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Colorectal cancer (CRC) is the second most common cause of cancer‐related deaths and the third most common cancer worldwide. Because of its importance in DNA biosynthesis, thymidylate synthase (TS) has gathered attention as a promising target for cancer therapy. Herein, we have designed and synthesized 12 novel 5‐(N‐Benzyl indol‐3‐yl) pyrido[2, 3‐d] pyrimidine based derivatives and assessed their anticancer activity against HCT 116, MCF‐7, Hep G2, and PC‐3 cell lines. For compounds 5 a and 5 f TS inhibitory activity was also performed along with in silico studies. Further, all the synthesized compounds exhibited anticancer activity, but particularly, compounds 5 a and 5 f were showed excellent anticancer activity having IC50 values of 1.09±0.61, 5.54±0.81, 6.44±0.91, and 5.12±0.65 μM and 1.03±0.96, 3.09±0.52, 4.12±0.59, and 7.06±0.60 μM respectively with control Raltitrexed (IC50 1.02±0.51, 1.88±0.61, 1.30±0.89, and 2.09±0.67 μM respectively) and hTS inhibitory activity with IC50 of 18.91±1.09 and 16.19±0.96 nM with control Raltitrexed (IC50 12.25±1.21 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 5 a and 5 f to the catalytic site of TS. Additionally, ADME characteristics were also in the acceptable range for these compounds. Based on the anticancer activity, SAR was also performed for lead optimization. [ABSTRACT FROM AUTHOR]

A facile and efficient protocol for one-pot three-component synthesis of a series of novel 4-substituted-2-thioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5(2H)-one derivatives has been developed. Compounds were synthesized by the reaction of 2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione, various aromatic aldehydes, and thiourea using Iodine as catalyst in acidic medium. The synthesized compounds obtained in good to excellent yields (52–83%) with improved reaction time and chloro substituent at four-position yielded the product in excellent quantity (83%). The synthesized compounds have been characterized by 1H, and 13C NMR, IR, and mass spectral analysis, and screened for their in vitro antibacterial activity against Bacillus subtilis, Salmonella typhemurium, Escherichia. coli, and Staphylococcus aureus using disk diffusion method. Biological screening revealed that the newly synthesized compounds exhibit interesting activities against several bacterial strains. Among all the synthesized compounds, the in vitro antibacterial activity displayed by compound 6j was highest against S. typhemurium with ZOI 23.5. mm (MIC = 3.125 µg/mL). Docking studies further supported the findings, and provided for the basis of linkages in terms of conventional hydrogen bonds, and pi- bonding patterns. In nutshell, the present study thus paved the way for developing lead compounds which could be potentially used as an efficient antibacterial drug in humans after appropriate animal, and clinical trials. [ABSTRACT FROM AUTHOR]

In this study, we designed and synthesized several novel fused [1,2,3]triazolo [4′,5′:3,4]pyrrolo[1,2‐a]thieno[2,3‐d]pyrimidine derivatives using in a single [3 + 2] reaction cycloaddition reaction of 3‐(3‐iodoprop‐2‐yn‐1‐yl)thieno[2,3‐d]pyrimidin‐4(3H)‐one (4) followed by C‐C bond coupling with various aryl azides in a PEG‐400 medium. All of the newly synthesized compounds were evaluated in vitro for EGFR kinase inhibitory action as well as anti‐breast cancer activity against MDA‐MB‐231 and MCF‐7 breast cancer cell lines. When compared to the reference molecule, erlotinib, the majority of the compounds demonstrated adequate efficacy. The most promising compounds, 5g and 5i, demonstrated excellent anticancer activity against both cancer cell lines, with IC50 values ranging from 04.17 ± 0.55 to 8.65 ± 0.89 μM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC50 = 0.467 ± 0.063 and 0.412 ± 0.081 μM). The in silico studies of five potent compounds 5f, 5g, 5h, 5i, and 5k were also carried out to identify the interactions against the EGFR receptor and found that the energy calculations were covenant with the obtained IC50 values. [ABSTRACT FROM AUTHOR]

Pyridopyrimidine are heterocyclic molecules enclosing fused pyridine and pyrimidine rings. Owing to its fascinating core structure and pharmacological applications a series of 7-([1,1′-biphenyl]-4-yl)-5-arylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones were synthesized and characterized using IR, 1H, 13C NMR and Mass spectral techniques. The antibacterial, antioxidant and anticancer activities were investigated for the synthesized compound 5a-5f. Compounds with electron-donating groups showed excellent free radical scavenging activity. Halogen-substituted compounds showed more potent antimicrobial and anticancer activity than other derivatives in comparison with their respective standards. Based on the IC50 value obtained from anticancer activity, 5c was further analyzed for apoptosis by AO/EB staining method. The findings suggested early apoptosis in the MCF-7 cell line. Molecular Docking studies of the synthesized compounds were performed with Kinase 1 inhibitors (PDB id: 2YEX), 5c exposed good docking results with minimum binding energy. Further, these compounds were acknowledged as orally active drug candidates from in-silico ADMET studies. Computational analysis supports biological findings indicating compound 5c as a promising anticancer agent against the human breast cancer MCF-7 cell line. [ABSTRACT FROM AUTHOR]

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

This work describes the design and synthesis of three series of hybrids of thienopyrimidines and sulfonamides. Dihydrofolate reductase enzyme was selected as a target for the in-silico screening of the synthesized thienopyrimidine–sulfonamide hybrid as an antibacterial, while squalene epoxidase was selected as an antifungal target protein. All screened compounds showed promising binding affinity ranges, with perfect fitting not exceeding 1.9 Å. The synthesized compounds were tested for their antimicrobial activity using agar well diffusion and minimum inhibitory concentration tests against six bacterial strains in addition to two Candida strains. Compounds 8iii and 12ii showed varying degrees of inhibition against Staphylococcus aureus and Escherichia coli bacterial strains, whereas the best antifungal activity against Candida was displayed by compound 8iii. Compound 12ii, the cyclohexathienopyrimidine coupled with sulfadiazine at position 3, has the best antibacterial activity, which is consistent with molecular docking results at the active site of the oxidoreductase protein. Interestingly, compound 12ii also has the highest docking binding energy at the antifungal squalene epoxidase active site. Investigating the physicochemical properties of the synthesized hybrids revealed their high tolerability with cell membranes, and moderate to poor oral bioavailability, and that all are drug-like candidates, among which 4i, the cyclohexathieno[2,3-d] pyrimidine core with sulphaguanidine incorporated at position 4, recorded the best score (1.58). [ABSTRACT FROM AUTHOR]

The current research is directed to construct a novel category of linear annulated chromeno[3',2':5,6]pyrido[2,3-d][1,3]thiazolo[3,2-a]pyrimidines. The chemical reactivity of the recently synthesized aldehyde 1 was examined toward a diversity cyclic methylene ketones, cyclic enamines and cyclic enols. Friedländer condensation of aldehyde 1 with 1,3-cyclohexanediones gave the multi-linear chromenopyrido- pyrimidothiazoloquinolines 2 and 3. Also, treating aldehyde 1 with some pyrazolones furnished annulated chromenopyridopyrazolopyridothiazolopyrimidines 4-6. Further, 1,3-thiazolidine-2,4-dione and barbituric acid condensed with aldehyde 1 giving chromenopyridothiazolopyridothiazolopyrimidine 7 and chromenopyridopyrimido-thiazolopyridopyrimidine 8, respectively. Moreover, reacting aldehyde 1 with cyclic enamines (6-amino-2-thiouracil and 6-amino-1,3-dimethyluracil) and cyclic enols (4-hydroxycoumarin and 1-ethyl-4-hydroxyquinolin-2(1H)-one) furnished polyfused heterocycles 9-12, respectively. During in vitro investigation of the antimicrobial efficiency, the synthesized compounds showed considerable activity against yeast and fungal strains, as well as moderate to high activity against Gram-positive and Gram-negative bacteria. Polyfused compounds 4-6 showed significant efficiency against all types of tested microorganisms. [ABSTRACT FROM AUTHOR]

New cytisine-thienopyrimidine hybrid molecules were synthesized by reacting cytisine with 4-chlorothieno [2,3-d]pyrimidines in the presence of Et3N. The solvent effect on the course of the reaction was studied. The structures of the obtained compounds were elucidated using IR, 1H and 13C NMR spectroscopy and TLC-MS spectrometry. X-ray crystal structure analyses of the synthesized compounds were performed. [ABSTRACT FROM AUTHOR]

The study focused on developing new triazolopyrimidine derivatives as potential DNA Gyrase inhibitors and antimicrobial agents. The compounds were designed, synthesized, and evaluated for their biological activities, safety, and ADMET properties. Encouragingly, the initial results showed promising potency and acceptable ADME parameters, forming a strong basis for further drug development research. The newly synthesized compounds were verified through spectra, mass, and elemental analysis. Notably, several compounds exhibited significant activity against both Gram‐positive and Gram‐negative bacteria, with MIC values ranging from 100 μg/ml to 250 μg/ml. importantly, the compounds were found to be safe, with no reported adverse effects or toxicities. Among the tested compounds, compound 2 m stood out as an excellent DNA Gyrase inhibitor, with an IC50 value of 0.89 μM, comparable to the reference drug ciprofloxacin with an IC50 value of 0.91 μM. Molecular docking studies confirmed that the compounds′ binding mode and docking scores were similar to ciprofloxacin, validating their antibacterial activity via DNA Gyrase inhibition. The research provides valuable insights into the potential of these newly synthesized triazolopyrimidine derivatives as DNA Gyrase inhibitors and antimicrobial agents. Their promising antibacterial activity and safe profile make them potential candidates for further development as antimicrobial agents. [ABSTRACT FROM AUTHOR]

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

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

A novel heterocyclic compounds containing pyrimido[4,5-d]pyrimidine (IIIa–IIIb) and (IVa–IVb), pyrazolo[3,4-d]pyrimidine (Va'–Ve') and (VIa'–VIe'), and pyrimido[4,5-b]quinoline (VIIa'–VIIe') and (VIIIa'–VIIIe') were designed and synthesized from the starting materials, 5-(bis(methylthio)methylene)-1,3-diphenylpyrimidine-2,4,6(1H,3H,5H)-trione (IIa) and 5-(bis(methylthio)methylene)-1,3-diphenyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (IIb) as efficient α,α-ketene dithioacetals is reported. The synthetic approaches of these types of compounds will provide an innovative molecular framework to the designing of new active heterocyclic compounds. In our study, we also present optimization of the method for synthesis along with antimicrobial evaluation of these newly synthesized compounds as antibacterial agents against the bacterial strains, like E. coli, B. subtilis, S. aureus, and P. aeruginosa also as antifungal agents against B. cinerea, C. arachidicola, A. solani, G. zeae, S. sclerotiorum, and R. cerealis. Preliminary bioassay showed that most of them exhibited certain-to-excellent antibacterial and antifungal activity. Among all the evaluated compounds, it was found that the synthesized compounds (IVb) and (VIIIc') showed the outstanding antibacterial activity (100%) against the strains E coli and S. aureus respectively comparable to the standard drug Ciprofloxacin at the same concenteration while the others exhibited better antifungal activity at 100 µg/mL. The outstanding antifungal activity (>90%) comparable to the positive controls trifloxystrobin and azoxystrobin exhibited by (VIIIc') against B. cinerea, (IVb) and (Vc') against A. solani, (IVb) against S. sclerotiorum alongwith compounds (VIb'–VIc') against R. cerealis. The structures of all the new synthesized compounds were elucidated by elemental analysis, IR, 1H NMR, and 13C NMR. [ABSTRACT FROM AUTHOR]

A novel family of 3-chloro-4-benzylidene-1-(pyrimidin-2-yl) azetidin-2-one 5a-o has been developed because antimicrobial resistance (AMR) poses a significant concern to global public health and has made it exceedingly difficult to effectively manage infectious diseases that have been connected to it. The structures of the relevant compounds have been determined and verified using spectral methods. As substances are tested against gram-positive and gram-negative strains of bacteria and fungi, results must be compared to those of conventional drugs. Products with chloro substituents in both the pposition and the m-position demonstrate good activity against the fungi Aspergillus niger and Fusarium javanicum, while those with nitro, methyl, and bromo substituents in the benzene ring's p-position, as well as those with the nitro group at the ring's m-position, demonstrate excellent activitiy against bacterial strains. [ABSTRACT FROM AUTHOR]

The starting substrate 5-chloro-4,9-dimethoxy-7-oxo-7H-furo[3,2-g]chromene-6-carbonitrile (2) was efficiently synthesized from chlorination of the corresponding hydroxy derivative. The presence of adjacent cyano and chloro functions was employed for construction a variety of five, six and seven membered rings annulated furo[3,2-g]chromenes. Treating precursor 2 with hydrazine, phenylhydrazine and hydroxylamine yielded furo[3,2:6,7]chromeno[4,3-c]pyrazoles 3, 4 and furo[3,2:6,7] chromeno[3,4-d]isoxazole 5, respectively. Also, reaction of compound 2 with a diversity of 1,3-N,N-binucleophiles such as guanidine, cyanoguanidine, thiourea, acetamidine and benzamidine produced annulated furo[3,2:6,7]chromeno[4,3-d]pyrimidines 6–10, respectively. Further, treatment of compound 2 with a variety of 1,4-binucleophiles namely ethylenediamine, o-phenylenediamine and 2-aminophenol yielded furo[3,2:6,7]chromeno[4,3-e][1,4]diazepine 11, furo[3,2:6,7]chromeno[4,3-b][1,5]benzodiazepine 12 and furo[3,2:6,7]chromeno[4,3-b][1,5]benzoxazepine 13, respectively. Some of the synthesized compounds seemed good antimicrobial activity especially compounds 3, 6 and 8. Using analytical and spectral results, the structures of the prepared compounds were established. [ABSTRACT FROM AUTHOR]

A new bunch of substituted aryl amino derivatives structurally modified pyrido[3,2-d]pyrimidines (10a–j) have been synthesized and evaluated for anticancer effects against PC3 (human prostate), A549 (human lung), MCF-7 (human breast) and Colo-205 (human colon) cancer cell lines by utilizing of MTT procedure. Most of the synthesized compounds were showed anticancer activity good to moderate activities with IC50 values range from 0.013 ± 0.0058 µM to 8.22 ± 5.87 µM, whereas, standard 9 etoposide used as standard drug) showed IC50 values from 0.14 ± 0.017 µM to 3.08 ± 0.135 µM, respectively. Among the synthesized compounds, five compounds 10a, 10b, 10c, 10d and 10e demonstrated more potent activity on all cell lines. Mainly, compound 10e displayed higher anticancer activity. [ABSTRACT FROM AUTHOR]

A novel series of heterocyclic compounds containing thiazolo[3,2-a]pyrimidine and pyrimido[5,4-d]thiazolo[3,2-a]pyrimidine analogues were designed and synthesized starting from α,α-ketene dithioacetals (I), and their structures were confirmed by elemental analysis, IR, 1H NMR, and 13C NMR. In our study, we also present optimization of the synthetic method along with a biological evaluation of these newly synthesized compounds as antioxidants and antifungal. Preliminary bioassay showed that most of them exhibited certain-to-excellent antioxidant and antifungal activity. Among all the evaluated compounds, it was found that some showed significant antioxidant activity at 10 µg/mL while the others exhibited better antifungalal activity at 100 µg/mL. Thiazolo[3,2-a]pyrimidines (IVa–IVb) and (IVc–IVd) showed higher than 80% inhibition activity against C. arachidicola and P. infestans respectively whereas the thiazolo[3,2-a]pyrimidines (VIc–VId) showed maximum activity against B. cinerea and C. arachidicola, as for the tested pyrimido[5,4-d]thiazolo[3,2-a]pyrimidines (IXc–IXd) against G. zeae, P. piricola, and P. sasakii. In particular, thiazolo[3,2-a]pyrimidines (IVc–IVd) exhibited outstanding activity (> 90%) against G. zeae. Among all the evaluated compounds, it was found that some showed significant antioxidant activity at 10 µg/mL and the maximum DPPH radical scavenging activity was observed with synthetic thiazolo[3,2-a]pyrimidines (VIIc–VIId) and pyrimido[5,4-d]thiazolo[3,2-a]pyrimidine (IXc–IXd), especially pyrimido[5,4-d]thiazolo[3,2-a]pyrimidine (IXc) which possessed the highest antioxidant activity in comparable to that of standard vitamin C at similar concentration. [ABSTRACT FROM AUTHOR]

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

A novel and highly efficient synthetic route to [1,3,4]thiadiazolo[3,2-a]pyrimidine derivatives from 5-amino-1,3,4-thiadiazole-2-thiol, various aromatic aldehydes, and Meldrum's acid in the presence of acetic acid in dry ethanol has been reported. We designed the three-component reaction with the incorporation of Knoevenagel condensation followed by an intermolecular nucleophilic addition reaction in one pot under mild conditions. The structural diversities of these synthesized compounds have been confirmed spectroscopically, by IR, 1H-, and 13C NMR, and elemental analysis, which agree with the proposed structures. [ABSTRACT FROM AUTHOR]

A facile, environmentally benign and proficient route has been developed for the diverse synthesis of pyrrolo[2,3-d]pyrimidine derivatives followed by heterocyclization starting from Amino uracil, arylgyoxal and malononitrile/thiols. Readily available thiamin hydrochloride organocatalyst was used as a green promoting medium. As well as the reaction progress was taken place under aqueous media. This procedure also offers a base and metal free approach which endowed high yields with better functional group tolerating ability and mild reaction conditions. Further, methodology had a widescope with recyclability and reuse of thiamin hydrochloride. DFT/TD-DFT calculations with B3LYP/6-311G++ level of theory were used to study the optimized geometry and HOMO-LUMO energy of the synthesized compounds (4b and 6i). [ABSTRACT FROM AUTHOR]

Structural-based drug design and solvent-free synthesis were combined to obtain three novel series of 5-arylethylidene-aminopyrimidine-2,4-diones (4, 5a–c, 6a,b), 5-arylethylidene-amino-2-thiopyrimidine-4-ones (7,8), and 6-arylpteridines (9,10) as dual BRD4 and PLK1 inhibitors. MTT assays of synthesized compounds against breast (MDA-MB-231), colorectal (HT-29), and renal (U-937) cancer cells showed excellent-to-good cytotoxic activity, compared to Methotrexate; MDA-MB-231 were the most sensitive cancer cells. The most active compounds were tested against normal Vero cells. Compounds 4 and 7 significantly inhibited BRD4 and PLK1, with IC50 values of 0.029, 0.042 µM, and 0.094, 0.02 µM, respectively, which are nearly comparable to volasertib (IC50 = 0.017 and 0.025 µM). Compound 7 triggered apoptosis and halted cell growth at the G2/M phase, similarly to volasertib. It also upregulated the BAX and caspase-3 markers while downregulating the Bcl-2 gene. Finally, active compounds fitted the volasertib binding site at BRD4 and PLK1 and showed ideal drug-like properties and pharmacokinetics, making them promising anticancer candidates. [ABSTRACT FROM AUTHOR]

Two series of compounds viz. spiro naphthyridine pyrimidine derivatives and N‐(quinolin‐8‐yl)acetamide derivatives which possess the quinoline core moiety were designed and synthesized. The spectral analysis viz. FT‐IR, 1H‐NMR, 13C‐NMR and mass was carried out to establish the structures for the synthesized compounds. In vitro anti‐tubercular activity was done against Mycobacterium tuberculosis H37Rv by following "microplate alamar blue assay (MABA)". The synthesized compounds showed good anti‐tuberculosis (TB) activity with the least minimum inhibitory concentration (MIC) value of 6.25 μg/mL. Computational molecular docking studies were performed out with Mycobacterium tuberculosis enoyl reductase (INHA) (PDB code: 4TZK) using AutoDock to predict the key binding interactions responsible for the activity and the Swiss ADME (absorption, distribution, metabolism, and excretion) tool computed the in silico drug likeliness properties. The synthesized title compounds create a way for the optimization and development of potential drugs against tuberculosis. [ABSTRACT FROM AUTHOR]

In here, a series of pyrimidin-(1(2H)-yl)acetamide and pyrimidin-(1(2H)-yl)isophthalimide derivatives were synthesised according to literature. The cytotoxic activity properties of these molecules were screened against human cancer cell lines as in vitro. The results demonstrated that these molecules had moderate effects on cancer cell lines for 48 h. The binding potential of the relatively active compound, ZF1, towards CDK1 (cyclin-dependent kinase 1) was investigated through molecular docking. The stability of the enzyme-ZF1 complex procured from the molecular docking was assessed through molecular dynamics (MD) simulation. Then, the electrochemical properties of the synthesised compounds were computed through density functional theory (DFT) studies. Computational pharmacokinetic analysis was also performed. The computational studies revealed that ZF1 could bind to CDK1 but its binding potential was less than the standard drug. The MD simulation exhibited that the compound could be stable inside the binding region during the simulation period. ZP3 is predicted to have the highest chemical stability among the synthesised compounds. Furthermore, the computational pharmacokinetic study revealed that ZP1, ZP2, and ZP3 had drug-like properties. [ABSTRACT FROM AUTHOR]

In this research, we synthesized new pyrimidine fused quinoline derivatives in high yields using multicomponent reaction of the 2-amino-4-hydroxyacetophenone, isopropenylacetylene, aldehydes, malononitrile or ethyl cyanoacetate, acetaldehyde and dimethylacetylene dicarboxylate in the presence of catalytic amounts of Fe3O4/KF/Clinoptilolite@MWCNTs magnetic nanocomposites using ionic liquid as green solvent at room temperature. Also, the catalytic activity of the green synthesized Fe3O4/KF/Clinoptilolite@MWCNTs MNCs was evaluated in the reduction of organic pollutants such as 4-nitrophenol (4-NP) in water at mild conditions. The results indicated that the biosynthesized NCs have very high and effective catalytic activity for organic pollutants within few seconds. The synthesized compounds have NH group in their structure and for this reason have good antioxidant activity. Also, employing Gram-positive and Gram-negative bacteria in the disk diffusion procedure confirmed the some pyrimidine fused quinoline derivatives antimicrobial effect. The results showed that synthesized compounds prevented the bacterial growth. This used procedure for preparation of pyrimidine fused quinoline derivatives has some advantages such as low reaction time, product with high yields, simple separation of catalyst and products. Green chemistry is the use of a set of principles to reduce or eliminate the use or generation of unsafe materials in the design, fabrication and applications of chemical products. Among solvents, water is a green solvents and very suitable for performing organic reaction. The present procedure avoids the use of toxic solvent. Specially fused N-heterocycles, having privileged motifs like pyrimidine and quinolines, are found in many drugs and bioactive natural products. Hybrid molecules having a pyrimidine ring fused with quinoline are also known as deazaflavins or 5-deazaisoalloxazines. [ABSTRACT FROM AUTHOR]

The present work is directed to synthesize and evaluate the antimicrobial activity of some novel 2-heteroarylchromeno[2,3-d]pyrimidines. 2-(6,8-Dimethylchromon-3-yl)-8-methoxy-4H-chromeno[2,3-d]pyrimidine-4,5(3H)-dione (4) was successfully synthesized and utilized as a building block to produce a variety of heterocyclic compounds. 2-(4-Pyrazolyl/isoxazolyl)chromeno[2,3-d]pyrimidines 5–7 were obtained from the reaction of compound 4 with hydrazine hydrate, phenylhydrazine, and hydroxylamine, respectively. Also, 2-(6-pyrimidinyl)chromeno[2,3-d]pyrimidines 8–12 were efficiently prepared from reacting compound 4 with guanidine, cyanoguanidine, thiourea, acetamidine, and benzamidine, respectively. Further, chromeno[2,3-d]pyrimidines linked diazepine 13, benzodiazepine 14, benzoxazepine 15 and benzothiazepine 16 were also synthesized. The synthesized compounds were examined for their antimicrobial efficiency. Pyrazolylchromeno[2,3-d]pyrimidines 5 and 6 showed the best activity against all kinds of microorganisms. Structures of the synthesized compounds were validated using analytical and spectral data. [ABSTRACT FROM AUTHOR]

The present study investigates the reaction of orthoamides of alkynecarboxylic acids with tautomeric compounds. Various heteroaromatic compounds were synthesized, including pyridine carboxylic acid esters, pyridine carbonitriles, imidazo[1,2-a]pyridines, and 4-aza-heptatriene carbonitriles. Some of the synthesized compounds showed antithrombotic effects. The results could be of importance for the development of new pharmaceutical agents. The text describes various chemical reactions in which orthoamides are reacted with different compounds. Detailed information is provided on the yields, melting points, and spectral data of the obtained products. In addition, crystal structure analyses are performed to determine the structure of some compounds. [Extracted from the article]

The heterocyclic ring system of pyrido [2,3-d]pyrimidines is a privileged scaffold in medicinal chemistry, possessing several biological activities. The synthesis of the pyrimidine derivatives was performed via the condensation of a suitable α,β-unsaturated ketone with 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate in glacial acetic acid. Chalcones were synthesized, as starting materials, via the Claisen–Schmidt condensation of an appropriately substituted ketone and an appropriately substituted aldehyde in the presence of aqueous KOH 40% w/v in ethanol. All the synthesized compounds were characterized using IR, 1H-NMR, 13C-NMR, LC-MS and elemental analysis. The synthesized compounds were evaluated for their antioxidant (DPPH assay), anti-lipid peroxidation (AAPH), anti-LOX activities and ability to interact with glutathione. The compounds do not interact significantly with DPPH but strongly inhibit lipid peroxidation. Pyrimidine derivatives 2a (IC50 = 42 μΜ), 2f (IC50 = 47.5 μΜ) and chalcone 1g (IC50 = 17 μM) were the most potent lipoxygenase inhibitors. All the tested compounds were found to interact with glutathione, apart from 1h. Cell viability and cytotoxicity assays were performed with the HaCaT and A549 cell lines, respectively. In the MTT assay towards the HaCaT cell line, none of the compounds presented viability at 100 μM. On the contrary, in the MTT assay towards the A549 cell line, the tested compounds showed strong cytotoxicity at 100 μM, with derivative 2d presenting the strongest cytotoxic effects at the concentration of 50 μΜ. [ABSTRACT FROM AUTHOR]

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds—4f, 4i, 4a, 4g, and 4d—possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC50 values of 1.629, 1.841, 2.958, 4.680, and 4.798 μM, respectively, compared to the reference drug with an IC50 value of 8.029 μM, thus demonstrating promising suppression power. Compounds 4i, 4g, 4e, 4d, and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i, werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein–ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski's rule of five and Veber's rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents. [ABSTRACT FROM AUTHOR]

Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) click chemistry and fluorescent probe are hot research topics of organic chemistry. Introducing it into undergraduate laboratory could help to cultivate creativity of students. However, how to avoid the use of azides is a great challenge to promote CuAAC click chemistry in undergraduate education. Herein, we report a modified CuAAC click reaction experiment for undergraduate laboratory teaching, featuring improved safety and interestingness. 5,7-dimethyltetrazolo[1,5-a]pyrimidine can be tautomerized into azide form in solution. Elegantly using this property could achieve the CuAAC reaction between 5,7- dimethyltetrazolo[1,5-a]pyrimidine and 4-acetylene anisole for the generation of triazole compound 5, avoiding the toxicity and explosive risk from the operation of azide compound. The synthesized compound 5 could selectively recognize zinc ions as a fluorescent probe. It is potentially useful for quantitative analysis of zinc ion concentration. [ABSTRACT FROM AUTHOR]

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement. [ABSTRACT FROM AUTHOR]

Methods have been developed for the synthesis of novel fused pyrano[4,3-b]pyridine derivatives from ethyl 3-amino-4-(furan-2-yl)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]pyridine-2-carbox-ylate. Reactions of its 3-(phenoxycarbonyl)amino derivative with primary and secondary amines have been studied. The reactions with primary amine were accompanied by cyclization with the formation of fused pyrimidines. In the reactions with secondary amines, the product structure depended on the conditions. The synthesized compounds showed a weak antibacterial activity. [ABSTRACT FROM AUTHOR]

A chromeno[4,3-d]pyrazolo[3,4-b]pyridinone derivative 3 bearing thieno[2,3-d]pyrimidine moiety, 5-methyl-1-phenyl-3-(thieno[2,3-d]pyrimidin-4-yl)chromeno[4,3-d]pyrazolo[3,4-b]pyridin-6(3H)-one, was efficiently prepared in 75% yield by the reaction of 3-phenyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-5-amine 1 with 3-acetyl-2H-chromen-2-one 2 in the presence of FeCl3-SiO2 as a catalyst in refluxing ethanol for 6 h. The structure of the new synthesized compound was characterized by 1H-, 13C- NMR, IR spectroscopy, mass-spectrometry, and elemental analysis. [ABSTRACT FROM AUTHOR]

A specific route for the synthesis of a novel benzo[4,5]thiazolo[2,3-b]quinazoline (IVa–e), (VIa–e), (VIIa–e), (VIIIa–e), (IXa–e), and (Xa–e) derivatives, where established using thiazolo[2,3-b]quinazoline-3,6(5H,7H)-dione derivatives (Ia–e) as an efficient starting materials. The present report briefly outlines relevant synthetic methods employed for this class of new compounds and intensively reveals significant antifungal and antioxidant activities along with SAR studies. The results of this study indicate that the target compounds (VIIa–e) and (VIIIa–e) exhibited better antifungal activity at 100 μg/ml compared with standard Trifloxystrobin and Azoxystrobin, respectively while compounds (IXa–f) particularly compound (IXd) showed good antioxidant activity at 10 μg/mL. Structures of newly synthesized compounds were confirmed by elemental analysis and spectral IR, 1H NMR and 13C NMR. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives (4-15) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8, 14, and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC50 0.061 ±0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity. [ABSTRACT FROM AUTHOR]

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

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

In the present study, a new series of nine Thiazolo[3,2-α] pyrimidine analogs were synthesized in good to excellent yields (87.9–96.9%) and improved reaction time using a ZnO nanoparticle-assisted protocol. All the synthesized compounds were characterized using a combination of physicochemical parameters, UV-visible, 1H-NMR, and 13C-NMR spectroscopic methods. Among the synthesized compounds, the in vitro antibacterial activity displayed by compound 16 was higher (14.67 ± 0.58 mm at 500 μg/mL) against P. aeruginosa compared to amoxicillin (12.33 ± 0.58 mm at 500 μg/mL), whereas compounds 14 and 18 showed comparable activity (12.00 ± 0.00 mm and 12.33 ± 0.58 mm at 500 μg/mL and 250 μg/mL, respectively) against the same strain. The activities displayed by compounds 14, 16, 18, and 20 were comparable (12.33 ± 1.15 mm, 12.65 ± 0.58 mm, 12.33 ± 0.58 mm, and 12.00 ± 1.00 mm, respectively, at 500 μg/mL) to amoxicillin (13.33 ± 1.15 mm at the same concentration) against E. coli. Compound 19 showed good activity (12.00 ± 1.72 mm at 500 μg/mL) against S. aureus compared to amoxicillin (16.33 ± 0.58 mm at the same concentration). Compound 19 displayed the highest percent inhibition of DPPH with an IC50 value of 9.48 g/mL using the DPPH free radical scavenging assay compared to ascorbic acid (3.21 g/mL) and promising inhibition of peroxide formation (76.28 ± 0.12%), demonstrating its potential in preventing the formation of lipid peroxides. Thus, according to our findings, both the biological activities and in silico computational results revealed that compounds 14, 16, and 18 are good antibacterial agents against P. aeruginosa and E. coli, whereas compound 19 was found to be a promising antibacterial agent against S. aureus and an antioxidant agent. The present study revealed that the synthesized compounds appear to be lead compounds for rational drug design. [ABSTRACT FROM AUTHOR]

A new series of pyrimidine derivatives are reported here as antitumor agents such as pyrimidine carboxamide linked to thiophene, pyrazole, and thiazole moieties have been synthesized from the readily available (2-cyano-N-(5-cyano-2-phenyl-6-arylpyrimidin-4-yl)acetamide (6a,b). All the new compounds were screened for their antitumor activity in vitro against a panel of three human tumor cell lines namely, hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, and mammary gland breast MCF-7. Compounds 9b, 10b, 11b, and 19b displayed a significant therapeutic activity. All the synthesized new compounds were established their structures by means of spectroscopic analysis. [ABSTRACT FROM AUTHOR]

In this research, we study here, the synthesis of 5-arylidenethiazolidin-4-one derivatives 5 which was used as a base for the synthesis of new thiazolo[4,5-d]thiopyrimidine derivatives and thiazolo[4,5-b] pyridine derivatives. New of their thioglycoside and N-glycoside derivatives were also studies. All the newly synthesized compounds exhibited high antimicrobial activity toward certain some microorganisms (bacteria and fungi). Some of these newly synthesized compounds were docked within the protein surface of 5AF1. The reports of this docking study revealed that the new compounds exhibit good antimicrobial activity. The structure of the newly synthesized compounds was characterized by spectral analysis such as IR spectrum, 1H NMR spectrum, and 13C HNMR spectrum. [ABSTRACT FROM AUTHOR]

Nowadays heterocyclic compounds containing pyrimidine scaffold attract the interest of many organic chemists due to their strong biological activity, so herein we present the synthesis of new polycyclic compounds starting from 4-chloro-9-phenyl-N-(p-tolyl)pyrimido[5',4':4,5]thieno[3,2-d][1,2,3]triazin-7-amine (1) which allowed to react with hydrazine hydrate to give hydrazinyl triazine compound (2) which subjected to some ring closure reactions using various reagents represented in triethyl orthoformate, acetyl acetone, and carbon disulfide to give compounds (3–5), respectively. Also, when the hydrazinyl compound was allowed to react with acetophenone, ethoxymethylene ethylcyano acetate, and diethyl malonate gave the derivatives (9–11), respectively. The structures of all newly synthesized compounds were confirmed using spectral analysis techniques as well as elemental analysis. Besides, four new compounds were screened for their antimicrobial activity using different strains of bacteria and fungi, and compound 5 displayed the best antimicrobial activity among all the tested compounds. [ABSTRACT FROM AUTHOR]

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

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by 1H, 19F, and 13C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus. [ABSTRACT FROM AUTHOR]

The study investigates the synthesis of fused pyridine and pyrimidine derivatives known for their diverse biological activities and structural versatility which serve as pivotal building blocks in organic synthesis. A series of indole-substituted cyanamide derivatives were synthesized by one-pot three-component cyclo-condensation between Indole-3-carboxaldehyde, malononitrile, and electron-rich aromatic and heterocyclic amines by employing several methods such as grinding, microwave irradiation and conventional reflux in the presence of ceric ammonium nitrate and DMF. The nuclei differ concerning the heterocyclic amines such as pyridine, pyrimidine, pyrazine, thiazole, and tetrazole. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, and Mass spectra. The reaction proceeds via Knoevenagel condensation, Michael addition, and intramolecular cyclization. The employed methodology offers the convenient advantages of cascade one-pot condensation, easy isolation, short reaction time, and excellent yield (83–95%). [Display omitted] [ABSTRACT FROM AUTHOR]

An unexpected efficient basic catalyzed heterocyclization reactions were carried out to build blocks of potentially bioactive 2-{pyrano[2,3-c]pyrazoles-4-ylidene}malononitrile skeleton fused with pyrazole, pyridine, pyrimidine, diazepine, chromone, pyrano[2,3-c]pyrazole, and pyrano[2,3-d]pyrimidine systems in novel molecular frames. The method depended on treatment of 6-amino-4-(4-oxo-4H-chromen-3-yl)-3-phenyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (1) with different nitrogen and carbon nucleophiles in ethanolic sodium ethoxide. Possible mechanisms for the reactions were suggested. Elemental analyses and spectral techniques confirmed the structures of the isolated products. The compounds were evaluated for cytotoxic activities. Among the synthesized compounds, both 4 and 11 exhibited the most potent cytotoxicity against all used cancer cell lines. [ABSTRACT FROM AUTHOR]

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

The histone deacetylases (HDACs) play an essential role in the transcriptional regulation of cells through deacetylation of nuclear histone proteins and are promising therapeutic targets for treatment of various diseases. Therefore, interest to the design and synthesis of novel HDAC inhibitors, among which hydroxamic acids occupy an important place, has been constantly increasing in recent years. Here, synthesis of pyrimidines with 1,3,4-oxadiazole or 1,2,4-triazole and hydroxamic acid moieties as potential HDAC inhibitors is described. The target compounds were obtained by sequential reactions of (O- and N-pyrimidinyl)alkanoates with hydrazine hydrate followed by cyclization reaction of the obtained hydrazides with potassium O-ethyl xanthate and alkylation of the synthesised oxadiazole(triazole)thiones with 2-chloro-N-hydroxyacetamide. One of 1,3,4-oxadiazole-2-thiones under the treatment with hydrazine hydrate underwent the recyclisation reaction to give the corresponding 4-amino-1,2,4-triazole. Investigation of the inhibitory activity of the synthesised compounds against HDAC4 and HDAC8 isoforms revealed that N-hydroxy-2-(5-(4-(6-(6-methyl-2-(methylthio)pyrimidin-4-yloxy) butyl)-1,3,4-oxadiazol-2-ylthio)acetamide exhibited a weak inhibitory activity against HDAC8 isoform (IC50 = 12.7 μM). [ABSTRACT FROM AUTHOR]

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

Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds 2, 3a, 3b, 4, 11 and 13 showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds 2 and 11 were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, 2 and 11 displayed drug-like in silico ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds 2, 3a, 3b, 4, 11 and 13. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers. [ABSTRACT FROM AUTHOR]

A new library of different substituted aryl derivatives of isoxazole-pyrazolo[1,5-a]pyrimidine (10a–j) were prepared, confirmed their structures by 1HNMR, 13CNMR and mass spectral data. Furthermore, the preliminary anticancer activities of newly developed compounds (10a–j) were tested against four human cancer cell lines PC3 (prostate), DU-145 (Prostate), A549 (lung) and MCF-7 (breast) by utilizing of MTT method. The obtained results of were compared with standard reference etoposide. Among all, compounds (10a, 10b, 10c, 10e, 10i and 10j) displayed highest anticancer activities than standard. Predominantly, one compound 10a with 3,4,5-trimethoxy substituent on the aryl ring showed excellent activity. The molecular modeling studies indicated the interactions of synthesized compounds with SARM, and DNA via hydrogen bonds and hydrophobic interactions. [ABSTRACT FROM AUTHOR]

We report the design, synthetic route, and cytotoxicity of a library of 49 newly synthesized tricyclic oxazolo[5,4‐d]pyrimidines. The condensed pyrimidinones were constructed from ethyl 5‐aminooxazole‐4‐carboxylate building blocks. A tricyclic ring system was built using the naturally occurring mackinazolinone alkaloid with a focus on the molecular diversity at position C‐2 of the oxazole ring. Synthesized compounds were evaluated against a panel of human cancer cell lines including MCF‐7 (breast), HeLa (cervical), and A549 (lung) in vitro. The results revealed that substitution of halogen‐related aromatic fragments at position C‐2 of the oxazole ring may serve as promising anticancer drug candidates. [ABSTRACT FROM AUTHOR]