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Objectives: Triazolopyrimidinones are compounds used in medicinal chemistry. In this study, three novel triazolopyrimidinone derivatives were synthesized as drug candidates: (5-(chloromethyl)-2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one) (S1-TP), 2-(4-methoxyphenyl)-5-(piperidinomethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one) (S2-TP), and 2-(4-methoxyphenyl)-5-(morpholinomethyl)-[1,2,4]triazolo[1,5-a] pyrimidin-7(3H)-one) (S3-TP). Their electrochemical properties were investigated for the first time using voltammetric techniques on carbon graphite electrodes. Moreover, stability tests for each drug candidate were performed on different days. After revealing the electrochemical properties of the drug candidates, their effect on double-stranded (ds) DNA was examined by measuring the oxidation currents of the guanine of dsDNA before and after the interaction. Materials and Methods: An electrochemical setup that included a pencil graphite electrode as the working electrode, an Ag/AgCl reference electrode, and a platinum wire as the auxiliary electrode was used in this study. Experiments for optimum pH, scan rate, and concentration of drug candidates were conducted. The interaction between Ss-TP and dsDNA was evaluated using differential pulse voltammetry. The stability of each drug candidate was tested on various days. Results: A comprehensive characterization of the S1-TP, S2-TP, and S3-TP compounds was performed for the first time. This study showed that the electrochemical oxidation of S1-TP and S2-TP was irreversible and diffusion-controlled. In addition, the transfer of electrons in S3-TP was controlled by adsorption. The interaction between Ss-TP and dsDNA resulted in notable changes in the peak potentialof dsDNA. The dsDNA peak potential shifted negatively after interaction with S1-TP, S2-TP, and S3-TP. Under optimum conditions, the detection limits for S1-TP, S2-TP, and S3-TP were 1.5 µg/mL, 1.0 µg/mL, and 2.0 µg/mL, respectively. Conclusion: From our experimental data, we concluded that these molecules can be used as drug molecules because of their remarkable effects on DNA. [ABSTRACT FROM AUTHOR]

Due to their extensive applications in pharmaceuticals and natural substances, organic synthesis and heterocyclic compounds have been at the forefront of research for many years. Pyrimidine is one of the heterocyclic compounds that have various derivatives with promising biological and pharmacological properties. This review article covers the synthesis and biological effects of pyrimidine derivatives, such as pyrano[2,3‐d]pyrimidines, pyrido[2,3‐d]pyrimidines, and furo[2,3‐d]pyrimidines. The compounds discussed in this review have a wide range of biological activities. Recent advances in green chemistry have led to the development of eco‐friendly synthetic methods for producing these bioactive heterocycles. This review aims to present various synthetic methods and biological effects of these compounds and provide new opportunities for organic chemists to develop potent nitrogen‐ and oxygen‐containing heterocycles for future applications. The review highlights examples of successful syntheses and applications of pyrimidine derivatives in the fields of antibacterial, antifungal, anticancer, enzyme inhibition, and antiviral research. [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]

A mild Oxone® mediated reaction for direct regioselective C−H selenylation and thiocyanation of pyrazolo[1,5‐a]pyrimidines is established at ambient temperature. This practical and efficient methodology employs Oxone® as a user friendly, green, non‐toxic and cheap reagent to facilitate selenylation and thiocyanation at room temperature. The present method offers high regioselectivity, broad substrate scope, mild conditions and excellent yields. Further, this eco‐friendly approach could easily be extended for mild C−H selenylation and thiocyanation of other heterocycles. Mechanistic studies indicate that the reaction occurs through electrophilic substitution mechanism via generation of an electrophilic chalcogen species. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of pyrido[2,3-d]pyrimidines, which are important heterocycles found in many pharmaceutically active molecules. The traditional methods for synthesizing these compounds are described, as well as the limitations of these methods. The article then presents a new catalytic system using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)/tert-Butyl Nitrite (TBN)/O2 for the synthesis of pyrido[2,3-d]pyrimidines. The reaction conditions and optimization are discussed, and the results show promising yields. This research provides a new and efficient method for the synthesis of pyrido[2,3-d]pyrimidines with potential bioactivities. The given document presents a table showing the results of control experiments on the reaction of uracils and 1,3-diarylpropenes. The table includes entries for different combinations of reactants and the corresponding products and yields. The experiments indicate that both TBN and O2 promote the reaction. The table provides specific details about the reactants and products, as well as the corresponding yields. This document describes a novel and efficient method for synthesizing pyrido[2,3-d]pyrimidines/thiopyrido[2,3-d]pyrimidines using easily available starting materials. The reaction involves oxidative coupling, intramolecular cyclization, [Extracted from the article]

The pyrido[2,3‐d]pyrimidine moieties are one of the most biologically widespread heterocyclic compounds as antimicrobial, antioxidant, antitubercular, antiviral and anti‐inflammatory. Hence, we synthesized an efficient new series of 2‐thioxo‐pyrido[2,3‐d]pyrimidinone, 2‐hydrazinyl‐(quinolin‐2‐yl)pyrido[2,3‐d]pyrimidinone,N′‐(quinolin‐2‐yl)‐pyrido[2,3‐d]pyrimidine‐(formo/aceto)‐hydrazide and substituted‐(quinolin‐2‐yl)pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidinone derivatives. The characterization of new compounds was corresponded by using spectroscopic techniques, IR, NMR and Mass spectra. In vitro, all compounds were evaluated as antimicrobial activity compared with cefotaxime sodium and nystatin as the standard drug. This work deals with the exploration of the new heterocyclic compounds and medicinal diversity of quinoline‐pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidine derivatives that might pave the way for long in the discovery of therapeutic medicine for future drug design. [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]

We report herein an unprecedented synthesis of difluoromethoxylated nitrogen‐containing heterocycles from the corresponding α‐(difluoromethoxy)ketones as versatile building blocks. Pyrazoles, isoxazoles and pyrimidines could be obtained via an enaminone intermediate, whereas in the direct reaction of α‐(difluoromethoxy)ketones with arylhydrazines, a Fischer indole synthesis was achieved. All these scaffolds, which are uncommon, or even sometimes novel, due to the directly attached emerging fluorinated group (EFG) −OCF2H, might be of high potential in life sciences and appear as an interesting alternative to more and more controversial classical fluorinated groups, such as the ubiquitous trifluoromethyl group. [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]

Pyrimidine annulated five‐membered heterocyclic scaffolds containing oxygen as furopyrimidine, particularly furo[2,3‐d]pyrimidine derivatives are an important class of heterocyclic compounds in pharmaceutical discovery research. Furo[2,3‐d]pyrimidines are generally synthesized either from a pyrimidine derivative by constructing a furan ring on the parent pyrimidine ring or from a suitably functionalized furan ring by generating the pyrimidine ring on the parent furan ring. Moreover, there is a wide range of multicomponent reactions that include barbituric acids as starting material for the synthesis of these compounds. Also, the reaction of barbituric acids with alkenes, alkynes, aldehydes, ketones, ninhydrin, and chloroacetylchloride, and Cloke–Wilson rearrangement of spirocyclopropyl barbiturates afforded furo[2,3‐d]pyrimidine derivatives. This review is an attempt to compile the literature of various synthetic procedures toward barbituric acids‐based furo[2,3‐d]pyrimidine and spirofuro[2,3‐d]pyrimidines. [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]

Despite extensive research on antimicrobial drugs, efforts to find suitable alternatives to older drugs have not been very successful yet, due to microbial resistance. Heterocycles including azole and pyrimidine derivatives were used to design antimicrobial activity in this research, 12 novel pyrimidine-azole derivatives (3a-3l) that were previously synthesized were screened for their antibacterial and antifungal activities by using CLSI standard method. In this study, we used four species of bacteria, seven species of fungi, and five species of yeast. Molecular docking studies were also performed to investigate their binding mode and orientation toward lanosterol 14-α-demethylase (CYP51), as a plausible mechanism of azole antifungal compounds. The biological results showed that none of the compounds had antibacterial and antifungal effects compared to the control drugs. The molecular docking study showed that the compounds had a low binding affinity in the active site of the lanosterol 14-α-demethylase target, which confirmed the weak antifungal and antibacterial activities of these compounds. [ABSTRACT FROM AUTHOR]

In this paper, thiazolo[3,2-a]pyrimidine-2,3-dicarboxylate and oxazolo[3,2-a]pyrimidine-2,3-dicarboxylate derivatives are produced in excellent yields via the multicomponent reaction of anilines, ethyl acetoacetate, aldehydes, urea or thiourea, activated acetylenic esters and triphenylphosphine in the presence of Ag/KF/CP@MWCNT as a high efficient catalyst in aqueous media at ambient temperature. The Ag/KF/CP@MWCNT is generated by water extract of rhizome Petasites hybridus as an environmentally media and moderate base. Also, Ag/KF/CP@MWCNT leads to increasing of yield of products and has notable reusability. Antioxidant ability of the resulted compounds is studied by DPPH (radical trapping of diphenyl-picrylhydrazine) and ferric reduction power tests. Also, the antimicrobial activity of some products is determined with the disk diffusion experiment on Gram-positive and Gram-negative bacteria. The advantages of this protocol include of short reaction time, high efficiency and easy separation of products and use of simple catalyst. 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. Compounds bearing fused thiazole and pyrimidine units play important role in organisms because they have good biological potentials. Thiazolopyrimidines are an interesting group of heterocyclic compounds and among them the thiazolo[3,2-a]pyrimidine skeleton are a key constructions and have vital biological activities and are widely found in important drugs such as Alzheimer's disease, anticancer, antimicrobial, anti-inflammatory, antioxidant, anti-human cytomegalovirus activity, antiparkinsonian, antitumor and antiviral. [ABSTRACT FROM AUTHOR]

C2‐functionalized pyrimidine derivative is a family of important nitrogen heterocyclic compounds due to their unique structure and multiple reaction sites. In this work, a novel method for the synthesis of C2‐functionalized pyrimidine derivatives through phenylalkynes and pyrimidine disulfides under ambient conditions is proposed. The reaction can be triggered by adding catalytic amounts of cesium fluoride, which is characterized by free‐catalyst and special activator. Importantly, this reaction has good compatibility with substrates substituted by electron‐donating and electron‐withdrawing groups at C4. Density functional theory (DFT) calculations also indicates that the production of C2‐functionalized pyrimidine derivatives is more favourable. [ABSTRACT FROM AUTHOR]

Cancer is a broad word for a set of diseases that can begin in virtually any organ or tissue of the body and spread to other organs. In 2020, cancer was the largest cause of death worldwide, accounting for 10 million fatalities, or one in every six deaths. Nitrogen containing heterocyclic compounds are a massive research focus because it has a unique position and is a cherished source of a wide range of bioactive molecules in medicinal chemistry. Over 75% of the currently accessible market is covered by FDA‐approved drugs containing nitrogen moieties. DNA topoisomerase II is a reassuring approach for novel anticancer heterocyclic medicines because it plays a crucial role in DNA metabolism, replication, recombination, and repair. Given the importance of topo II in chemotherapy, there is a pressing necessity to boost topo II or multi‐target topo II inhibitors in order to combat drug resistance and minimize toxicity. Following the trend of researching the advancement of effective topo II inhibitors with minimal toxicity, the current review article consolidates a detailed account of nitrogen‐containing heterocyclic compounds and categorizes them into different classes based on structural characterization, such pyrimidine, triazine, pyridine, quinazoline, fluoroquinolones, quinones, pyrazoles, quinoline, carbazoles, β‐carboline, quinolone, naphthalimide, acridone, benzoxazole, pyridophenoxazine, pyrrole, piperazine and imidazole, along with their structure activity relationship, mechanistic aspects, and docking studies (wherever appropriate) were explored. We are certain that the current review paper will help future medical researchers investigate prospective topoisomerase inhibitors as anticancer medicines in a variety of clinical settings. [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]

This brief review presents recent advances at the Ivan Franko National University of Lviv in the application of Meerwein arylation for the synthesis of complex compounds including following heterocycles – 2-aminothiazoles, 2-aminoselenazoles, 3,4-dihydroisocoumarines, 3-hydroxythiophenes, dihydropyrimidin-2(1H)-ones, 3-arylpyran-2-ones, and heterocyclic systems such as pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidine, 4,5-dihydro[1,2,3]triazolo-[1,5-a]pyrazin-6(7H)-ones, thienopyridinediones, 4H-thieno[2,3-c]-chromen-4-one, hexahydro-4H-furo[2,3-f]isoindoles. [ABSTRACT FROM AUTHOR]

Organic compounds containing heteroatoms have been comprehended to exhibit a remarkable tendency towards corrosion mitigation. This corrosion mitigating tendency is enabled by the presence of electron clouds composed of lone pairs, pi-electrons, which allow them to be adsorbed over metallic equivalents. Because of the availability of nitrogen as heteroatoms, these compounds are being extensively used for corrosion diminution. This article looks at a variety of heterocyclic organic compounds like imidazole, triazole, pyridine, pyrazole, quinoline, tetrazole, pyrimidine, purine and pyrrole, having nitrogen as their prime constituent heteroatom for their anti-corrosive properties. The anti-corrosive properties of these nitrogen-based compounds in acidic conditions have been demonstrated using all available experimental techniques such as EIS, PDP and other theoretical investigations such as DFT and MD. Furthermore, the shift in the trend of these compounds inhibitory efficiencies has been noted and underlined here. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a rare, cumulative neurological deteriorating disease that disturbs the neurons (nerve cells) that control voluntary muscle movement (those muscles we choose to move). Currently, the Food and Drug Administration (FDA) approved drugs such as Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta to treat ALS. Given the wide range of pharmaceutical applications of heterocyclic compounds, especially those containing the nitrogen ring systems such as pyridine, pyrimidine, and indole. These molecular frameworks have piqued the interest of medicinal chemists for further investigation in a variety of diseases. We have found several review works done on this research topic. Until now, no reviews published on the nitrogen heterocycles for treating ALS. This review examines the major causes of ALS, a brief history of medications that have been used to treat it so far, and the most recent breakthroughs in nitrogen ring systems for treating ALS. The novelty of this study provides insights on several effective synthetic techniques for nitrogen-based heterocyclic medications that operate as potent anti-inflammatory treatments and guard against ALS. Key points: • Pharmacological activity of heterocyclic compounds. • Neurodegenerative diseases and their drawbacks are discussed in detail. • Recent survey of nitrogen heterocycles in treating ALS disease are highlighted. [ABSTRACT FROM AUTHOR]

This review covers articles published in the period from 2010 to mid-2022 on synthetic advances in the formation of pyrimidine and related heterocyclic compounds. Special emphasis has been given to the different types of cycloadditions, taking into account the number of their components and leading to the formation of the pyrimidine ring. Due to the large number of publications on the Biginelli reaction and related reactions, this will be dealt with in a separate review in the near future. [ABSTRACT FROM AUTHOR]

Pyrimidine heterocycles are proven to be biologically active heterocycles, found in many biological systems, displaying a broad spectrum of biological activities including anticancer, anxiolytic, antioxidant, antiviral, antifungal, anticonvulsant, antidepressant and antibacterial activities. New substituted 2-oxopyrimidines have been synthesized from the chalcones linked via indane-1,3-dione moity by the methods discussed in experimental section. We have synthesized some new 2-[6-(substituted phenyl)-2-oxo-1,2,5,6-tetrahydropyrimidin-4-yl]-indane-1,3-dione by reacting chalcones (step-1 compounds have been reported by us) with urea. [ABSTRACT FROM AUTHOR]

Arylformylacetonitriles are versatile and attractive synthons in organic synthesis owing to their high reactivity. Among the numerous transformations involving arylformylacetonitriles, multicomponent reactions (MCRs) offer straightforward and effective routes to assemble the reactants into a wide range of five‐ and six‐membered heterocyclic systems including pyrrole, pyrazole, triazole, furan, pyridine, pyrimidine, and pyran. This review collects the recent advances and applications of arylformylacetonitriles in MCRs for the synthesis of monocyclic or polycyclic heterocycles published in the literature since 2001. [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]

Heterocyclic compounds bearing the pyrimidine core are of tremendous interest as they constitute an important class of natural and synthetic compounds exhibiting diverse useful biological activities that hold attractive potential for clinical translation as therapeutic agents in alleviation of a myriad of diseases. Heterocycles possessing a pyrimidine scaffold have piqued tremendous interest of organic and medicinal chemists owing to their privileged bioactivities. Drugs having the pyrimidine motif have manifested to exhibit gratifying biological activity like anticancer, antiviral, anti‐inflammatory, antibacterial, and antihypertensive activities. This heterocycle, being a significant endogenous component of the body, the pyrimidine derivatives can easily interact with enzymes, genetic materials, and bio components within the cell. The landscape of FDA approved drugs, presently marketed incorporating the pyrimidine scaffold continues to evolve in number and diversity. There is a tremendous surge in discovery of new targets across many diseases especially those involving emerging resistance to clinically used battery of drugs. Pyrimidine scaffolds will continue to be explored expanding their chemical space portfolio in an effort to find novel drugs impacting these targets. This review aims to provide an elaborate recapitulation of the recent trends adopted to synthesize propitious pyrimidine incorporated hits and also focuses on the clinical significance reported for functionalized pyrimidine analogues that would quintessentially aid medicinal chemists for new research explorations in this arena. [ABSTRACT FROM AUTHOR]

The reaction of 2-thiouracil or theophylline with phosphacumulene ylides furnished phosphoranylidene pyrimidinone or phosphanylidene purine diones, respectively. The formation of phenylaminoazetone and phenyliminoazetamine was observed when 2-chloroquinoline phenylhydrazine was reacted with phosphacumulenes. On the other hand, Lawesson's reagent can be transformed by reaction with 2-thiouracil or theophylline into pyrimidine dithione and thioxopurinone, respectively. Treatment of 2-chloro-phenylhydrazonoquinoline with Lawesson's or Japanese reagent under reflux conditions afforded 2-chloroquinoline derivatives, but the dimer was isolated when the same reaction was applied at room temperature. Further reaction of chloro(hydrazineylidenemethyl)quinoline with Lawesson's or Japanese reagents under reflux provided the corresponding chloroquinoline derivatives. In addition, treatment of chloroquinoline oxime with Lawesson's reagent at room temperature afforded chloroquinoline thiohydroxylamine, but phosphinodithioic acid and diazetidinedithiol-2-chloroquinoline were isolated when the same reaction was carried out under reflux. The effect of some of the tested compounds on membrane permeability in human colorectal carcinoma (HCT-116), human liver carcinoma (HepG-2) and human breast adenocarcinoma cells (MCF-7) were examined. Majority of the tested compounds have potent anticancer activity. [ABSTRACT FROM AUTHOR]

A large portion of the chemical subspace is the multi‐component reaction (MCR). Apart from Domino reactions, MCR is one of the most promising routes for one‐pot synthesis. Thus, MCR derived product can be considered as a synthetic hub to a vast diversity of novel cyclic or acyclic compounds. Heterocyclic moiety such as naphthyridines, quinolines, dihydropyridines (DHPs), quinazolines, pyrimidines, imidazoles, diazepines, and spiro‐heterocycles are widely recognized in clinical evaluation. Because of their relevant significance, vast literature exists to accomplish the synthesis of these biologically important compounds. Therefore, this review highlights the last ten years of developments in the one‐pot synthesis of these heterocyclic moieties which are widely recognized by the industry in addition to academia. [ABSTRACT FROM AUTHOR]

A novel ionic liquid-coated nanomaterials (CaO@SiO2@BAIL) was successfully synthesized by anchoring the 1-(3-(trimethoxysilyl)propyl)-1,3,5,7-tetraazaadamantan-1-ium chlorozincate (II) bi-functional ionic liquid (BAIL) onto the surface of silica‐coated CaO nanoparticles. The structure of catalyst was characterized using various analytical techniques such as Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDS), WDS map scan, thermogravimetric (TGA), and inductively-coupled plasma-mass spectrometry (ICP-MS). The performances of prepared hybrid nanomaterial (CaO@SiO2@BAIL) as a catalyst were evaluated for the efficient synthesis of the pharmaceutically valuable heterocyclic compounds. A variety of pyridine, pyrimidine, and pyrazoline derivatives were synthesized in the presence of CaO@SiO2@BAIL within green conditions. The presented method has several advantages such as high yields, low reaction times, and easy preparation of the catalyst. The bi-functional heterogeneous nanocatalyst can be reused at least six times without considerable loss of its catalytic activity. [ABSTRACT FROM AUTHOR]

To Explore two heterocyclic based scaffolds; Pyrimidine and Imidazole for Anticancer activity targeting Human Lung cancer cell lines. The designed compounds were synthesized and evaluated for their invitro Anticancer activity against Human Lung Cancer Cell line A549. In vitro anticancer activity revealed that 14h showed more potent anticancer activity as compared to the standard drug Sunitinib. This compound exhibited apoptosis thus, arresting the cell cycle at G0/G1 phase itself. To conclude, the above findings clearly demonstrated that the compound 14h may serve as good anticancer agent for further development. [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]

The methylenebisflavonoids 7-hydroxy-3-hetaryl-8-(4-oxo-4H-3-chromenylmethyl)-4H-4-chromenones and 7-hydroxy-3-hetaryl-8-(4-oxo-4H-3-chromenylmethyl)-2H-2-chromenones were synthesized via the reaction of 7-hydroxy-8-dialkylaminomethyl-3-hetarylcoumarins and chromones with 3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one. Recyclization of 3-(1,3-benzthiazol-2-yl)-7-hydroxy-8-(4-oxo-4H-3-chromenylmethyl)-2H-2-chromenone through the action of N,N- and N,O-binucleophiles produced new 3-benzthiazolylcoumarin derivatives modified by pyrazole, isoxazole, and pyrimidine heterocycles. [ABSTRACT FROM AUTHOR]

Several five and six-membered aromatic systems with three heteroatoms such as S, O, and N have been intensively researched due to their intriguing pharmacological properties. Heterocyclic compounds are chemicals that allow life to exist. Aside from that, all heteroatoms in the ring interact better with amino acids, and these interactions aid in reducing transactivation, and enhancing lipophilicity, solubility, and absorption, all of which can be exploited to improve therapeutic action. Heterocyclic nucleus 1,3,4-thiadiazole, benzimidazole, quinazoline, and pyrimidine derivatives have shown considerable biological actions such as anticancer, antimicrobial, anti-inflammatory, antidepressant, antioxidant, antifungal, antimicrobial, Carbonic anhydrase inhibitors, anticonvulsant, antibacterial activity, etc. All ring system members play a significant role in the development of novel drugs. In this review, we have highlighted the FDA approved drugs of heterocyclic compound which will pave the way for development of new entities. The current analysis focuses on synthetic derivatives of thiadiazole, benzimidazole, quinazoline, and pyrimidine that have significant anticancer biological effects on several cancer cell lines. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles are some of the most important compounds that are found in nature or synthesized otherwise. These heterocyclic rings are found almost invariably in living systems ranging from the tiniest prokaryotes to the largest eukaryotes. Various enzymes, proteins, and most importantly, DNA, consist of nitrogen heterocycles. Benzo[4,5]imidazo[1,2-a]pyridines and benzo[4,5]imidazo[1,2-a]pyrimidines also fall in this category and are quite important due to their ability to bind with various living systems. Many drugs contain these moieties at their cores. The potential of various derivatives of these skeletons to be used not only as drugs, but also as organoelectronic materials; fluorescent materials, etc. cannot be ignored. This review focuses on the synthesis of various derivatives of these scaffolds by a wide range of methodologies for the last decade. We have also demonstrated detailed synthetic pathways of each methodology and also highlighted variation of yields in different points of view. [ABSTRACT FROM AUTHOR]

DFT‐calculations allow prediction of the reactivity of uncommon N‐heterocyclic scaffolds of pyrazolo[1,5‐a]pyrimidines and imidazo[1,2‐b]pyridazines and considerably facilitate their functionalization. The derivatization of these N‐heterocycles was realized using Grignard reagents for nucleophilic additions to 5‐chloropyrazolo[1,5‐a]pyrimidines and TMP2Zn ⋅ 2 MgCl2 ⋅ 2 LiCl allowed regioselective zincations. In the case of 6‐chloroimidazo[1,2‐b]pyridazine, bases such as TMP2Zn ⋅ MgCl2 ⋅ 2 LiCl, in the presence or absence of BF3 ⋅ OEt2, led to regioselective metalations at positions 3 or 8. Subsequent functionalizations were achieved with TMPMgCl ⋅ LiCl, producing various polysubstituted derivatives (up to penta‐substitution). X‐ray analysis confirmed the regioselectivity for key functional heterocycles. [ABSTRACT FROM AUTHOR]

Background: Heterocyclic compounds and their fused analogs, which contain pharmacophore fragments such as pyridine, thiophene and pyrimidine rings, are of great interest due to their broad spectrum of biological activity. Chemical compounds containing two or more pharmacophore groups due to additional interactions with active receptor centers usually enhance biological activity and can even lead to a new type of activity. The search for new effective neurotropic drugs in the series of derivatives of heterocycles containing pharmacophore groups in organic, bioorganic and medical chemistry is a serious problem. Methods: Modern methodology of drugs involves synthesis, physicochemical study, molecular modeling and selection of active compounds through virtual screening and experimental evaluation of the biological activity of new chimeric compounds with pharmacophore fragments. For the synthesis of new compounds, classical organic methods were used and developed. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. For docking analysis, various soft ware packages and methods were used. Results: As a result of multistep reactions, 11 new, tri- and tetracyclic heterocyclic systems were obtained. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures as well as some psychotropic effects. The biological assays evidenced that nine of the eleven studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of the compounds is low, and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity, it was found that the selected compounds have an activating behavior and anxiolytic effects on the "open field" and "elevated plus maze" (EPM) models. The data obtained indicate the anxiolytic (antianxiety) activity of the derivatives of tricyclic thieno[2,3-b]pyridines and tetracyclic pyridothieno[3,2-d]pyrimidin-8-ones, especially pronounced in compounds 3b–f and 4e. The studied compounds increase the latent time of first immobilization on the "forced swimming" (FS) model and exhibit antidepressant effects; compounds 3e and 3f especially exhibit these effects, similarly to diazepam. Docking studies revealed that compounds 3c and 4b bound tightly in the active site of γ-aminobutyric acid type A (GABAA) receptors with a value of the scoring function that estimates free energy of binding (∆G) at −10.0 ± 5 kcal/mol. Compound 4e showed the best affinity ((∆G) at −11.0 ± 0.54 kcal/mol) and seems to be an inhibitor of serotonin (SERT) transporter. Compounds 3c–f and 4e practically bound with the groove of T4L of 5HT_1A and blocked it completely, while the best affinity observed was in compound 3f ((∆G) at −9.3 ± 0.46 kcal/mol). Conclusions: The selected compounds have an anticonvulsant, activating behavior and anxiolytic effects and at the same time exhibit antidepressant effects. [ABSTRACT FROM AUTHOR]

Efficient approaches to the gram‐scale synthesis of fluorinated pyrazoles and pyrimidines bearing saturated (hetero)cyclic substituents are described. The methods rely on the heterocyclizations of sp3‐enriched β‐bromo‐α,α‐difluoroketones and fluorinated enaminones (in turn prepared from saturated heterocyclic α‐fluoroketones), respectively; these compounds themselves are useful synthetic intermediates that have been prepared on multigram scale for the first time. LogP and aqueous solubility measurements, as well as lead‐likeness assessment using the Nelson's LLAMA tool show that the 19 synthesized sp3‐enriched fluorinated building blocks meet the lead‐oriented synthesis criteria. [ABSTRACT FROM AUTHOR]

Rhinitis is an allergic disease that causes troubles and restlessness for patients. In this research work we will focus on finding promising organic molecules with potential ability to target histamine receptor with no sedative side effect. Phalazines and their isosteres, pyrimidines and pyridines have been reported to target H1 receptors, for this reason we have searched for library of these basic scaffolds, this library which has 184 organic molecules will be subjected for further explorations through computer aided drug design techniques. Swiss ADMET will be used to gather these compounds in clusters. Cluster with low potential to penetrate BBB is selected for virtual screening through pharmacophore model. Then molecular docking that revealed the stability of the complex formed between the investigated molecules and H1 receptor. ADMET profile showed three compounds (XVIII), (XX), and (XXI) with no toxicity on liver and no effect on CYP2D6, these three compounds were subjected to molecular dynamic simulations and compound (XVIII) showed the most stable complex with the target protein (H1). Finally, we can say this work helped us to find new compounds with promising potential to target H1 without ability to penetrate BBB, so they can be used as useful candidates in treatment of rhinitis and deserve to be subjected for preclinical and clinical investigations. [ABSTRACT FROM AUTHOR]

Recent advances in the synthesis of trifluoromethyl or trifluoroacetyl substituted heterocyclic compounds by use of trifluoromethyl‐α,β‐ynones are summarized. Seven approaches will be reviewed and divided into (a) synthesis of trifluoromethyl‐pyridines, trifluoromethyl‐quinolines, and trifluoroacetyl‐quinolines; (b) synthesis of trifluoromethyl‐oxazinopyridines and trifluoromethyl‐oxazinoquinolines; (c) synthesis of trifluoromethyl‐pyrazoles, trifluoromethyl‐isoxazoles, and trifluoromethyl‐pyrazolo[1,5‐a]pyridines; (d) synthesis of trifluoromethyl‐pyrroles, trifluoromethyl‐thiophenes, trifluoromethyl‐dihydrofurans, and trifluoromethyl‐isochromanone; (e) synthesis of trifluoromethyl‐pyrimidines, (f) synthesis of trifluoroacetyl‐1,2,3‐triazoles; (g) synthesis of trifluoromethyl‐aziridines and trifluoromethyl‐[1,4]diazepines. [ABSTRACT FROM AUTHOR]

Background: Continuing our interest in preparing of new heterocyclic compounds and examining their various biological activities, this work was designed to prepare new condensed and non-condensed heterocyclic compounds 9a-c, 10a-c, 11a-c, 13a-c and 14a-c were synthesized starting with pyrimidine-2-thiones 4a-c. Results: Thiazolo[3,2-a]pyrimidines 9a-c were synthesized by S-alkylation of pyrimidine-2-thiones,4a-c, internal cyclization in alkaline medium with ammonia, condensation with benzaldehyde and finally reaction with hydroxylamine hydrochloride.[1,2,4]thiadiazolo[4,5-a]pyrimidines 11a-c were formed by heating of the 4a-c with benzoylcholride to afford 10a-c followed by reaction with sodium hypochlorite, ammonia and sodium hydroxide. Cyclocondensation of 4a-c with ethyl acetoacetate or formic acid yielded pyrazol-3-ones 13a-c or [1,2,4] triazolo[4,3-a]pyrimidines 14a-c, respectively Elements analysis, IR, 1H-NMR, 13C-NMR and mass spectra were used to validate the structures of newly synthesized heterocycles. Screening of the selected compounds 4a, 6a, 7a, 9a, 10a, 13a and 14a against colon carcinoma cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2). Conclusions: Elements analysis, IR, 1H-NMR, 13C-NMR and mass spectra were used to validate the structures of newly synthesized heterocycles. Screening of the selected compounds 4a, 6a, 7a, 9a, 10a, 13a and 14a against colon carcinoma cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2) showed that compound 10a exhibited the most cytotoxic, while compounds 4a, 6a and 14a exhibited considerable cytotoxic activity. [ABSTRACT FROM AUTHOR]

Condensed pyrimidines are a popular class of heterocyclic compounds because they have a wide range of biological activity. This article aims to evaluate the simple, catalyst‐free procedure of synthesis of novel fused pyrimidothiazines. An efficient access to a series of pyrazolo[4′,3′:5,6]pyrimido[2,1‐b][1,3]thiazinium, pyrazolo[3′,4′:5,6]pyrimido[2,1‐b][1,3]‐thiazinium, and benzo[b]thieno[4′,3′:5,6]pyrimido[2,1‐b][1,3]thiazinium trihalogenides was developed via electrophilic heterocyclization of corresponding pyrimidine cinnamyl thioethers under the action of halogens. The XDR and complex NMR investigations were used for solving of final products structure; the anisochronism was observed in the NMR spectra of synthesized compounds for the pairs of ortho‐ and meta‐protons, as well as the N‐phenyl substituents associated with them. [ABSTRACT FROM AUTHOR]

Pyrimidines and their hybrid molecules have continued to be a favorable area for organic chemists owing to their richness in natural and synthetic compounds with multifarious involvement in pharmaceuticals and polymers and act as ligands. Different novel and greener synthetic protocols were developed in the last decades, but microwave‐assisted synthetic protocols played a significant role in constructing pyrimidine and its derivatives. In this article, we summarized the microwave‐supported strategy for the construction of pyrimidine fused or linked/tethered with other heterocycles, polysubstituted pyrimidines, solid‐supported synthesis of pyrimidines, and ionic liquid‐catalyzed strategies for the synthesis of pyrimidine and its derivatives reported in the last decade. Solid‐supported protocols using resins and ionic liquid‐catalyzed strategies afforded the corresponding products with excellent yield by dual activation. In most of the reports, the microwave‐irradiated approach was compared with conventional/traditional heating and found better in terms of reaction time, yield, atom economy, adherence with green chemistry principles, and reduction in purification wastage. Various authors evaluated the in vitro potential of synthesized pyrimidine derivatives for antimicrobial and antimalarial potential, and found moderate to excellent biological activity. [ABSTRACT FROM AUTHOR]

Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and induced genotoxic stress and p53-mediated cell death of cycling nonmyocytes. As nonmyocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of the ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors using small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in nonmyocyte cells and augmented cardiac repair and postinfarct heart function. These observations demonstrate that the cardiac muscle cell regulates pyrimidine metabolism in nonmuscle cells by releasing adenine and specific nucleosides after heart injury and provide insight into how intercellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair. [ABSTRACT FROM AUTHOR]

Amongst heterocyclic compounds, quinoline and its derivatives are advantaged scaffolds that appear as a significant assembly motif for developing new drug entities. Aminoquinoline moiety has gained significant attention among researchers in the 21stcentury. Considering the biological and pharmaceutical importance of aminoquinoline derivatives, herein, we review the recent developments (since 2019) in various biological activities of the 4-aminoquinoline scaffold hybridized with diverse heterocyclic moieties such as quinoline, pyridine, pyrimidine, triazine, dioxine, piperazine, pyrazoline, piperidine, imidazole, indole, oxadiazole, carbazole, dioxole, thiazole, benzothiazole, pyrazole, phthalimide, adamantane, benzochromene, and pyridinone. Moreover, by gaining knowledge about SARs, structural insights, and molecular targets, this review may help medicinal chemists design cost-effective, selective, safe, and more potent 4-aminoquinoline hybrids for diverse biological activities. [Display omitted] • N -Containing heterocycles play an important role in the design and synthesis of novel biological active molecules. • Currently, diverse 4-aminoquinoline hybrids have been widely studied for biological potency. • Here in, we summarized 10 different biological activities of 4-aminoquinoline scaffolds. • The majority hybrids showed promising activity against all the tested strains. [ABSTRACT FROM AUTHOR]

A new series of pyrazolopyrazinoselenolotriazolopyrimidines was synthesized by a facile method based on condensation of 5‐amino‐3‐methyl‐1‐phenyl‐1H‐pyrazolo[3,4‐b]selenolo[3,2‐e]pyrazine‐6‐carbonitrile (3) with triethyl orthoformate followed by intramolecular cyclization with hydrazine to afford 7‐amino‐8‐imino‐3‐methyl‐1‐phenyl‐1,8‐dihydro‐7H‐pyrazolo[3″,4″:5′,6′]pyrazino[2′,3′:4,5] selenolo[3,2‐d]pyrimidine (5). The latter compound was utilized as a multipurpose precursor for the construction of other new triazoles fused to the pyrazolopyrazino‐ selenolopyrimidine moiety. Alternatively, acetylation and chloro‐acetylation of compound 3 using acetic anhydride and chloroacetyl chloride yielded the acetyl amino 11 and chloroacetamido 12 derivatives, respectively. Compound 12 underwent nucleophilic substitution upon reaction with morpholine to provide the morpholinyl acetamide 13. Furthermore, the pyrazolopyridoselenolopyrazine ring system 14 was synthesized by the reaction of the o‐amino‐carbonitrile 3 with malononitrile. Assignment of the chemical structures for the new compounds was confirmed depending on elemental and spectral techniques. On the other hand, most of the synthesized compounds revealed promising results against various bacterial and fungal strains. [ABSTRACT FROM AUTHOR]

A method for the introduction of the N,N-dimethylformamidine protective group in a series of six-membered 2-aminohetarene N-oxides was developed. It was shown that 2-amino derivatives of N-oxides of various six-membered heterocycles (pyridines, pyrimidines, pyrazines, tetrazines) successfully enter the reaction. The stability of the N,N-dimethylformamidine protecting group in 2-aminohetarene N-oxides was found to depend on the type of reaction medium. [ABSTRACT FROM AUTHOR]

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

A new series of pyrazole, pyrimidine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyrazole and pyrazolo[5,1-b]quinazoline derivatives containing indane moiety are prepared by using N-(2,3-dihydro-1H-inden-5-yl)carbonohydrazonoyl dicyanide (2) as starting material to synthetic different heterocyclic compounds (3–11) by the reaction with different bifuncation reagents. Moreover, 4-((2,3-dihydro-1H-inden-5-yl)diazenyl)-1H-pyrazole-3,5-diamine (3) was taken as a precursor to prepare different pyrazolo[1,5-a]pyrimidine derivatives (12–20). The structures of newly synthesized compounds were confirmed on the basis of their IR, 1H NMR, 13C NMR, and mass spectral data. All compounds were evaluated as anti-inflammatory activity by using carrageenan-induced rat paw edema test. In comparison to the standard drug diclofenac sodium, compounds 3, 7, 9, and 11 exhibited potent activity than standard drug. The compounds 2 and 8 showed the most significant anti- anti-inflammatory with 64.83 and 63.95% inhibition of edema. [ABSTRACT FROM AUTHOR]