their mode of cytotoxicity. With IC 50 values of 0.163 (EGFR), 0.116 (HER2) for compound 6a and 0.126 (EGFR), 0.083 (HER2) for compound 6b were the most effective dual EGFR/HER2 kinase inhibitors. Finally, molecular docking research showed that compounds 6a and 6b firmly binds to EGFR and HER2 via hydrogen bonding interactions, leading to irreversible dual kinase inhibition. The substances displayed favorable characteristics of drugs and might be applied as prototypes for further improvement. [Display omitted] [ABSTRACT FROM AUTHOR]

• US assisted synthesis of novel adamantane-pyrazolo[1,5- a ]pyrimidine hybrids. • Crystal analysis of adamantane-pyrazolo[1,5- a ]pyrimidine hybrid 14c. • Docking analysis of the hybrids against target 3CLpro of SARS-CoV-2. • Drug-likeness analysis of the hybrids using Swiss ADME. Multi-step synthesis of adamantyl-pyrazolo[1,5- a ]pyrimidine derivatives under ultrasound irradiation has been described adopting the technique of molecular hybridization, whereby two core bioactive units- adamantanamine and pyrazolo[1,5- a ]pyrimidine templates have been brought together into a new chemical entity. Ultrasound irradiation of N -(adamantan-1-yl)-3-amino- 1H -pyrazole-4-carboxamide with formylated active proton compounds yields the desired hybrids in good to excellent yields. The N -(adamantan-1-yl)-3-amino pyrazolo[1,5- a ]pyrimidine carboxamide derivatives were successfully identified with the help of spectral and analytical data. X-ray crystallography of ethyl 3-(adamantan-1-ylcarbamoyl)-7-methylpyrazolo[1,5- a ]pyrimidine-6-carboxylate (14c) unambiguously confirmed the formation of the desired hybrid. The results and the findings of the docking scores indicate that the active ligands 7a and 11b exhibited highest binding energies with a score of –7.33 Kcal/mol and – 8.73 Kcal/mol, respectively. The inhibition constant (KI) for ligands 7a and 11b were found to be 4.24 µM and 396.32 µM, respectively which are comparatively lower than the control favipiravir thereby conforming to the drug-likeness prediction. These compounds as such become favorable for screening as drug candidates compared to the control favipiravir with lower binding energy, lower lipophilicity range and very high KI constant. The active ligands have promising functions to inhibit and interfere with the replication and maturation of Chymotrypsin-like protease (3CLpro) of SARS-Coronavirus 2. The lower KI, high binding energy and drug-likeness efficiency of the compounds can be further developed into a potent drug molecule against the uncontrollable SARS-COV-2. [Display omitted] [ABSTRACT FROM AUTHOR]

• Chemoselective routes to new imidazo[1,2-a]pyrimidine derivatives, or regioisomeric hydrazonamide adducts. • Heterocyclic product outcome shown to be dictated by aromatic substituents in predictable manner. • Several compounds identified showing MIC values against gram+ve/–ve bacteria at sub-0.5 ug / mL. • Screening against HeLa cells identified a new imidazo[1,2-a]pyrimidine compound which an in silico target fishing analysis and modelling suggests could be targeting one or more of Tankyrase-2 (Tank-2), Cyclin-dependent kinase (CDK2) and Epidermal growth factor tyrosine kinase receptor (EGFR). Reaction of a series of hydrazonoyl chlorides with substituted aminopyrimidines afforded good selectivity in most cases leading either to formation of new imidazo[1,2-a]pyrimidine derivatives, or regioisomeric hydrazonamide adducts. The compounds were evaluated for antibacterial and anticancer activities. Screening against E. Coli, P. aeruginosa, S. aureus, S. epidermidis, B. subtilis and K. rhizophila did identify several different compound types with MIC of 0.1-0.4 mg/mL. Anticancer evaluation against a HeLa cell line identified one imidazo[1,2-a]pyrimidine lead. An in silico target fishing analysis suggest three possible high value protein targets, Tankyrase-2 (Tank-2), Cyclin-dependent kinase (CDK2) and Epidermal growth factor tyrosine kinase receptor (EGFR), with modelling fit against co-crystallized known ligands. This provides a new structural family lead for further investigation of molecular targets and potential SAR activity development. [Display omitted] [ABSTRACT FROM AUTHOR]

• The novel napthofuran-pyrimidine-traizne analogs 6(a-f) were synthesized. • Spectral analysis and DFT calculations were made. • The Anti-TB and antioxidant activities were disclosed. • Drug likeness prediction were investigated. • The molecular docking study and molecular dynamics were evaluated. Napthofuran and its fused heterocyclic derivatives evaluated with varied biological activity functional groups comprise an important class of compounds for new chemical entities. We here in reporting synthesis of new 3-(4-substituted phenyl)naphtho[1′,2′:4,5]furo[2,3- e ][1,2,4]triazolo[4,3- c ]pyrimidines 6(a-f). Structures of the newly synthesized compounds were confirmed by making use of spectroscopic techniques like IR, NMR and Mass. The DFT calculations were taken for the selected molecules using B3LYP hybrid functional with a 6–31+ G (d, p) all-electron basis set using the Gaussian 09 package. The bioactivity predictions were evaluated for the synthesized compounds. The In vitro biological activities were reported for the all compounds 6(a-f). The compound 6a showed high activity of anti-TB and antioxidant activity with at MIC 1.6 μg/ml and at percentage of inhibition (72.54±0.21) at 10μg/ml respectively. The compound 6f (73.21±0.11) showed antioxidant activity better than standard drug BHA (71.32±0.13) at 10 μg/ml. Furthermore, the docking studies for the newly synthesized molecules were carried out by Auto dock software with proteins InhA (4TZK), Cytochrome c peroxidase (2 × 08) and protease (Mpro) of SARS-CoV-2 Omicron (PDB ID: 7TOB). All the compounds showed a strong binding affinity for the docked proteins. The outcome of docking results showed that compound 6a had excellent binding energies -10.8, -9.4, and -9.0 kcal/mol with 4TZK, 2 × 08, and 7TOB respectively. Lastly, the protein stability, fluctuations of APO-Protein, protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3 and potential lead molecules were identified. [Display omitted] [ABSTRACT FROM AUTHOR]

• New imidazo[1, 2- a ]pyrimidine Schiff-bases derivatives have been synthesized. • Spectroscopic characterization was performed with 1H, 13C NMR, LC-MS, and FT-IR analyses. • The DFT studies, FMO, MEP, QTAIM and RDG analysis were done. • Molecular docking studies targeting the h ACE2 and the Spike, key entrance proteins of SARS-CoV-2 have been performed. • In silico ADMET and drug-likeness analysis were investigated. • This study may contribute to the ongoing efforts to develop effective treatments against SARS-CoV-2 or the upcoming variants. In the present work, a new series of imidazo[1,2- a ]pyrimidine Schiff base derivatives have been obtained using an easy and conventional synthetic route. The synthesized compounds were spectroscopically characterized using 1H, 13C NMR, LC-MS(ESI), and FT-IR techniques. Green metric calculations indicate adherence to several green chemistry principles. The energy of Frontier Molecular Orbitals (FMO), Molecular Electrostatic Potential (MEP), Quantum Theory of Atoms in Molecules (QTAIM), and Reduced Density Gradient (RDG) were determined by the Density Functional Theory (DFT) method at B3LYP/6–31 G (d, p) as the basis set. Moreover, molecular docking studies targeting the human ACE2 and the spike, key entrance proteins of the severe acute respiratory syndrome coronavirus-2 were carried out along with hACE2 natural ligand Angiotensin II, the MLN-4760 inhibitor as well as the Cannabidiolic Acid CBDA which has been demonstrated to bind to the spike protein and block cell entry. The molecular modeling results showed auspicious results in terms of binding affinity as the top-scoring compound exhibited a remarkable affinity (-9.1 and -7.3 kcal/mol) to the ACE2 and spike protein respectively compared to CBDA (-5.7 kcal/mol), the MLN-4760 inhibitor (-7.3 kcal/mol), and angiotensin II (-9.2 kcal/mol). These findings suggest that the synthesized compounds may potentially act as effective entrance inhibitors, preventing the SARS-CoV-2 infection of human cells. Furthermore, in silico, ADMET, and drug-likeness prediction expressed promising drug-like characteristics. [Display omitted] [ABSTRACT FROM AUTHOR]

• Pyrimidine compounds are important heterocyclic compounds and have important research significance in pharmaceutical chemistry and synthetic chemistry. have also been well explored for the past decades and are still under investigation. • With the development of catalytic methods, a series of synthesis methods of pyrimidine compounds have been well explored for the past decades and are still under investigation. • Start with "post-modification" and "co-synthesis" two strategies for the synthesis of homo-trisubstituted pyrimidines compounds, we have reviewed nearly 50 literatures published in the last 10 years on the synthesis methods in details. • In this review we have focused on "co-synthesis" strategy, we classified it by the number of reaction reactants constructed into a pyrimidine ring. Then we discussed the catalyst, solvent and other factors affecting the reaction, and summarized the reaction mechanism. • Through the analysis of the reaction mechanism, the existing problems of the existing reactions are pointed out, and the new methods for the synthesis of pyrimidine rings are prospected. Pyrimidine compounds are an important class of heterocyclic compounds. The excellent bioactivity of pyrimidine skeleton makes it of important research value in the treatment of diseases. Therefore, efficient synthesis of pyrimidine skeleton compounds is of great significance in the fields of synthetic chemistry and pharmaceutical chemistry. In the present research, a variety of methods for building pyrimidine rings have been reported. In this regard, we have reviewed the recent update on the synthesis methods of homo-trisubstituted pyrimidines compounds in details. Through the analysis of the reaction mechanism, the existing problems of the existing reactions are pointed out, and the new methods for the synthesis of pyrimidine rings are prospected. [Display omitted] [ABSTRACT FROM AUTHOR]

• Sixteen novel polyheterocyclic compounds were created in high yields (>80%) via three-component reaction. • The synthesized compounds showed good to high cytotoxicity against MCF-7 cancer cell line. • The products demonstrated high to excellent anti-oxidant activities. • These compounds exhibited moderate antibacterial properties only against Gram-positive bacteria. In this study, pyrano[3,2- e ]pyrazaolo[1,5- a ]pyrimidine derivatives were produced in high yields (80–89%), at room temperature, by three-component reactions involving alkyl isocyanides, dialkyl acetylenedicarboxylates, and 7‑hydroxy pyrazolo[1,5- a ]pyrimidines. Using FT-IR, 1H and 13C NMR, and mass spectral data, the structure of the synthesized compounds was identified. The created molecules were tested against cancer, bacteria, and free radicals to evaluate how effective they could be. It was determined whether or not the tested substances had any cytotoxic effects on the MCF-7 (breast cancer) and the MCF-10 (breast epithelial) cell lines. Compound 4l , in comparison to other compounds, has shown the most potent anti-cancer activity (IC 50 =19.70±0.89 µM), which is roughly as excellent as the standard medicine etoposide (IC 50 = 18.71±1.09 µM). Also, the antioxidant properties of the products were investigated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The results demonstrated that compound 4 h had the highest free radical scavenging effect (IC 50 = 12.12±0.40 µM), which was very close to the value for ascorbic acid (IC 50 = 11.85±0.30 µM), as the antioxidant standard. The Kirby-Bauer disk diffusion technique was applied to examine the bactericidal impact of the synthesized compounds. According to the findings, virtually all the compounds had a modest level of action against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus). [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesis, characterization of pyrimidine - Carbonitrile ligand and its metal complexes. • Mass and suggested fragmentation for the studied ABTTPC ligand. • Thermo gravimetric analysis and magnetic moment and UV–Visible spectroscopic studies of ABTTPC ligand and metal (II) complexes. • Molecular geometry optimization, atomic charges, bond lengths and bond angles of ABTTPC ligand and metal (II) complexes. • Powder X-ray diffraction pattern of ABTTPC ligand and metal (II) complexes. Elements, molar conductivity, IR, electronic absorption, magnetic susceptibility, and thermal decomposition data were used to describe single-core pyrimidine-carbonitrile complexes of the type [M(L) 2 (H 2 O) 2 ]Cl 2. (M = Co(II), Ni(II), Mn(II), Zn(II), Cu(II)and Cd(II)) and [Fe(L) 2 (H 2 O) 2 ]Cl 3. Elemental analyses, IR, 1HNMR , and mass spectral study were used to establish the identification and purity of the synthesized pyrimidine ligand (L). The DFT-B3LYP computational approach was used to conduct a theoretical analysis of (L) to support experimental findings. According to X-ray powder diffraction, the Fe(III) complex is amorphous, but the Cu(II), Co(II), Ni(II), and Mn(II) complexes also contain crystalline phases. Through molecular docking studies, it revealed good docking in the minor groove of the DNA of the Gram-negative bacteria (E. coli (3t88) and 5i39— P. aeruginosa), the Gram-positive bacteria (3ty7— S. aureus), and the fungi (C. albicans (1M78) receptors. When tested against multi-stranded microorganisms such as Gram-positive bacteria (Staphylococcus aureus and Staphylococcus mutans), Gram-negative bacteria (Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa), and fungal species (Candida albicans and Aspergillusniger), the ligand and its metal complexes were found to have very good potency for their antibacterial and antifungal activity. [ABSTRACT FROM AUTHOR]

• Two series of novel chiral heterocyclic compounds, 3a-e (formula A) and 5a-e (formula B), were designed and synthesized via a one-pot double Mannich-type reaction as possible COX-2 inhibitors. • All designed compounds were selected by NCI for anticancer evaluation against 60 distinct human cancer cell lines. • The most active compounds were assessed against leukemia (HL-60 (TB)), ovarian cancer (SK-OV-3), and breast carcinoma (MCF-7) cell lines using the cell viability MTT assay. • The promising compounds were screened for COX-2 inhibition. • Cell cycle progression and apoptosis induction was investigated. • Molecular docking and in silico studies were carried out. Two series of chiral novel compounds were designed and synthesized using a one-pot double Mannich-type reaction, with pyrimidine, purine, and purine bioisosteres as a central heterocyclic scaffold with a methylamino chain as a linear core 3a-e (formula A) or a purine nucleus as a central core bearing two vicinal phenyl and different heteroaryl moieties 5a-e (formula B). The NCI selected all the designed compounds for anticancer testing against 60 distinct human cancer cell lines. Compounds 3d and 5d demonstrated strong antitumor activity against a wide range of cancers, with mean growth inhibition of 59.61% and 44.30%, respectively. Both compounds showed the highest anticancer activity against breast cancer cell lines MCF-7 (94.62%, 99.76%) and MDA-MB-468 (85.81%, 92.64%). Interestingly, almost all leukemia cell lines were sensitive to both 3d and 5d Besides, compound 3d was sensitive to all-colon, ovarian, and prostate cancer cell lines. Additionally, the IC 50 values of compounds 3d and 5d against the most sensitive leukemia (HL-60 (TB)), ovarian cancer (SK-OV-3), and breast carcinoma (MCF-7) cell lines were determined to be (3d , IC 50 =11.96±2.74, 9.46±2.27, and 6.68±2.14 µM) and (5d , IC 50 = 17.89±2.19, 8.89±2.50, and 8.75±1.99 µM), respectively. Both compounds exhibited strong antiproliferative activity that was nearly comparable to or half that of doxorubicin (IC 50 = 12.54±2.10, 7.7±0.48, and 3.34±0.21 µM) and about 2- and 3-fold better than 5-FU (IC 50 = 19.99±2.81, 21.8±2.09, and 16.79±2.18 µM). A COX-2 inhibition assay was performed to assess the target compounds' ability to inhibit COX-2. Compounds 3d and 5d displayed interesting COX-2 inhibition activity, exerting IC 50 values in the nanomolar range in comparison to celecoxib (IC 50 = 53.76±2.05 nM). However, compound 3d exerted higher anti-COX-2 activity, with an IC 50 value of 69.79±2.14 nM, than compound 5d (89.92±2.17 nM). Further, compound 3d was able to arrest cell growth at the S and G2/M phases, indicating apoptosis induction. Moreover, the molecular docking of both compounds revealed a high affinity for the COX-2 receptor, with energy scores (S) = −6.63 and −7.00 kcal/mol, which were comparable to celecoxib (S) = −6.42 kcal/mol. Besides, in silico studies of compounds 3d and 5d revealed good pharmacokinetics profiles, physicochemical features, and drug-likeness data that were nearly identical to celecoxib. [ABSTRACT FROM AUTHOR]

• A novel family of spirocyclic aminopyrimidine derivatives was synthesized. • The antibacterial activity of these compounds was investigated against different bacterial pathogens including multi-drug resistant strains. • Compounds 4, 6, 8e were found to possess potent antibacterial activity. • Compound 6 exhibited the highest activity in terms of MIC values compared to ciprofloxacin. • Molecular dynamic simulations and docking studies were investigated. The rise of new bacterial pathogens that ascribed as multi-drug resistant became a major concern, particularly in the medical sectors. In the current study, we designed novel molecular hybrids based on spirocyclic pyrimidine which feature either triazolo ring or various functionalities such as alkyl, hydrazino, azomethine motifs. The newly synthesized spirocyclic pyrimidines were screened for their bactericidal activities against some bacterial pathogens such as Salmonella typhimurium and Proteus vulgaris in addition to the multi-drug resistant Pseudomonas aeruginosa and Staphylococcus aureus (MRSA). Compounds coded 4, 6 , and 8e were found to possess potent bactericidal activities compared to the standard drugs (Ciprofloxacin and Cephradine). Interestingly, compound 6 exhibited the highest antibacterial activity with low MIC value close to that obtained for ciprofloxacin. Molecular dynamic simulations and docking studies were investigated to check the performance of our compounds upon binding to the protein active sites as well as their interactions and stabilities through the simulation process. [Display omitted] [ABSTRACT FROM AUTHOR]

• A series of new pyrano[2,3- c ]pyrazole and pyrazolo[4′,3′:5,6]pyrano[2,3- d ]pyrimidine derivatives were synthesized using facile green approach in excellent yields. • Compound M2 was isolated as an un expected novel compound. • The antimicrobial, antioxidant, and anti-cancer activities of the titled compounds were evaluated in vitro and most of the compounds manifested auspicious biological outcomes. • Compound M21 was the most promising anti-bacterial agent with potential binding affinity against the penicillin-binding protein. • Compound M5 was the most cytotoxic compound with potential binding affinity against CDK2 proteins. An eco-friendly approach was conducted for synthesizing pyrano[2,3- c ]pyrazoles M1 - M25 via a one-pot reaction of hydrazine hydrate 99%, ethyl acetoacetate or diethyl malonate, carbonyl group source, and active methylene compounds. Besides, pyrazolo[4′,3′:5,6]pyrano[2,3- d ]pyrimidines M26 - M31 was synthesized via intramolecular cyclization of M10 and M13. Thereafter, the antimicrobial, antioxidant, and anti-cancer activities of the titled compounds were evaluated utilizing an array of techniques. Fortunately, the vast majority of the compounds exhibited promising biological activities. Over and above, in silico study was employed to determine the expected mode of action of the synthesized compounds. M21 was the most promising anti-bacterial agent, while M5 was the most cytotoxic compound. Finally, DFT theoretical calculations were used to study the stability and structural parameters of the newly synthesized compounds. DFT calculations showed the energy gaps between the HOMO-LUMO with all the investigated compounds in a range of 4.04–5.66 eV allowing for easy exchange of electrons and the reactivity. [Display omitted] [ABSTRACT FROM AUTHOR]

• Facile synthesis of pyrido[2,3-d]pyrimidines and benzo[4,5]imidazo[1,2-a]-pyrimidine-3-carbonitriles. • Introduction of a new TiO 2 based catalyst. • Introduction of a new acidic ionic liquid. • Use of immobilization method for the preparation of a new efficient catalyst. In the present study, a new as a heterogeneous, efficient, green and recyclable nano catalyst was synthesized via the immobilization of N,N -bis(3-(trimethylsilyl)propyl)octan-1-aminium hydrogen sulfate ionic liquid on nonporous TiO 2 (TiO 2 -[bipocam]-HSO 4) and was characterized by different analysis methods such as XRD, FESEM, TGA and FTIR. In continue, it was used in the three-component one pot synthesis of pyrido[2,3- d ]pyrimidines and benzo[4,5]imidazo[1,2- a ]-pyrimidine-3-carbonitriles derivatives. The main advantages of this method are compatibility with green chemistry rules, short reaction times (4-60 min.), high isolated yields (97-98%), easy product separation, use of non-toxic and safe catalyst, solvent-free conditions in reactions and reusability of the catalyst for five times without significant reduction in its catalytic activity. [Display omitted] [ABSTRACT FROM AUTHOR]

• One-pot synthesis of fused [ 1 , 2 , 3 ]triazolo-pyrrolo[1,2- a ]pyrido[4,3- d ]pyrimidines (5a-5n) via CuAAC followed by C C bond coupling. • The fused 1,2,3-triazoles exhibited anti-cancer activity and epidermal growth factor receptor (EGFR) was carried out for potent compounds. • In silico ADME and molecular docking studies were also held potent compounds for the future anticancer drug discovery initiatives. • Theoretical investigation of compound 5n utilized DFT/B3LYP basis set and characterized their physical properties. Herein, we synthesized some new fused [1,2,3]triazolo-pyrrolo[1,2-a]pyrido[4,3-d]pyrimidines via click chemistry followed by carbon-carbon bond coupling as key approach and then characterized their structures by IR, NMR, mass and CHN analysis techniques. The structural parameters of compound 5n were also derived from geometry optimization. Molecular electrostatic potential (MEP), HOMO–LUMO energy gap, and Mulliken atomic charges were calculated. Later, the anticancer activity of the synthesized compounds was screened in vitro against different human cancer cell lines like MCF-7, NCI-H460, and A-549 and the results were compared with standard drug erlotinib. Most of the investigated compounds like 5c, 5e, 5f, 5j, 5 m and 5n were found to be active against MCF-7. Specifically, compounds 5c and 5n had superior activity against MCF-7 and remarkable activity against A-549. The results of the inhibitory assay of most active compounds 5c and 5n against the wild type tyrosine kinase EGFR (PBS Bioscience, catalog # 40321), which is one of the enzymes expressed in the MCF-7 and A-549 cell lines revealed that both compounds had greater potency in inhibiting tyrosine kinase EGFR than the standard drug erlotinib. The in silico studies of six active compounds 5c, 5e, 5f, 5j, 5 m, 5n and erlotinib were also carried out on EGFR receptor and observed that all the six compounds had appreciable binding energies and inhibition constants than the standard drug erlotinib. Finally, the in silico pharmacokinetic profile was predicted for potent compounds 5c, 5e, 5f, 5j, 5 m and 5n using SWISS/ADME and pkCSM, where, all the compounds followed Lipinski, Lipinski, Veber, Egan and Muegge rules without any deviation. [Display omitted] [ABSTRACT FROM AUTHOR]

• A series of pyrazolo [3,4- d ]pyrimidine-based dual HDAC/Topo II inhibitors were synthesized and evaluated for their anticancer activity. • Most of them showed exhibited excellent inhibitory activity against HDAC and selective inhibition for Topoisomerase II. Compounds 10f, 12, 22e, 22f and 22g showed excellent inhibitory activities against HDAC and Topo II. • Most of them showed potential anticancer activity in vitro. • Compounds 12 and 24 could promote apoptosis in MCF-7 cells. A series of pyrazolo [3,4- d ]pyrimidine-based dual HDAC/Topo II inhibitors were designed and synthesized by the pharmacophore fusion strategy. Their inhibitory activities towards HDAC and Topo and their cytotoxicity in cancer cell lines were evaluated. Among all of the synthesized compounds, 10f, 12, 22e, 22f , and 22g showed excellent dual inhibitory activities against HDAC and Topo II. MTT assays indicated that all the compounds displayed potent activity and compounds 10g, 12, 16b , and 24 which IC 50 value was 4.22 μM, 3.57 μM, 4.82 μM and 4.61 μM respectively significantly inhibited the migration of MCF-7 cells. Further studies revealed that compounds 12 and 24 could promote apoptosis in MCF-7 cells. Molecular docking studies revealed significant interaction of compounds 12 and 24 with active sites of HDAC and Topo II. [ABSTRACT FROM AUTHOR]

• Introduction of TiO 2 -[bip]-NH 2 + C(NO 2) 3 − as a new and effective nano-catalyst. • Effective synthesis of imidazo[1,2- a ]pyrimidine-3-carbonitriles and 1,2,4-triazolo[4,3- a ]pyrimidines derivatives. • Use of FT-IR, EDX, FESEM, TGA and XRD for the characterization of the catalyst. • Simple procedure, short reaction times, high yields and no column chromatographic separation. • Recyclability and reusability of the catalyst for several times. In this article a simple method is reported for the promotion of the synthesis of imidazo[1,2- a ]pyrimidine-3-carbonitriles and 1,2,4-triazolo[4,3- a ]pyrimidines derivatives via three component one-pot condensation of various aromatic aldehydes, malononitrile and 2-aminobenzimidazole or 3-amino-1,2,4-triazole using TiO 2 -[bip]-NH 2 + C(NO 2) 3 − as a new efficient nano-catalyst. All the products which were obtained under mild and solvent-free conditions were identified with the comparison of their physical properties and spectral data with the authentic samples. The structure of the prepared catalyst was characterized using Fourier transform infrared spectroscopy (FT-IR), energy dispersive X-ray analysis (EDX), field emission scanning electron microscopy (FESEM), thermo gravimetric analysis (TGA) and X-ray diffraction (XRD). The significant features of this procedure are short reaction times, high yields of the products, ease of separation of the products and easy preparation of the catalyst. Also the catalyst can be recycled and reutilized for several cycles in the studied reactions. [Display omitted] [ABSTRACT FROM AUTHOR]

• Imidazopyrimidines can exist several tautomeric forms. • Some 2D-NMR techniques were used for the structural elucidation of regioisomeric products. • Structure confirmation of 4 were also supported by its XRD crystallography. Imidazopyrimidines have some interconvertible tautomeric forms. Regioselectivities were resolved for N -benzylations of some 8-(substituted phenyl)chloropurines with benzyl or 4-chlorobenzyl bromides under basic conditions (K 2 CO 3) in DMF. It was observed that, while N -benzylation of 2‑chloro-8-(4-substituted)phenylpurines occur on the five-membered imidazole ring (1a, 1b, 2a and 2b) to the contrary, same alkylation reaction of 6‑chloro-8-(4-fluorophenyl)purine (3) occurs on the six-membered pyrimidine ring (4). Their structures were established by combination of 1H–1H NOE (Nuclear Overhauser Effect Spectroscopy, NOESY) and 1H–13C/15N HMBC (Heteronuclear Multiple Bond Correlation) methods. X-ray crystallographic data of compound 4 was also used for further confirmation. [Display omitted] [ABSTRACT FROM AUTHOR]

• Twenty tetrahydropyrido[4,3- d ]pyrimidine analogs were designed as potent ATX inhibitors. • Structure based optimization furnished the most powerful ATX inhibitor 11c (3.72 nM). • The binding mode of 11c with ATX ideally elucidated its excellent enzymatic potency. • 11c presented potent antiproliferative effects with apoptosis-inducing action. • 11c dose-dependently suppressed tumor cell colony formation and migration ratio. Aberrant ATX-LPA signaling turns out to be a powerful driver for the development of various cancers. Herein, a series of unique tetrahydropyrido[4,3- d ]pyrimidine compounds were designed and synthesized via a hybrid strategy to serve as novel ATX inhibitors. Benzamide fragment was introduced perpendicular to the 4-positon of tetrahydropyrido[4,3- d ]pyrimidine skeleton to obtain compounds 7∼12c. To retrieve satisfying druggable profile, 4-aminopiperidine analogs (14a∼15b) were investigated in parallel. ATX enzymatic assay indicated the series of compounds endowed with moderate to satisfying ATX inhibitory activity. Delightfully, the benzamide 11c bearing a N 6-benzyl group was identified as the optimal compound with an excellent IC 50 value of 3.72 nM against ATX enzyme, accompanied by impressive cytotoxicity, especially on MCF-7 (0.67 µM) and RAW264.7 (0.83 µM) cell lines. Furthermore, wound healing assays and colony formation assays demonstrated 11c could significantly suppress the MCF-7 cell migration rate and colony formation in a dose dependent manner. Meanwhile, 11c was capable of inducing apoptosis on MCF-7 cells in the immunofluorescence assays. Taken together, the novel compound 11c with favorable druggability may serve as a promising candidate in cancer treatment. [Display omitted]. [ABSTRACT FROM AUTHOR]

• New fluoroquinolone hybrids (4a− h and 5a− h) have been synthesized. • We assessed their purity and confirmed the elucidation of their structures. • Their antibacterial, DNA gyrase, and urease inhibitory activities were checked. • Significant antibacterial activity, superiorly against E. coli , was observed. • The hybrids 4 g, 5 g, 4 h and 5e were the most potent dual DNA gyrase and urease inhibitors. Fluoroquinolones (FQs) are well known antibacterial chemotherapeutics with DNA gyrase inhibitory activity and a potential urease inhibitory activity. New FQ hybrids (4a− h and 5a− h) have been synthesized by combining ciprofloxacin or norfloxacin with different thiouracil and thioxopyrimidine derivatives. The purity of the newly developed compounds was assessed through thin-layer chromatography, and the elucidation of their structures was confirmed through proton nuclear magnetic resonance, infrared spectroscopy, high resolution mass spectrometry, and microanalyses. The new hybrids were evaluated for their antibacterial, DNA gyrase, and urease inhibitory activities. The potential co- and cross-resistance in Escherichia coli (E. coli) as well as the frequencies of the resistance were evaluated for the new hybrids. The new hybrid compounds displayed a significant antibacterial activity against a panel of Gram-positive and Gram-negative bacterial strains. The majority of the tested ciprofloxacin and norfloxacin hybrids displayed a superior activity against E. coli. The 4 g and 4 h hybrids were the most active E. coli DNA gyrase inhibitors (IC 50 : 0.62 and 0.58 µM, respectively), and displayed an inhibitory activity that was comparable to that of ciprofloxacin (IC 50 : 0.40 µM). The 5 g and 5e hybrids exhibited an improved inhibitory activity (IC 50 : 0.76 and 0.80 µM, respectively) when compared to norfloxacin (IC 50 : 0.93 µM). Most of the tested hybrids were shown to be able to additionally inhibit the urease activity (IC 50 range: 9.71–80.64 μM). Hybrids 4e and 5c were the most potent urease inhibitors (IC 50 : 11.68 and 9.71 μM, respectively), capable of displaying a 3 − 4-fold increase in their activity when compared to ciprofloxacin, norfloxacin, and thiourea (IC 50 : 42.74, 36.07, and 32.25 μM, respectively). [Display omitted] [ABSTRACT FROM AUTHOR]

• 4 H -Pyrano[2,3- d ]pyrimidine−1,2,3-triazole− d -glucose hybrid compoundssynthesized. • Some compounds inhibited for MCF7, HepG2, HeLa cell lines with IC 50 < 4 μM. • Compounds 8v,8z,8zc , and 8zf exhibited against EGFR and HER2 tyrosine kinases. • Induced fit docking and MM-GBSA simulations for 8zc on EGFR enzyme. The polysubstituted 4 H -pyrano[2,3- d ]pyrimidines 6a-zj containing propargyl group on nitrogen atom 3 of ring have been synthesized by ring-closing reaction of corresponding 2-amino-3-cyano-4 H -pyrans 4a-zj with acetic anhydride and trifluoroacetic acid as catalyst, followed by alkylation with propargyl bromide under ultrasound conditions. A series of 36 analogs of 4 H -pyrano[2,3- d ]pyrimidine 8a-zj bearing d -glucose moiety tethered 1,2,3-triazole derivatives, including eighteen new ones, were synthesized by click chemistry between these N -propargyl derivatives and peracetylated d -glucopyaranosyl azide, with using CuNPs@Montmorillonite as a catalyst under ultrasound condition in the presence of DIPEA in t -BuOH/H 2 O at 25°C for 20 min. These compounds exhibited potent anticancer activity against tested cancer cells, including MCF-7, HepG2, and HeLa. Amongst tested compounds, some compounds exhibited strong activity against tested cancer cell lines with IC 50 < 4 μM, such as 8v,8x,8z,8zc,8zf and 8zg against MCF-7, 8s,8t,8w,8zh , and 8zi against HepG2, 8h,8j,8zf and 8zh against HeLa cancer cell lines. Compounds 8v,8z,8zc , and 8zf exhibited remarkable inhibitory activity against EGFR and HER2 tyrosine kinases in comparison with Lapatinib. The resulted docking studies showed that compound 8zc displayed binding mode like Erlotinib on EGFR enzyme and showed good binding energies. Induced fit docking, MM-GBSA calculation, and molecular dynamics simulations were carried out to elucidate the inhibitory potential of compound 8zc against tested enzyme 4HJO. Docking analysis showed that amongst the hydrophilic and hydrophobic interactions at the active site of EGFR enzyme, the hydrogen-bond bindings between acetate function and appropriate amino acid residues displayed the most important contribution in intensifying their potency against this enzyme. [Display omitted] [ABSTRACT FROM AUTHOR]

• Lactic acid:Melamine:NH 4 Cl DES play two essential role, catalyst and reaction media. • A new and efficient route for the one-pot synthesis of pyrido[2,3- d ]pyrimidine derivatives is described. • The reaction of substituted benzaldehydes, N,N -dimethyl-6-amino, and 2,4-thiazolidinedione is investigated in the presence of Fe 3 O 4 MNPs and Lactic acid:Melamine:NH 4 Cl DES. • The use of Fe 3 O 4 MNPs along with the Lactic acid:Melamine:NH 4 Cl DES significantly improved the reaction time and increased the product yields. Deep eutectic solvents (DESs) are among novel and more eco-friendly alternatives to ionic liquids (ILs) prepared by combining the components and the hydrogen bonds developed between them. The strong hydrogen bond interactions between the constituents of DESs make a considerable decline in the melting points in comparison to pure constituents. These green solvents have unique properties, making them a reliable and safe alternative to ILs and conventional organic solvents. In this study, we investigate the role of Fe 3 O 4 nanoparticles (NPs) in Lactic acid:Melamine:NH 4 Cl (as a novel deep eutectic solvent) in the green synthesis of pyrido[2,3- d ] pyrimidine derivatives. The prepared DES was characterized using FT-IR, 1H NMR, 13C NMR, TGA/DTA, DSC and physical properties, including viscosity, acidity, refractive index, surface tension, and density. The DES used during the experiments plays both catalytic roles and serves as a green environment for this reaction. In addition, magnetic DES can operate under very mild reaction conditions and be recycled easily with no significant catalytic activity loss. The fast and complete synthesis and high yield of the desired product are the remarkable benefits of this catalytic system. [Display omitted] [ABSTRACT FROM AUTHOR]

• A diversity of heterocyclic rings annulated pyrimidine ring was synthesized. • Antimicrobial and Antitumor activity of the synthesized compounds 2 - 16 were screened. • Molecular modeling studies and DFT calculations were performed. • QSAR was used to dessign the associations between molecular descriptors and pIC50. • Lipinski's rule of five (ROF) is used to detect substances drug-like compounds. 6-Amino-5-formyluracil (1) was efficiently utilized for construction of a variety of novel heteroannulated pyrimidines. Friedländer condensation reaction of compound 1 with some cyclic active methylene ketones including 1,3-cyclohexanedione, dimedone, 1,3-indanedione, substituted pyrazolones, 1,3-thiazolidine-2,4-dione and thiobarbituric acid gave a variety of heterocycles fused pyrido[2,3-d]pyrimidines. Compound 1 reacted with some cyclic enamines such as 5-amino-3-methyl-1 H -pyrazole, 6-aminouracil and 6-amino-1,3-dimethyluracil yielded pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine and pyrimido[5′,4′:5,6]pyrido[2,3-d]pyrimidines. In addition, reaction of compound 1 with some heterocyclic enols namely 4-hydroxycoumarin, 1-ethyl-4-hydroxyquinolin-2(1 H)-one and 2-hydroxy-4 H -pyrido[1,2-a]pyrimidin-4-one produced a diversity of polyfused systems. On the basis of DFT, the molecular structural parameters as well as a variety of global reactivity descriptors were calculated to inspect the optimized structures of the synthesized compounds. The values of energy gap of the present compounds ranging from 3.75- 4.82 eV; where compound 16 has the lowest value of energy barrier. To investigate for electrophilic and nucleophilic reactivity, the molecular electrostatic potential (MEP) of each molecule was measured. The synthesized compounds were screened in vitro for their bioassays against fungal strains, gram-positive and gram-negative bacteria, showing moderate and high inhibitory action. Also, most of the present compounds revealed good to excellent activities against colon carcinoma cell lines (HCT-116) and human Hepatocellular carcinoma cell lines (HePG-2). Compounds 5 and 10 - 12 showed higher antiproliferative activity (from 2.68 to 16.82 µg/mL) against the two types of cancer cell lines as compared with the reference drug (5-fluoeouracil). Quantitative structure activity relationship (QSAR models) were created using a multiple linear regression analysis (MLR) procedures and were used to design the correlations between molecular descriptors and antitumor activity of the prepared compounds. [Display omitted] [ABSTRACT FROM AUTHOR]

• The first X-ray studies of pyrido[3,2- e ]tetrazolo[1,5- a ]pyrimidine scaffold. • Novel synthetic method for 5-substituted pyrido[3,2- e ]tetrazolo[1,5- a ]pyrimidines. • The use of azide as leaving group in regioselective S N Ar reactions. • Characterization of azide-tetrazole equilibrium of azidopyrido[2,3- d ]pyrimidines. C -5 Substituted pyrido[3,2- e ]tetrazolo[1,5- a ]pyrimidines were obtained by simple azidation of 2,4-dichloropyrido[2,3- d ]pyrimidine followed by S N Ar reactions with S -, N - and O -nucleophiles. Their NMR and IR studies revealed that the mono-azido products undergo azide-tetrazole equilibrium, whereas 2,4-diazidopyrido[2,3- d ]pyrimidine exists in four tautomeric forms in various solutions, and its solid phase tautomer was established by the X-ray analysis. In total, nine of the obtained products are fully characterized by their single crystal X-ray structures and seven of them revealed a novel annulated pyrido[3,2- e ]tetrazolo[1,5- a ]pyrimidine skeleton. Among the studied products the amino derivatives - 5-aminopyrido[3,2- e ]tetrazolo[1,5- a ]pyrimidines - exist mainly in their tetrazole form both in the solid phase and in the solutions. However, also the latter enter the tautomeric equilibrium and the liberated azido group is able to undergo copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and form the corresponding 1,2,3-triazole derivatives. Free Gibbs energies of the tautomerization of C -5 substituted cyclohexylmercapto-, isopropyloxy- and phenoxy-pyrido[3,2- e ]tetrazolo[1,5- a ]pyrimidines were found to be -21.30, -23.19 and -17.02 kJ/mol, respectively. [Display omitted] [ABSTRACT FROM AUTHOR]

• Three new ternary complexes of sulfaquinoxaline were synthesized and characterized. • Intra and intermolecular contacts stabilize the crystal structure of the complexes. • Zn complex is more cytotoxic against tumoral cells than the Ni and Cu compounds. Three monomeric ternary complexes of Ni(II) (1), Cu(II) (2), and Zn(II) (3) with sulfaquinoxaline (SQO), and 2,2'-bipyrimidine (bpm) as ligands have been prepared and their crystal structures have been determined. The complexes are formulated as M(SQO) 2 bpm·2H 2 O, completing MN 6 coordination spheres. Hirshfeld surface analysis was employed to study the intermolecular interactions in the crystal lattices of the compounds. From these studies, it was found that hydrogen bonding and π-stacking interactions play an important role. Besides, the complexes have been characterized by FTIR and UV-Visible spectroscopies, and thermogravimetric techniques. The cytotoxicity of the complexes was screened against the tumoral A549 (human lung adenocarcinoma) and MG-63 (human osteosarcoma) cell lines. The complexes showed enhanced antibacterial activity against S. aureus and S. epidermidis as compared with the free SQO ligand. [ABSTRACT FROM AUTHOR]

• Ligands binding to the colchicine biding site of the tubulin protein act as tubulin polymerization inhibitors. • A series of 4-Phenyl-1,2,3-triazole substituted pyrimidine derivatives have been synthesized and evaluated for antiproliferative and antitubulin activities. • AV-6 and AV-14 were found to be active against the three tested cancer cell lines. • 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. • In the mechanistic studies these compounds were found to induce mitochondria mediated apoptosis. 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 IC 50 values of 1.2 µM, 5.5 µM, and 1.9 µM while AV-14 displayed IC 50 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. [ABSTRACT FROM AUTHOR]

• Novel cyclohepta[ b ]thiophene incorporating pyrimidine, pyridine, and chromene moiety were designed and evaluated for their antimicrobial activities. • Time-kill kinetics, antibiofilm activity, and the DNA gyrase inhibition of the active thiophene compounds were evaluated. • Levofloxacin and Ciprofloxacin are used as the reference standards drugs. • The ɣ-radiation effect on the antimicrobial activity of most active synthesized thiophenes was analyzed. • In silico assessment of all the potent compounds pharmacokinetic and drug-likeness was performed. • The docking examination was carried out for the most promising derivatives inside the active site of DNA gyrase (4URO). The emergence of drug-resistant microbes is responsible for high morbidity and mortality worldwide. In our endeavors to cultivate novel and effectual antimicrobial agents, we present the triumphant synthesis of a novel class of cyclohepta-thieno-pyrimidins 4-8 , cyclohepta[ b ]thiophene appended 2-imino-2 H -chromene-3-carboxamide and 3-imino-3 H -benzo[ f ]chromene-2-carboxamide derivatives 9-11 molecules, to enrich their biological behavior. The desired molecules had undergone in-vitro appraisal for their antimicrobial activity, demonstrating encouraging results. Besides, the time-kill kinetics, antibiofilm activity and the DNA gyrase inhibition of the active thiophene compounds were evaluated. The DNA gyrase inhibition by the active thiophenes was also determined with IC 50 values to range between (5.3-18.7µM) compared with Levofloxacin and Ciprofloxacin. Also, the sum of the Fractional Inhibitory Concentration Index (ΣFICI) was used to assess synergy between thiophenes and Levofloxacin. Additionally, the antimicrobial activity of the most active thiophene derivative was analyzed after ɣ -irradiation. Moreover, the in-silico prediction methodology was contemplated for foretelling the physicochemical, pharmacokinetic and ADME traits of the most active synthesized compounds and the standard reference drugs: Levofloxacin and Ciprofloxacin. The docking examination was carried out for the most promising derivatives 1, 2, 3, 4, 9 , Novobiocin, and Levofloxacin inside the active site of DNA gyrase, and their respective docking scores were contrasted with the scores of the above-mentioned standard drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

• A new series of pyrimidine-5-carbonitriles have been designed and synthesized. • Potent VEGFR-2 inhibitory activity correlated cytotoxicity of compound 5a. • Compounds 5a and 6c showed significant cytotoxic activity against HepG2 cells • Compounds 5a and 6c arrested the cell cycle at G2/M phase and induced apoptosis by increasing pre-G1 phase • The pro-apoptotic activity for compounds 5a and 6c were due to up-regulation of p53, Bax and downregulation of Bcl2. A new series of pyrimidine-5-carbonitriles has been designed and synthesized as potent anticancer agents. Pyrimidine-5-carbonitriles 2-6d have been assessed for their cytotoxic activity against hepatocellular carcinoma (HepG2) cell line. Results revealed that, N -(2-chlorophenyl) acetamide pyrimidine derivative 5a and pyrimidine acetamide phenylpropanoic acid 6c revealed good cytotoxic activity against HepG2 cells compared with Sorafenib as a reference standard. Compounds 5a and 6c showed potent inhibition of VEGFR-2 with IC 50 value 0.067 and 0.44 µM. Active compounds 5a and 6c elicited pre G1 apoptosis and cell cycle disturbance at G1 phase in a manner similar to Sorafenib. Furthermore, qRT-PCR assay revealed that, 5a and 6c were found to induce apoptosis via elevation of p53, Bax and downregulation of Bcl2. Finally, compounds 5a and 6c were found to upregulate C aspase 3/7 level 1.21- fold higher than SOR as elicited by green flow cytometry analysis. [ABSTRACT FROM AUTHOR]

• A series of 1,2,4-triazole derivatives containing fluorine, phenyl sulfonyl and pyrimidine moieties was designed and synthesized. • New compounds were confirmed by different spectral techniques. • All the newly synthesized compounds were screened for their herbicidal activity. • The results indicated that compound Ⅳ-8 5-{1-[(4-methoxyphenyl) sulfonyl]-5-[(4-fluorophenoxy)methyl]-1H-1,2,4-triazol-3-yl)}-2-propylthio-6-(methylthio) pyrimidin-4-amine showed better herbicidal activity than the commercial herbicide flumetsulam, and is a promising candidate for herbicide development. In this study, 4-amino-2-(alkylthio)-6-(methylthio) pyrimidine-5-carbonitrile Ι were employed as the starting materials to synthesize a novel series of 1,2,4-triazole derivatives containing fluorine, phenyl sulfonyl and pyrimidine moieties Ⅳ-1 ∼ Ⅳ-39. The preliminary bioassay indicated that many newly synthesized compounds exhibited moderate to good herbicidal activities against the monocotyledons (Echinochloa crusgalli, Sorghum bicolor) and dicotyledons (Raphanus sativus, Brassica campestris, Cucumis sativus , and Medicago sativa) at the concentrations of 100 mg·L−1 and 10 mg·L−1. Especially, compound (Ⅳ-8) displayed good herbicidal activity, with 100% inhibition against Brassica campestris, Cucumis sativus , and Medicago sativa at a concentration of 100 mg·L−1. [ABSTRACT FROM AUTHOR]

• A new fluorinated pyrazole[1,5- a ]pyrimidine derivatives were synthetized. • The structure of the designed compounds was confirmed by spectroscopic techniques. • Anti-viral and SAR study were evaluated and discussed. • The HVC protease were determined for the most promising compounds. • Docking study and ADMA were carried out as well as some physicochemical properties. Starting compound 2-cyanomethyl-7-(thiophen-2-yl)-5-trifluoromethylpyrazolo[1,5- a ]pyrimidine-3-carbonitrile 3 reacts with aromatic aldehydes, aromatic diazonium salts, o -hydroxybenzaldehyde and isatin, a series of new fluorinated pyrazolo[1,5- a ]pyrimidine derivatives were obtained. Additionally, the enamine derivative of compound 3 reacts with each of hydrazine hydrate and guanidine hydrochloride to form fluorinated ployheterocycles. The newly synthesized compounds were characterized by spectral data (IR, 1H NMR, 13C NMR and MS) and elemental analyses. Some selected compounds were tested in vitro for antiviral activity against Coxsackie virus B 4 (COX-B 4), Rift Valley Fever (RVF), Vesicular stomatitis virus (VSV), and Encephalomyocarditis (EMCV) virus. The results of the antiviral evaluation of some new compounds 3, 5c, 5i, 7b , and 15 showed good antiviral activity against the tested viruses, for example compound 5c containing the withdrawing group (Cl) showed 26.6% inhibition against COX-B4, while 5i containing the furan moiety showed decreased activity compared to 5c (21%). Furthermore, compound 15 which is a fused compound showed an inhibitory effect 23%. Also, compounds 3, 5c, 5i, 7b and 15 were evaluated against the HCV-NS3 protease using Sovaldi as a control. The results showed that compound 5c had a good inhibitory effect on hepatitis C virus protease (HCV-NS3), with an IC 50 of 7.33 ± 0.51 μg/ml, compared to IC 50 of Sovaldi 3.20 ± 1.33 μg/ml. The virucidal activity of 5c was also determined by direct and indirect methods. The direct method showed moderate antiviral activity (0.76 log (10) / ml, corresponding to the percentage depletion of the virus infectivity titer of 13.8%. In contrast, the indirect method showed better antiviral activity, which was dependent on the time of application (1.75 log (10) /ml), which is 31.828%. Molecular Operating Environment software (MOE, 2015.10) was used to dock compounds 3, 5c, 15 compared to Sovaldi as a reference drug with the active site of co-crystallized B-Raf (PDB code: 3II5). The results showed good formation of hydrogen bonds between the functional groups NH, CO, CN, S atom and N atom of the target compounds with His 573, Thr 528, Cys 531, Glu 500, lle 591, Asp 593 and Gly 595 residues in terms of bond length and binding energy compared to Sovaldi. In addition, Absorption Metabolism Distribution Excretion studies (ADME) are used in the drug development process to study various factors that influence drug action and efficacy. Thus ADME was performed for compounds 3, 5c and 15 and showed that compound 3 could be absorbed through the gastrointestinal tract compared to other compounds tested. [Display omitted] [ABSTRACT FROM AUTHOR]

• Polysubstituted thienopyrimidine derivatives were designed and synthesized. • Compound (8c) showed significant activities against studied cancer cell lines. • Molecule (8c) docked with EGFR kinase to study its interaction with the anticancer enzyme. • SAR was preliminarily discussed through cytotoxic activity data and analysis of molecular docking. Thienopyrimidine scaffold is a fused heterocyclic ring system that has been found to be an integral part of pharmaceutical products to the improvement of pharmacological and biological activities. A series of polysubstituted thieno[2,3- d ]pyrimidine derivatives have been synthesized and tested for their cytotoxic activity against Hela and A549 cancer cell lines in which EGFR is highly expressed. Most of the target compounds 8a-8e showed excellent activity against Hela and A549 cancer cell lines. The most promising compound 8c exhibited the similar IC 50 values on A549 cell lines to the lead drug Olmutinib. The molecular docking results indicated that compound 8c bound to EGFR kinase in a different method with Olmutinib. The preliminary structure-activity relationship (SAR) suggested that the introduction of oxygen substituents was more favorable for antitumor activity. Compound 8c proved to be a promising antitumor agent. [Display omitted] [ABSTRACT FROM AUTHOR]