Series Of Pyrido Research Articles

An efficient synthesis of 3′-indolyl substituted pyrido[1,2-a]benzimidazoles as potential antimicrobial and antioxidant agents

A new class of indole-based pyrido[1,2-a]benzimidazole derivatives 4a–r have been synthesized by one-pot cyclocondensation reaction of 2-phenyl-1H-indole-3-carboxaldehyde 1a–i, malononitrile 2 and 2-cyanomethylbenzimidazole 3a–b in the presence of catalytic amount of NaOH. In vitro antimicrobial activity of the synthesized compounds were investigated against a representative panel of pathogenic strains specifically three Gram-positive bacteria (Streptococcus pneumoniae, Clostridium tetani, Bacillus subtilis), three Gram-negative bacteria (Salmonella typhi, Vibrio cholerae, Escherichia coli) and two fungi (Aspergillus fumigatus, Candida albicans) using broth microdilution MIC (minimum inhibitory concentration) method. In vitro antioxidant activity was evaluated by ferric-reducing antioxidant power (FRAP) assay method. Compounds 4c, 4e, 4l and 4q have been found to be most efficient antimicrobial members while compounds 4h and 4p possess better ferric reducing antioxidant power. A series of pyrido[1,2-a]benzimidazole derivatives 4a-r have been synthesized. Antimicrobial activity against a representative panel of pathogenic strains and antioxidant activity were carried out. Compounds 4c, 4e, 4l and 4q emerged as most efficient antimicrobial members while compounds 4h and 4p showed better antioxidant power.

Studies on the chemical reactivity of 1H-benzimidazol-2-ylacetonitrile towards some 3-substituted chromones: synthesis of some novel pyrido[1,2-a]benzimidazoles

A simple and convenient synthesis of a novel series of pyrido[1,2-a]benzimidazoles was efficiently achieved from the condensation reactions of 1H-benzimidazol-2-ylacetonitrile (1) with some 3-substituted chromones, chromone-3-carboxylic acids, chromone-3-carboxamides, ethyl chromone-3-carboxylates and chromone-3-carbonitriles. Reaction of compound 1 with 2-aminochromone-3-carboxaldehydes produced 2-amino-3-(1H-benzimidazol-2-yl)chromeno[2,3-b]pyridines. The reaction mechanisms and spectral data were also discussed.

Design and synthesis of pyrido[3,2-α]carbazole derivatives and their analogues as potent antitumour agents

A series of pyrido[3,2-α]carbazole derivatives and their analogues have been prepared and evaluated for their antitumour activity against human lung cancer A549 cells and colon cancer HT29 cells. The intermediates 4a–4k are successfully synthesized from 1a–1k and ethyl 2-(3-bromopyridin-2-yl)acetate by Knoevenagel condensation and intramolecular Heck-type reaction, and this is a novel and efficient synthetic approach to the core scaffold of the target compounds. These target compounds have shown an interesting antitumour profile towards the tested cell lines with IC50 values ranging from 0.07 μM to 4.45 μM. Among all the compounds synthesized, 8 compounds show higher potency than R16, 12 compounds are as potent as R16, and 6 compounds are less potent than R16. The best compound 24 is 7 times and approximately 10 times as potent as R16 against A549 and HT29 cells, respectively.

Design, Synthesis, and Molecular Modeling of Novel Pyrido[2,3-d]pyrimidine Analogues As Antifolates; Application of Buchwald–Hartwig Aminations of Heterocycles

Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg), and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogues. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR.

Discovery of pyrido[2,3-d]pyrimidine-based inhibitors of HCV NS5A

Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional ‘E’ ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series.

One step synthesis of pyrido[1,2-a]benzimidazole derivatives of aryloxypyrazole and their antimicrobial evaluation

Abstract A new series of pyrido[1,2- a ]benzimidazole derivatives bearing the aryloxypyrazole nucleus have been synthesized by base-catalyzed cyclocondensation reaction through multi-component reaction (MCR) approach. All the synthesized compounds were investigated against a representative panel of pathogenic strains using broth microdilution minimum inhibitory concentration (MIC) method for their in vitro antimicrobial activity. Reviewing the data, majority of the compounds were found to be active against employed pathogens. SAR study explores that antimicrobial activity is strongly depends on the nature of the substituents at the ether linked aryl ring attached to the pyrazole unit, together with the substituent present on the C 5 of the benzimidazole unit.

Synthesis and antitumor activity of new pyrido[2,3-d]pyrimidine derivatives

New series of pyrido[2,3-d]pyrimidines such as; 5-(4-aryl-5-sulfanyl-4H-[1,2,4]triazol-3-yl) 1H,3H,8H-pyrido[2,3-d]pyrimidine-2,4,7-triones 6, 7; S-[3-(2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)-4-(4-substituted phenyl)-4H-[1,2,4]triazol-5-yl]-2-(4-phenylpiperazin-1-yl)ethanethioates 10, 11; 2,4,7-trioxo-N′-[(4-substituted piperazin-1-yl)acetyl]-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazides 13–16 and N′-arylidene-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazides 17–19 was synthesized through the reaction of the key intermediate 2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-5-carbohydrazide 3 with different reagents. The structures of the newly synthesized compounds were elucidated through microanalysis, IR, 1H NMR, 13C NMR, and mass spectroscopy. These compounds have been subjected to in vitro antitumor evaluation by bleomycin-dependant DNA damage assay. The most active antitumor compound 6 was selected for further in vivo evaluation of antineoplastic activity against Ehrlich ascites carcinoma in mice. It was observed that our target compound has a potent antitumor activity.

Synthesis and anticancer activity of some novel fused pyridine ring system

New series of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (7a,b) and thieno[2,3-b:4,5-b'] dipyridine (11a-c) were synthesized from 4-aryl-6-(4-chlorophenyl)-2-thioxo-1,2-dihydro pyridine-3-carbonitriles 4a,b via application of Thorpe-Zielger reaction. The novel target compounds were evaluated in vitro for their anticancer activity against human breast adenocarcinoma MCF-7 and colon carcinoma cell line (HCT 116). Most of the tested compounds exploited potent to moderate growth inhibitory activity, in particular compound 11d, which exhibited superior potency to the reference drug Doxorubicin (IC(50) = 5.95, 6.09 and 8.48, 8.15 μM, respectively). The structures of the compounds obtained were determined by spectroscopic data.

Pyrido[1,2-a]pyrimidin-4-ones as antiplasmodial falcipain-2 inhibitors

Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is a promising target for antimalarial chemotherapy and inhibition of this protease affects the growth of parasite adversely. A series of pyrido[1,2-a]pyrimidin-4-ones were synthesized and evaluated for their in vitro FP-2 inhibitory potential. Compounds (14,17) showed excellent FP-2 inhibition and can serve as lead compounds for further development of potent FP-2 inhibitors as potential antimalarial drugs.

ChemInform Abstract: A Clean and Efficient Cyclocondensation to Pyrido[2,3‐d]pyrimidine Derivatives in Aqueous Media.

Abstract A series of pyrido[2,3-d]pyrimidine derivatives were easily constructed by cyclocondensation reactions of 6-aminouracils or 6-aminothiouracil with α,β-unsaturated carbonyl compounds (aldehyde, ketone and ester) possessing a leaving group on the β position, in H2O under reflux conditions.

An Efficient Synthesis of Pyrido[2,3-<i>d</i>]pyrimidine Derivatives via One-Pot Three-Component Reaction in Aqueous Media

A series of pyrido[2,3-d]pyrimidines derivatives have been prepared by one-pot three-component reaction of 4(6)-aminouracil, malononitrile and aromatic aldehydes. This efficient synthesis was done under microwave irradiation conditions (method A) and also using catalytic amount of diammonium hydrogen phosphate [(NH4)2HPO4] (DAHP) in aqueous media (method B). This procedure has the advantages of good yields, easy work-up, and benign environmentally friendly character. Reaction could proceed via domino Knoevenagel-Michael-cyclization reactions.

Synthesis and Evaluation of Some Novel Benzothiazole Derivatives as Potential Anticancer and Antimicrobial Agents

Intensive efforts are underway worldwide to develop anticancer and antimicrobial agents. Therefore, a novel series of pyrido[2,1-b]benzo [d]thiazole and 2-(benzo [d] thiazol-2-ylamino)pyrimidine derivatives was synthesized. The synthesized compounds were evaluated for their anticancer activity. Among the tested compounds, compounds 3a, 3b, and 7 exhibited more cytotoxic action than the control drug doxorubicin (CAS 23214-92-8; IC50: 52 microg/ml). Compound 7 was the most potent cytotoxic, with an IC50 of 42.55 pg/ ml, while compounds 3a and 3b induced high cytotoxic action with IC50 values of 50.15 pg/ml and 50.45 pg/ml, respectively. Moreover, the synthesized compounds were screened for their antibacterial and antifungal activities. Compound 6 exhibited moderate antifungal activity against C. albicans with a minimum inhibitory concentration of 125 pg/ml.

Synthesis and biological activity of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine derivatives as novel and potent phosphodiesterase type 4 inhibitors

A series of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure–activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.

A clean and efficient cyclocondensation to pyrido[2,3-d]pyrimidine derivatives in aqueous media

Abstract A series of pyrido[2,3-d]pyrimidine derivatives were easily constructed by cyclocondensation reactions of 6-aminouracils or 6-aminothiouracil with α,β-unsaturated carbonyl compounds (aldehyde, ketone and ester) possessing a leaving group on the β position, in H2O under reflux conditions.

Selenium-containing heterocycles 3*. synthesis and reactions of selenolo- [2,3-b]pyridine derivatives and related fused tricyclic systems

A new series of pyrido[3',2':4,5]selenolo[3,2-d]pyrimidine derivatives is reported. The structures of the newly synthesized compounds were elucidated by elemental analyses and spectral data (IR, 1H and 13 C NMR, MS).

Design and synthesis of potent and selective aldose reductase inhibitors based on pyridylthiadiazine scaffold

A series of pyrido[2,3- e]-[1,2,4]-thiadiazine 1,1-dioxide acetic acid derivatives were synthesized and tested for their inhibitory activity against aldose reductase (ALR2). These derivatives were found to be potent aldose reductase inhibitors with IC 50 values ranging from 0.038 μM to 11.29 μM. Most but not all of them showed a strong ALR2 inhibition activity and significant selectivity, which were further supported by docking studies. Of these inhibitors, compound 7d exhibited highest inhibition activity. Structure–activity relationship studies indicate the requirement of N2-benzyl group with electron-withdrawing substituents and N4-acetic acid group in the pyridothiadiazine scaffold.

Synthesis and Biological Activity of Pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines as Phosphodiesterase Type 4 Inhibitors

A series of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (PTP) has been synthesized and tested as phosphodiesterase IV inhibitors (PDE4), a target for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, are presented. The gem-dimethylcycloalkyl moiety fused to the pyridine ring proved to be a key element of the scaffold in order to get a higher affinity in the enzyme.

One‐Pot Synthesis of Some New Pyrido[2,3‐d]pyrimidine Derivatives Catalyzed by Sodium Lauryl Sulfate in Aqueous Media

A series of pyrido[2,3‐d]pyrimidine derivatives were synthesized by the three‐component reaction of aromatic aldehyde, malononitrile and 6‐amino‐4‐hydroxy‐2‐mercaptopyrimidine catalyzed by sodium lauryl sulfate (SDS) in aqueous media. It was interesting that further aromatization took place automatically. This method provides several advantages such as easier work‐up, milder reaction conditions and environmental friendly.

Synthesis and Anti Cancer Activity of Pyrido(2,3-c)Pyridazine Derivatives

Cancer is not just one disease, but a large group of almost one hundred diseases. Its two main characteristics are uncontrolled growth of the cells in the human body and the ability of these cells to migrate from the original site and spread to distant sites. If the spread is not controlled, cancer can result in death. There has been continuous progress in the development of therapy for cancer. The successful treatment of cancer still remains a challenge. A new series of pyrido[2,3-c]pyridazine derivatives (8-14) were synthesized and screened for their anticancer activity. Amongst them few of the compounds have exhibited promising cytotoxicity along with good safety index. These compounds could be of use in designing new anti-cancer agents.

Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.