Synthesis Of Novel Pyrido Research Articles

Synthesis of novel pyrido[3,4‐d]pyrimidine‐thiazolidione‐1,2,4‐oxadiazoles as potent EGFR targeting anticancer agents

AbstractIn this study, we designed and synthesized a number of novel pyrido[3,4‐d]pyrimidine‐thiazolidine‐1,2,4‐oxadiazole derivatives and investigated them in vitro for their inhibitory action toward epidermal growth factor receptor (EGFR) kinases and antiproliferative activity against two different cell lines, MCF‐7 and A‐549. When compared to the lead chemicals, 5‐fluorouracil and erlotinib, some of the compounds demonstrated acceptable activity. Among them, the most promising compounds 4d and 4e displayed potent anticancer activity against both MCF‐7 and A‐549 cell lines (IC50 values remaining: 1.97 ± 0.28 μM to 8.14 ± 0.52 μM, respectively); the comparative IC50 values for 5‐fluorouracil and erlotinib in these cell lines were 5.56 ± 0.34 μM, 12.66 ± 0.76 μM, and 3.64 ± 0.49 μM, 9.54 ± 0.75 μM, respectively; as well as excellent kinase inhibitory activities (EGFR: IC50 = 0.34 ± 0.07 μM and 0.42 ± 0.06 μM) were more effective than the conventional drug Erlotinib (IC50 = 0.42 ± 0.02 μM).

Design, Synthesis of Novel Pyrido[2,3-d] pyrimidine Derivatives as SARS-CoV-2 Mpro Inhibitors for COVID-19 Therapy

Some of the interesting pyrido[2,3-d] pyrimidines (3a, 3b), 4, (5a–d), (6a, b), 7–13, and (15a–c) based on uracil moiety were synthesized efficiently using a conventional method and ultrasonic irradiation. Heterocyclic scaffolds such as pyrido[2,3-d] pyrimidines are vital structural elements in drug discovery. Their interactions with different viral mechanistic pathways will be leveraged in future research to create heterocycle-based antivirals. Therefore, the purpose of this work is to demonstrate the anticipated contribution of heterocyclic scaffolds to the advancement and identification of SARS CoV-2 treatment, The newly synthesized compounds were characterized by spectral data, and screened for their binding activity toward the main protease of COVID-19 utilizing a molecular docking study, according to the outcome of our initial screening and docking study, the produced compounds 3a, 4, 6a, 13, 15b, and 15c achieved an evaluation in vitro using the SARS-CoV-2 Mpro utilizing the main protease assay, the results of the evaluation showed that the hydrazinylpyridopyrimidine 4 (IC50 value: 10.69 µM) and triazolopyrimidin 15c (IC50 value 8.723 µM) had the greatest inhibitory effects on SARS-CoV-2 Mpro. Additionally, this study was conducted to assess the inhibitory efficacy of the synthesized compounds 4 and 15c, which show moderate inhibition for the replication of SARS CoV-2. Additional molecular dynamics and docking simulations were performed to prove the binding mechanism of 15c.

Novel mono substituted pyridoimidazoisoquinoliniums via a silver-catalyzed intramolecular cyclization and their applications in cellular imaging.

Cationic heterocycles, an important class of organic compounds soluble in polar solvents, have been gaining attention in the construction of fluorescent probes. This paper reports the quick synthesis of novel pyrido[1',2';2,3]imidazo[5,1-a]isoquinoliniums starting from 2-(2-ethynylphenyl)imidazo[1,2-a]pyridines at room temperature via intramolecular cyclization by employing a catalytic amount of silver trifluoromethanesulfonate in addition to lithium trifluoromethanesulfonate and silica gel as the counter anion source and additive, respectively. The designed pyridoimidazoisoquinoliniums consisted of an imidazo[1,2-a]pyridine fused isoquinolinium. The X-ray diffraction results revealed that pyrido[1',2';2,3]imidazo[5,1-a]isoquinolinium trifluoromethanesulfonate contained considerable planar parent skeletons and interacted by π-π stacking with neighbouring molecules. Furthermore, in a methanol solution the designed 6-phenyl derivative exhibited strong fluorescence in the 420-450 nm region in addition to strong mitochondrial specificity in a cell staining assay.

Synthesis of novel pyrido[2,3-d]pyrimidine-thiazolidine-1,2,3-triazoles: Potent EGFR targeting anticancer agents

In this study, we designed and synthesized a number of novel pyrido[2,3-d]pyrimidine-thiazolidine-1,2,3-triazole derivatives and investigated them in vitro for their inhibitory action toward EGFR kinases and anti-proliferative activity against two different cell lines. When compared to the lead chemical, erlotinib, the majority of the compounds demonstrated acceptable activity. Among them, the most promising compounds 4d and 4e exhibited excellent anti-proliferative activity against the MCF-7 cancer cell line with IC50 values of 4.19 ± 0.24 and 3.52 ± 0.12 µM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC50 = 0.53 ± 0.02 and 0.39 ± 0.03 µM). In silico docking studies were performed to evaluate the molecular interactions of 4a-4o compounds with the human epidermal growth factor receptor, EGFR (PDB: 1M17) proteins with a co-crystallized ligand (erlotinib) and observed that four of the compounds (4d, 4e, 4m, and 4o) had appreciable binding energies compared to the standard drug erlotinib. Finally, the in silico pharmacokinetic profile was predicted for potent compounds 4d, 4e, 4m, and 4o using SWISS/ADME, where the 4m and 4o compounds had a better profile compared to the 4d and 4e compounds.

Palladium‐catalyzed synthesis of novel pyrido[3,4‐d]pyridazin‐1(2H)‐ones as promising α‐glucosidase, α‐amylase and EGFR inhibitors along with molecular docking

AbstractA novel route has been established for the synthesis of novel pyrido[3,4‐d]pyridazin‐1(2H)‐one derivative. Synthesis of intermediate 4‐methyl‐7‐(piperazin‐1‐yl)pyrido[3,4‐d]pyridazin‐1(2H)‐one carried out in the presence of Pd(PPh3)2Cl2 catalyst. Ten novel derivatives were synthesized, isolated, and characterized by various spectroscopic techniques. All synthesized molecules were screened for in silico parameters and evaluated for α‐glucosidase and α‐amylase inhibitory assay. Furthermore, all synthesized molecules were screened for anticancer activity against human lung cell line (A549), human melanoma cell line (A375) and breast cancer (MCF‐7) cell lines and their cytotoxic effects were compared. Among the compounds, 8i showed higher inhibition than standard acarbose in the antidiabetic assay. In addition, 8 g exhibited more potency than positive control doxorubicin on lung, breast, and melanoma cancer cell lines. A molecular docking study was carried out on 1RPK and 4HJO as Epidermal growth factor receptor (EGFR) proteins.

Synthesis, In Silico and In Vivo Toxicity Assessment of Functionalized Pyridophenanthridinones via Sequential MW-Assisted Intramolecular Friedel-Crafts Alkylation and Direct C–H Arylation

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a-f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a-f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C-H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a-f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study.

Discovery of Mesoionic Derivatives Containing a Dithioacetal Skeleton as Novel Potential Antibacterial Agents and Mechanism Research.

In this study, the design and synthesis of novel pyrido[1,2-a]pyrimidinone mesoionic derivatives incorporating dithioacetal structures were carried out. The three-dimensional quantitative structure-activity relationship (3D-QSAR) model was built according to the EC50 values and directed the synthesis of compound A32. The biological activity test against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc) indicated that compound A32 showed good antibacterial activity with EC50 values of 10.9 and 17.5 mg/L, which were lower than the EC50 values of bismerthiazol (29.3 and 39.8 mg/L) and thiodiazole copper (64.8 and 78.1 mg/L). Furthermore, the in vivo antibacterial activity against bacterial leaf blight (BLB) and bacterial leaf streak (BLS) revealed that the protective activity of compound A32 was 43.9 and 41.7%, respectively, which was better than the protective activity of thiodiazole copper (40.6 and 35.0%). In addition, the protective activity against bacterial leaf blight of compound A32 was associated with the increasing rice defensive enzyme activity and the upregulation of proteins involved in oxidative phosphorylation. Moreover, compound A32 could upregulate the expression of complex I (nicotinamide adenine dinucleotide hydrogen (NADH) dehydrogenase) in the oxidative phosphorylation pathway, which was verified by complex I activity evaluation.

Synthesis of novel pyrido[2,1-b]benzothiazole and N-substituted 2-pyridylbenzothiazole derivatives showing remarkable fluorescence and biological activities

Abstract The synthesis of novel pyrido[2,1-b]benzothiazole and pyrido[2,1-b]benzoimidazole derivatives was achieved via the reaction of N-aryl-2-cyano-3,3-bis(methylthio)acrylamide with benzothiazoleylacetonitrile and benzoimidazoleylacetonitrile, respectively, while N-substituted 2-pyridylbenzothiazole derivatives were synthesized by reacting 2-(benzo[d]thiazol-2-yl)-3-(dimethylamino)acrylonitrile with either cyanoacetamide, aryl cyanoacetamides or 2-cyano-N’-(4-substituted benzylidene)acetohydrazide. Based on the steady state fluorescence measurements, the newly synthesized N-substituted 2-pyridylbenzothiazole derivatives exhibited remarkable fluorescence properties with considerably high quantum yields (0.25–0.29). In addition, the antimicrobial and antiviral activities were evaluated for all the newly synthesized derivatives. The antimicrobial examination revealed that triazolo-pyridone 21a had the highest potency among all tested compounds against Escherichia coli, Klebsiella pneumonia and Staphylococcus aureus while pyrido[2,1-b]benzoimidazole derivatives 9a and 9b had the highest potency over other compounds against Candida albicans fungus.

Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands

The study enabled obtaining a number of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine 9.1–9.27 having conformationally restricted tryptamine moiety. In vitro studies (RBA) have shown that derivatives 9.1, 9.2, 9.4, 9.7, 9.9, 9.14 and 9.27 exhibit high affinity to molecular targets 5-HT1A receptor and SERT protein. In general, compounds with an unsubstituted or a para-substituted benzene ring of the pyrido[1,2-c]pyrimidine residue in the terminal part were characterized by higher binding ability, which can be justified by the greater flexibility of the structure. For the selected compounds 9.1, 9.7, 9.9 and 9.27, further in vitro, in vivo and metabolic stability tests were performed. The in vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) indicated their selectivity toward the 5-HT1A receptor and SERT protein. The in vivo studies (8-OH-DPAT-induced hypothermia in mice, FST) revealed that the compound 9.1 has the properties of presynaptic agonist of the 5-HT1A receptor, and compound 9.7 demonstrated the properties of a presynaptic antagonist of the 5-HT1A receptor. Metabolic stability studies, in turn, showed that compounds 9.1, 9.7 and 9.9, having an unsubstituted indole residue, were more resistant to biotransformation reactions of the first pass phase than was compound 9.27 containing a 5-methoxy-substituted indole residue. The obtained results allowed further optimization of the structure.

Studies on synthesis of novel pyrido[2,3-d]pyrimidine derivatives, evaluation of their antimicrobial activity and molecular docking

A series of novel pyrido[2,3-d]pyrimidine derivatives 6 were prepared starting from 2-amino-3-cyano-4-trifluoromethyl-6-phenyl pyridine 3 via Grignard’s reaction, cyclization followed by coupling with aliphatic and cyclic amines. All the compounds 6 were screened for antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition activity as well as antifungal and minimum fungicidal concentration (MFC) activities. Among the screened compounds, the compounds 6e, 6f, and 6m which showed exhibiting promising activity have been identified. The results reveal that the compound pyrido[2,3-d]pyrimidine derivative 6e altered the sterol profile which may exert its antifungal activity through inhibition of ergosterol biosynthesis and could be an ideal candidate for antifungal therapy. The molecular docking results also validated the antifungal results.

Synthesis of Pyrido[2, 3‐a]phenoxazines and Pyrido[2, 3‐a]phenothiazines via Successive SNAr Processes

AbstractAn efficient method was developed for the synthesis of novel pyrido[2, 3‐a]phenoxazines and phenothiazines. The base‐promoted reaction of 8‐chloro‐5,7‐dinitroquinoline with binucleophiles (o‐aminophenols and o‐aminothiophenols) results in substitution of the chlorine atom followed by replacement of the nitro group. In case of aminothiophenols the products of in situ Smiles rearrangement were isolated.

A viable and efficacious catalyst, CeO2/HAp, for green synthesis of novel pyrido[2,3-d]pyrimidine derivatives

A facile one-pot green protocol at room temperature has been devised for the synthesis of novel pyrido[2,3-d]-pyrimidine derivatives catalyzed by CeO2-doped hydroxyapatite (CeO2/HAp) with ethanol as solvent. This highly selective method with excellent yields (89–96%) involves a four-component reaction between malononitrile, substituted aldehyde, dimethylbarbituric acid and ammonium acetate. CeO2/HAp was synthesized and characterized by P-XRD, TGA, TEM and SEM analyses. The structures of the target molecules were confirmed by diverse spectroscopic methods (1H NMR, 15N NMR, 13C NMR, and HRMS). Additional benefits of this eco-friendly approach are the operational simplicity, a stable catalyst with good reusability (at least 6 times), short reaction times (< 45 min) and no need for chromatographic separations. All these features make the proposed method economical and sustainable.

Three-component one-pot synthesis of novel pyrido[2,3-d]pyrimidine indole substituted derivatives and DFT analysis

Pyridopyrimidines are heterocyclic aromatic compounds known by their antibacterial and medicinal properties. In this work, a series of pyrido[2,3-d]pyrimidine indole derivatives were synthesized by three-component one pot cyclocondensation Michael reaction between 2,6-diaminopirimidin-4(3H)-one, 3-(2-cyanoacetyl)indole and aromatic aldehydes in boiling acetic acid as solvent. The compounds differ with respect to the substituents of the aromatic aldehyde which are comprised by -C6H5, -4-ClC6H4, -4-NO2C6H4, -3,4-OCH2OC6H3, -3-OCH3,4-OH,5-NO2C6H2, and -3,4,5-tri-H3COC6H2, respectively. The compounds were synthesized with reasonable yields. They were characterized by and IR, mass, and NMR spectrometry. The protocol employed offers the convenient advantages of a one-step synthesis, considerable savings of solvents, and easy isolation of reaction products. In addition, DFT and TD-DFT quantum chemical calculations were used to characterize the geometry and electronic structure of the compounds.

An efficient synthesis of novel pyridothieno-fused thiazolo[3,2- a ]pyrimidinones via Pictet–Spengler reaction

Abstract An efficient method for the synthesis of novel pyrido[3″,2″:4′,5′]thieno[3′,2′:2,3]pyrido [4,5:d][1,3]thiazolo[3,2-a]pyrimidine-4-one derivatives (5) has been developed using a Pictet–Spengler reaction between 2-(3-aminothieno[2,3-b]pyridin-2-yl)thiazolo[3,2-a] pyrimidin-5-one (3), which could be obtained from the condensation of 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1) with 3-cyanopyridine-2-thione (2) via Thorpe–Ziegler isomerization, and aromatic aldehydes under NH2SO3H as catalysis in good yields.

Metal-free C–N bond formations: one-pot synthesis of pyrido[2′,1′:2,3]imidazo[4,5-c]cinnolines, benzo[4′,5']thiazolo- and thiazolo[2′,3′:2,3]imidazo[4,5-c]cinnolines

An efficient one-pot synthesis of novel pyrido[2′,1′:2,3]imidazo[4,5-c]cinnoline derivatives has been achieved with moderate to good yields, with two C–N bond formations through C–H functionalization of 2-arylimidazo[1,2-a]pyridines.

Synthesis of Novel Pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxide Derivatives with Potential Anticancer Activity

A series of novel 3-/2,3-substituted pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxides 4–28 have been synthesized by the reaction of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-yl-sulfonyl)guanidine with either 2-oxoalkanoic acids and its esters, or phenylglyoxylic hydrates in glacial acetic acid. Some of them exhibited reasonable or moderate anticancer activity toward human cancer cell lines, HCT-116, MCF-7 and HeLa. The structure of this novel heterocyclic ring system was confirmed by 1D-NMR and 2D-NMR spectroscopic data including COSY, ROESY and HMBC, elemental analyses and MS spectrometry.

Synthesis of Novel Pyrido[1,2-a]pyrimidine-3-carboxamide Derivatives and Their Anticancer Activity.

A series of novel pyrido[1,2-a]pyrimidine-3-carboxamide derivatives 6a-n were prepared starting from 2(1H) pyridone 1 via hydrolysis, de-carboxylation, selective O-alkylation followed by rearrangement to give pyridine-2-amine 3. Compound 3 on reaction with ethoxy methylene malonic diethyl ester (EMME) under a conventional method followed by cyclization under micro wave irradiation (MWI) conditions resulted in product 5. Compound 5 on coupling with diverse substituted aliphatic amines formed title compounds 6a-n. All the products 6a-n were screened against four human cancer cell lines and compounds 6h-k and n which showed promising anticancer activity have been identified.

Cellulose Sulfuric Acid as an Eco-Friendly Catalyst for Novel Synthesis of Pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones

A novel synthesis of a series of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones has been developed from reactions of 1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-arylprop-2-en-1-ones and 7-amino-1,3-disubstituted[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones in dioxane under thermal conditions, using cellulose sulfuric acid as an eco-friendly acid catalyst. The reaction mechanism was proposed and the structures of the newly synthesized compounds were established on the basis of spectral data (mass spectrometry, infrared, 1H and 13C nuclear magnetic resonance) and elemental analyses.

One-pot synthesis of novel pyrido[2,3-d]pyrimidines using HAp-encapsulated-γ-Fe2O3 supported sulfonic acid nanocatalyst under solvent-free conditions

Novel pyrido[2,3-d]pyrimidine derivatives were synthesized through a one-pot three-component approach using HAp-encapsulated-γ-Fe2O3 [γ-Fe2O3@HAp-SO3H] catalyzed condensation of 6-amino-2-(methylthio or ethylthio)pyrimidin-4(3H)-one, Meldrum's acid and aryl aldehydes at 60 °C and under solvent-free conditions. In this protocol the use of nanocatalyst provided a green, useful and rapid method to generate the products in short reaction times and excellent yields (88%–94%).

ChemInform Abstract: Molecular Iodine Promoted Synthesis of New Pyrido[2,3‐d]pyrimidin‐4‐ols.

A highly ef?cient synthesis of novel pyrido[2,3-d]pyrimidin-4-ols was developed via an iodine-catalyzed tandem oxidative cyclization under focused microwave irradiation. Pyrido[2,3-d]pyrimidin-4-ols were obtained from easily available 2-amino-4-aryl-6-arylnicotinamides and benzylic amines with good to excellent yields.