Pyridopyrimidine Derivatives Research Articles

Synthesis, antiviral screening, and in silico investigations of new pyrimidine and pyridopyrimidine derivatives: Finding new therapeutic prospects to combat the herpes simplex virus (HSV-1)

In the quest for novel antiviral agents, a new set of fourteen pyrimidine and pyridopyrimidine derivatives (4–11) have been synthesized via different chemical transformations starting from 1,3-indandione 1. These derivatives were characterized by 1H NMR, 13C NMR, FT-IR, and MS. Following the in vitro evaluation of some derivatives of these synthetic compounds against HSV-1, the most promising compounds, 4b and 6, had their mechanisms of action examined. The most potent compounds (4b and 6) were also examined by applying density-functional theory (DFT) to ascertain their molecular structures and geometries. Molecular docking studies for compounds 4b, 5b, and 6 were performed against the Herpes simplex virus type-1 target proteins (PDB ID: 2GIY, 2KI5, and 3FOT) to anticipate the antiviral active sites of the compounds under investigation. Docking results and the compound's strong contact with the target proteins indicated that compounds 4b and 6 had energy scores that were on par with or higher than those of the acyclovir drug. Both in silico and in vitro results are in agreement.

New pyridopyrimidine derivatives as dual EGFR and CDK4/cyclin D1 inhibitors: synthesis, biological screening and molecular modeling.

Aim: A series of pyridopyrimidine derivatives 5-20 was designed, synthesized and examined for antitumor activity using four types of malignant cells.Materials & methods: Cervical cancer (HeLa), hepatic cancer (HepG-2), breast cancer (MCF-7) and colon cancer (HCT-166) cells, as well as normal human lung fibroblast cells (WI-38) were used to determine the cytotoxicity.Results: Pyrazol-1-yl pyridopyrimidine derivative 5 was found to be the most active compound against three malignant cells Hela, MCF-7 and HepG-2 with IC50 values of 9.27, 7.69 and 5.91μM, respectively, related to standard Doxorubicin. Moreover, compounds 5 and 10 showed good inhibition against cyclin dependent kinase (CDK4/cyclin D1) and epidermal growth factor (EGFR) enzymes.

Novel oxadiazole functionalized pyridopyrimidine derivatives; their anticancer activity and molecular docking studies

AbstractA series of novel oxadiazole functionalized pyridopyrimidine derivatives prepared starting from 6‐methyl/ethyl‐2‐oxo‐4‐(trifluoromethyl)‐1,2‐dihydropyridine‐3‐carbonitrile 1. This compound 1 on reaction with sulfuric acid obtained compound 2, further compound 2 on reaction with chloroacetamide followed by reaction with ethoxy methylene malonic diethyl ester coupling and further cyclization to obtain compound 5. Compound 5 on reaction with hydrazide hydrate obtained hydrazide derivatives 6. Compound 6 on reaction with diverse substituted aromatic acids to get oxadiazole derivatives 7a–l. All the final compounds 7a–l evaluated for anticancer activity against four human cancer cell lines such as HeLa—cervical cancer (CCL‐2); COLO 205—colon cancer (CCL‐222); HepG2—liver cancer (HB‐8065); and MCF7—breast cancer (HTB‐22) and promising compounds 7d and 7k have been identified and evaluated for molecular docking interactions.

Exploring the Antiproliferative Potency of Pyrido[2,3-d]Pyrimidine Derivatives: Studies on Design, Synthesis, Anticancer Evaluation, SAR, Docking, and DFT Calculations.

Herein, an efficient method for the synthesis of a new series of pyrido[2,3-d]pyrimidine derivatives has been adopted through the reaction of hydrazinyl pyrido[2,3-d] pyrimidine derivative (1) with different electrophilic species, such as ethyl cyanoacetate and different 1,3 diketone derivatives, gave the corresponding derivatives (2-5). Meanwhile, pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines (6-11) were synthesized via reaction of hydrazine derivative 1 with phenylisothiocyanate, potassium thiocyanate, and carbon disulfide. Compound 1 was also submitted to react with different carbonyl compounds to afford pyrido-pyrimidine derivatives (12-15). All the newly synthesized compounds were tested in vitro for their antiproliferative activities against HCT-116 and MCF-7 cell lines. Compounds 2, 3, 7, and 8 displayed very strong inhibitory activity against the two cell lines compared with the standard drug doxorubicin. Furthermore, a docking study of the most active compounds was performed with the thymidylate synthase enzyme (PDB: Code 6qxg). Moreover, DFT calculation was carried out for the most biologically active compounds and a reference drug (Doxorubicin) using the B3LYP/6-31G+(d,p) level of theory. The calculated EHOMO and ELUMO energies were used to calculate the global reactivity parameters. Finally, Molecular electrostatic potential (MEP) and structure activity relationship (SAR) were studied to correlate the relation between chemical structure and reactivity.

An Expedient Three-component Synthesis of Novel Pyrido-pyrimidine Derivatives: Antimicrobial Activity, Molecular Docking, and ADME Studies

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.

Novel carboxamide and carbohydrazide functionalized pyridopyrimidine derivatives and their anticancer activity

A series of novel carboxamide and carbohydrazide functionalized pyridopyrimidine derivatives was prepared starting from 6-methyl/ethyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile 1. Compound 1 on reaction with sulphuric acid gave compound 2. Compound 2 on reaction with chloroacetamide followed by reaction with EMME coupling and further cyclization gave compound 5. Compound 5 on reaction with hydrazine hydrate produced hydrazide derivatives 6. Compound 6 on reaction with diverse substituted aromatic aldehyde gave Schiff’s base derivatives 7a-j. Ester derivatives 5 on reaction with different aliphatic amine gave carboxamide derivatives 8a-f. All the final 7a-j and 8a-f compounds were evaluated for anti cancer activity against four human cancer cell lines such as HeLa - Cervical cancer (CCL-2), COLO 205- Colon cancer (CCL-222); HepG2- Liver cancer (HB-8065), MCF7 - Breast cancer (HTB-22) and promising compounds 7e, 7h and 7j have been identified.

EXPLORATION OF NEWER POSSIBILITIES TO THE SYNTHESIS OF SMALL MOLECULES OF MEDICINAL INTEREST FROM ISATIN

A ‘chemistry driven approach’ to the synthesis of small molecules of medicinal interest was launched to explore the versatility of 3-benzoylmethyl indolin-2-one (3) (resulted on the reaction of isatin with acetophenone followed by reduction of the obtained enone derivative 2 with Na2S2O4 ) to provide synthetically acceptable protocols to the formation of indolin-2-one analogues substituted on its 3-position with isoxazole (5), pyrazole (6), pyridine (7), pyrido pyrimidine (8,9) and quinoline carboxylic acid derivatives 10 resepectively. In a related reaction the Beckmann rearrangement of the oxime of 3, with acid and with TCT + DMF allowed the formation of the amide 13 which underwent cyclocondensation with NH4OAc in AcOH to give the corresponding pyrrolo-indole derivative 15 whose structure was unequivocally established from its micro analyses and spectral data. KEY WORDS: Isatin, indolin-2-one, Pfitzinger reaction, Beckmann rearrangement

Pyridopyrimidines as Anticancer Agents

The main purpose of this review is to provide an overview of the current knowledge for development of new molecules of pyridopyrimidines by using different multi-component reactions that lead to give effective anticancer agents. Thus, the developed compounds have been derived from pyridine and pyrimidines fusion or from possible isomeric forms of pyridopyrimidine derivatives. They are obtained from different approaches of multistep synthesis reaction such as Tandemaza-witting reaction, annulations, and Biginelli type reactions. Apart from the synthetic schemes, their biological applications with an alternative mechanism of action, such as growth inhibitors by cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and mutation, are also understood. These receptors and enzymes are responsible for causes of cancer because disruptions of dihydrofolate reductase, tyrosine kinase, cyclin-dependent kinase-4 and 6, and fibroblast growth factor receptor. Among heterocyclic compounds, pyridopyrimidine compounds are privileged structure in medicinal chemistry, especially with FGFR-TK, CDK-4, ABCG-2, Ef-2 kinase, and Type-II pan-RAF kinase inhibitors (Figure 1). The present review illustrates that pyridopyrimidines have been developed by using new strategies and may be utilized for treatment of various cancer.

Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-d], [3,2-d], [3,4-d] and [4,3-d]pyrimidine Derivatives.

The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3-d]pyrimidines, pyrido[3,4-d]pyrimidines, pyrido[4,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine.

Design and synthesis of novel pyridopyrimidine derivatives with anchoring non-coplanar aromatic extensions of EGFR inhibitory activity

The present study describes the synthesis of three series of 4-substituted pyridopyrimidin derivatives 4a-h, 5a-d. 6a-d, starting from 2-amino-6-(4-methoxyphenyl)-4-(4-(substituted) phenyl)nicotinonitrile 2a-d via the reaction with N,N-dimethyl-N-' substituted phenyl formimidamide to obtain 4a-h or with either phenyl isothiocyanate 1:1 and 1:2 to obtain 5a-d, 6a-d respectively. The synthesized compounds were evaluated for their effectiveness as EGFR inhibitors against Gefitinib. Six compounds; 4b,g,h, 5c and 6a,d prompted significantly higher EGFR inhibitory activity relative to that of Gefitinib. While two compounds 4d and 4f showed IC50 values non-significantly different from that of the reference drug. Furthermore, compounds 4a, 4 h, 6a and 6d were chosen to be assessed in vitro for their cytotoxicity against two EGFR-overexpressing cell lines; two human cancer cell lines namely: MCF7 and MDA-MB-361. Moreover, cell cycle analysis and apoptotic assay was applied for compound 4b that showed most potent inhibitory activity on EGFR, and the highest cytotoxicity against MCF7 and MDA-MB-361, where cell cycle arrest was achieved at pre G and S phases with increased apoptosis. Additionally, a molecular docking study was achieved to inspect the interaction of this compound with the active site of EGFR-TK.

Sol-gel TiO2 nanostructures single doped with copper and nickel as nanocatalysts for enhanced performance for the Liebeskind–Srogl reaction

Design of nanostructured catalytic materials plays a strategic role in the synthesis of organic compounds with outstanding physicochemical properties. In this regard, titanium dioxide nanostructures doped with a single metal, namely, nickel and copper, were successfully prepared by a sol-gel method, and their phase structures, elemental compositions and morphologies were extensively characterised. In particular, X-ray diffraction (XRD) diffractograms and Raman spectra mainly revealed a rutile-phase structure for Cu-doped TiO2 and a biphasic anatase–rutile structure for Ni-doped TiO2. In addition, catalytic activities of Cu- and Ni-doped titanium dioxide nanostructures were evaluated for the synthesis of pyridopyrimidine derivatives from sulphur intermediates by the Liebeskind–Srogl reaction under UV illumination. Under the optimized reaction conditions, the target compounds were obtained in a yield of up to 87% by using the Cu-doped TiO2 catalyst and with a slightly lower yield of up to 79% for Ni-doped TiO2 in 12 h. Overall, the catalytic activity of Cu-doped TiO2 was greater than that of Ni-doped TiO2.

Algal magnetic nickel oxide nanocatalyst in accelerated synthesis of pyridopyrimidine derivatives

This research presents a novel biological route for the biosynthesis of nickel oxide nanoparticles (NiO NPs) using marine macroalgae extract as a reducing and coating agent under optimized synthesis conditions. XRD and TEM analyses revealed that phytosynthesized NiO NPs are crystalline in nature with a spherical shape having a mean particle size of 32.64 nm. TGA results indicated the presence of marine-derived organic constituents on the surface of NiO NPs. It is found that biogenic NiO NPs with BET surface area of 45.59 m2g−1 is a highly efficient catalyst for benign one-pot preparation of pyridopyrimidine derivatives using aqueous reaction conditions. This environmentally friendly procedure takes considerable advantages of shorter reaction times, excellent product yields (up to 96%), magnetically viable nanocatalyst (7 runs), low catalyst loadings, and free toxic chemical reagents.

Design, Synthesis and Antibacterial Studies of Some New Pyridopyrimidine Derivatives as Biotin Carboxylase Inhibitors

Present study reports the development of novel pyridopyrimidine derivatives as biotin carboxylase inhibitors with potent antibacterial activity. These compounds were designed to avoid possibility of resistance development. Accordingly eighteen compounds were synthesised and characterized on the basis of spectral data. These compounds were tested for their antibacterial potential by the enzyme kinetic assay against the biotin carboxylase. The minimum inhibitory concentration (MIC) and single step resistance studies were also performed. Compound 2-((2-Phenylpyrido[2,3-d]pyrimidin-4-yl)amino)phenol (6o) showed promising activity in biotin carboxylase inhibition with low MIC. It showed molecular docking score of -7.96, this compound showed formation of hydrogen bonds with the active site residues and van Der Walls intractions. The MIC of compounds under investigation was in the rage of 2-5µg/mL over most of the strains studied. It also showed the mutant selection windows of around five which is better than the reference compound rifampin. This compound 6o can be studied further and developed into a potential antibacterial lead molecule.

Corrosion Inhibition Effect of some Pyridopyrimidine Derivatives for Carbon Steel in 0.5 M HCl Solution

Corrosion Inhibition Effect of some Pyridopyrimidine Derivatives for Carbon Steel in 0.5 M HCl Solution

In silico study combining QSAR, docking and molecular dynamics simulation on 2,4-disubstituted pyridopyrimidine derivatives

2,4-Disubstituted pyridopyrimidine derivatives were studied against ABCG2 enzyme. The modeling of pyridopyrimidine derivatives were done using two methods of multiple linear regression and support vector regression and four molecular descriptors of BIC4, log p, VRA2, and binding energy were selected for modeling. The statistical results were satisfactory. The interactions of ABCG2 enzyme with pyridopyrimidine derivatives were investigated using molecular docking method. Based on the results, increasing of binding energy and hydrophobicity of the compounds increase their inhibitory activity. Protein stability in complex with pharmaceutical derivatives was discussed using molecular dynamics simulation method.

Synthesis of pyridopyrimidine derivatives based on benzenesulfonyl acetonitrile compounds via a one-pot sequential four-component domino reaction and microwave-mediated molecular cyclization

A concise, rapid and highly efficient method for the one-pot synthesis of novel pyridopyrimidine derivatives has been demonstrated by the “four-component” domino reaction of aromatic aldehyde, benzenesulfonyl acetonitrile, 1,1-dimethylthio-2-nitroethylene and 1,3-propanediamine, using piperidine as a catalyst and ethanol as solvent under microwave irradiation. This methodology was established with many advantages, including higher reaction yields, broad substrate scopes, experimental simplicity, short time and utility of easily available starting materials. The synthesized compounds are confirmed by 1H NMR, IR and HR-ESI-MS.

Conventional and Microwave Synthesis of some new pyridine derivatives and evaluation their antimicrobial and cytotoxic activities.

The newly synthesized compounds based on 2-amino-6-(2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)nicotinonitrile 1. The reactivity of pyridine derivative 1 was studied towards different reagents by its reaction with malononitrile, 2-(4-chlorobenzylidene)malononitrile, ethyl cyanoacetate, cyano acetic acid, m-nitro benzaldehyde, sodium azide, formamide, acetic anhydride and/or acetic anhydride/H2SO4 to give compounds 2-5,7, 10-13, respectively. The reaction of 5 with acetyl acetone gave the bipyridine derivative 6, while reaction of compound 7 with chloroacetyl chloride and phenacyl bromide gave the azetidinone derivatives 8 and 9. The formimidate 14 were obtained via reaction of compound 1 with triethylorthoformate, while reaction of 14 with phenylene diamine and/or acetamide gave the formimidamide and pyridopyrimidine derivatives 15 and 16 respectively. Compound 1 was also allowed to react with urea, thiourea, phthalic anhydride, succinic anhydride, benzoyl chloride, chloroacetonitrile, chloroacetyl chloride, p-toluenesulfonylchloride and ethyl bromoacetate to give compounds 17a,b - 24. Reaction of compound 1 with dichloro reagents in 1:1 ratio gave the bicyclic derivatives 25a–c, while its reaction with oxalyl chloride, dichloro and tetrachlorobenzoquinone derivatives, and/or dichloronaphthoquinone gave the imidazopyridine derivatives 26-29. Reaction of compound 29 with o-phenylenediamine in 1:2 ratio afforded the di-condenesed product 30 while, reaction of compound 1 with dichlororeagents in 1:2 ratio gave the polyalkyl derivatives 31a-b. The newly synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR and mass spectra. On the other hand the antimicrobial and anticancer activities of some of the newly synthesized compounds was studied and evaluated.

New Inhibitors of Breast Cancer Resistance Protein (ABCG2) Containing a 2,4-Disubstituted Pyridopyrimidine Scaffold.

Multidrug resistance (MDR) occurring during cancer chemotherapy is a major obstacle for effectiveness and response to therapy and is often caused by ATP-binding cassette (ABC) efflux transporters. Belonging to the family of ABC transporters, breast cancer resistance protein is getting more and more in the spotlight of research. As a strategy to overcome MDR, inhibitors of ABC transporters were synthesized, which could be applied in combination with cytostatic drugs. For this purpose, 2,4-disubstituted pyridopyrimidine derivatives were synthesized. The investigations confirmed three key characteristics of good inhibitors: a low intrinsic cytotoxicity and a high potency and selectivity toward ABCG2. For selected compounds the interaction with ABCG2 was elucidated and their effect on ATPase activity and conformation sensitive 5D3 antibody binding was investigated. Their ability to reverse MDR in coadministration with the active metabolite of irinotecan and mitoxantron was confirmed.

Eco-friendly synthesis, characterization, and drug-likeness properties of new uracils and their biological evaluation

Abstract Several pyridopyrimidine derivatives have been synthesized through different synthetic processes. The different physicochemical factors for their synthesis were also discussed. A comparison between the conventional and microwave-assisted synthesis was conducted by comparing total time of reaction and its yield percentage. Most of the produced uracils were established for their anti-inflammatory, analgesic, and antioxidant activities. Compounds 1 and 3 were demonstrated as the best results against DNA damage, whereas compounds 2a and 2b exhibited an effective anti-inflammatory activity. Moreover, the Lipinski rule parameters were calculated for the synthesized compounds. The results indicated that compounds 1, 2a and 5 have good potential for subsequent development bioactivity.

Computational Analysis of Pyridopyrimidine-based Polo Like Kinase 2 (PLK2) Inhibitors: Examining the Structural Basis for Anticancer Activity

Background: Polo like kinase 2 (PLK2) has been reported as a new target for developing novel anticancer drugs. Here, three-dimensional quantitative structure-activity relationship (3D-QSAR), docking and molecular dynamics (MD) simulation studies were carried out on 70 pyridopyrimidine derivatives to focus on the structural necessities of potent PLK2 inhibitors. Keywords: Cancer, polo like kinase 2, pyridopyrimidine, 3D-QSAR, molecular docking, molecular dynamics simulation.