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Bioorganic & Medicinal Chemistry Letters Sep 2013A series of substituted aryl pyrimidine derivatives was synthesized and evaluated in vitro for their antileishmanial potential against intracellular amastigotes of...
A series of substituted aryl pyrimidine derivatives was synthesized and evaluated in vitro for their antileishmanial potential against intracellular amastigotes of Leishmania donovani using reporter gene luciferase assay. Among all, 8 compounds showed promising IC50 values ranging from 0.5 to 12.9 μM. Selectivity indices (S.I.) of all these compounds are far better than reference drugs, sodium stibogluconate (SSG) and miltefosine. On the basis of good S.I., compounds were further screened for their in vivo antileishmanial activity against L. donovani/hamster model. Compounds 2d, 4a and 4b have shown significant inhibition of parasitic multiplication that is 88.4%, 78.1% and 78.2%, respectively at a daily dose of 50 mg/kg × 5 days, when administered intraperitoneally. Compound 2d is most promising one, which may provide a new lead that could be exploited as a new antileishmanial agent.
Topics: Antiprotozoal Agents; Dose-Response Relationship, Drug; Drug Design; Leishmania donovani; Molecular Structure; Parasitic Sensitivity Tests; Pyrimidines; Structure-Activity Relationship
PubMed: 23910597
DOI: 10.1016/j.bmcl.2013.06.060 -
Journal of Enzyme Inhibition and... Dec 2007Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title...
Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.
Topics: Antineoplastic Agents; Azepines; Cell Line, Tumor; Cell Proliferation; Humans; Molecular Structure; Pyrimidines; Structure-Activity Relationship
PubMed: 18237024
DOI: 10.1080/14756360701306073 -
Scientific Reports Jan 2024Hybrid molecules maintain their stronghold in the drug market, with over 60% of drug candidates in pharmaceutical industries. The substantial expenses for developing and...
Hybrid molecules maintain their stronghold in the drug market, with over 60% of drug candidates in pharmaceutical industries. The substantial expenses for developing and producing biologically privileged drugs are expected to create opportunities for producing hybrid molecule-based drugs. Therefore, we have developed a simple and efficient copper-catalyzed approach for synthesizing a wide range of triazole-linked glycohybrids derived from pyrazolo[1,5-a]pyrimidines. Employing a microwave-assisted copper-catalyzed approach, we developed a concise route using various 7-O-propargylated pyrazolo[1,5-a]pyrimidines and 1-azidoglycosides. This strategy afforded a series of twenty-seven glycohybrids up to 98% yield with diverse stereochemistry. All were achieved within a remarkably shortened time frame. Our investigation extends to evaluating the anticancer potential of these synthesized triazole-linked pyrazolo[1,5-a] pyrimidine-based glycohybrids. In-vitro assays against MCF-7, MDA-MB231, and MDA-MB453 cell lines reveal intriguing findings. (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(((5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate emerges as a standout with better anticancer activity against MDA-MB231 cells (IC = 29.1 µM), while (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-(((5-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate demonstrates the best inhibitory effects against MCF-7 cells (IC = 15.3 µM) in all derived compounds. These results align with our docking analysis and structure-activity relationship (SAR) investigations, further validating the in-vitro outcomes. This work not only underscores the synthetic utility of our devised protocol but also highlights the promising potential of these glycohybrids as candidates for further anticancer therapeutic exploration.
Topics: Humans; Copper; Triazoles; Pyrimidines; Structure-Activity Relationship; MCF-7 Cells; Pyrans; Catalysis; Antineoplastic Agents; Molecular Structure; Drug Screening Assays, Antitumor
PubMed: 38177184
DOI: 10.1038/s41598-023-50202-4 -
Carbohydrate Research Oct 2013The synthesis of a set of pyrimidine-fused derivatives (L1-L8), resulting from the incorporation of different fragments on the pyrimidine-fused heterocycle (PFH) of the...
The synthesis of a set of pyrimidine-fused derivatives (L1-L8), resulting from the incorporation of different fragments on the pyrimidine-fused heterocycle (PFH) of the earlier reported α-glucosidase (α-Gls) inhibitor (C1-C5), allowed the discovery of new ligands with modest and selective inhibitory activity. The PFH core (substructure 2) was proved to play a significant role in their inhibitory properties. Additionally, the substituent on substructures 1 and 3 of the heterocyclic ring was demonstrated to be important in the enzyme inhibitory action of the pyrimidine-fused derivatives. Moreover, these ligands show selective inhibitory properties for α-Gls over porcine pancreatic α-amylase (α-Amy) which is important in terms of their reduced susceptibility for the possible development of intestinal disturbance side effects. Therefore, low to moderate α-Amy inhibition with effective α-Gls inhibitory action may offer a better therapeutic strategy. Overall, these compounds can potentially offer a new opportunity to develop novel antidiabetic drugs with selective inhibitory action against α-Gls.
Topics: Animals; Chemistry Techniques, Synthetic; Glycoside Hydrolase Inhibitors; Hypoglycemic Agents; Ligands; Mice; Models, Molecular; Protein Structure, Secondary; Pyrimidines; Saccharomyces cerevisiae; Swine; alpha-Amylases; alpha-Glucosidases
PubMed: 23978663
DOI: 10.1016/j.carres.2013.07.008 -
Nucleosides, Nucleotides & Nucleic Acids 2002The chemical synthesis of some acyclic alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides (10-12)a-c is described. The treatment of...
The chemical synthesis of some acyclic alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylamide nucleosides (10-12)a-c is described. The treatment of IH-pyrazolo[3,4-d]pyrimidin-4-thione 1 with compounds 2a-c gave, regioselectively, ethyl alpha-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)thioalkylates 3a-c, respectively. These heterocycles were alkylated, separately, with alkylating agents 4, 5 and 6 to give, regioselectively, the N1-acyclic nucleosides (7-9)a-c which were deprotected to afford the desired products (10-12)a-c. All synthetic compounds were characterized on the basis of their physical and spectroscopic properties. The products (10-12)a-c were evaluated for their inhibitory effects against the replication of HIV-1 (III(B)), HIV-2 (ROD), various DNA viruses, a variety of tumor-cell lines and M. tuberculosis. No marked biological activity was found.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Drug Screening Assays, Antitumor; Microbial Sensitivity Tests; Nucleosides; Pyrazoles; Pyrimidines; Tumor Cells, Cultured; Vero Cells
PubMed: 11991143
DOI: 10.1081/NCN-120003180 -
Bioorganic & Medicinal Chemistry Letters Mar 2010The synthesis of a novel series of pyrimidin-4-yl-1H-imidazol-2-yl derivatives 7, 8, 9 and their antiproliferative activities against A375P human melanoma cell line and...
The synthesis of a novel series of pyrimidin-4-yl-1H-imidazol-2-yl derivatives 7, 8, 9 and their antiproliferative activities against A375P human melanoma cell line and WM3629 cell line were described. Most compounds showed superior antiproliferative activities compared to Sorafenib, the well-known RAF inhibitor. Among them, 7a exhibited potent activities on both cell lines (IC(50)=0.62 and 4.49muM, respectively) and turned out to be a selective and potent CRAF inhibitor.
Topics: Antineoplastic Agents; Benzenesulfonates; Binding Sites; Cell Line, Tumor; Crystallography, X-Ray; Drug Discovery; Humans; Imidazoles; Melanoma; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-raf; Pyridines; Pyrimidines; Sorafenib; Structure-Activity Relationship
PubMed: 20149658
DOI: 10.1016/j.bmcl.2010.01.064 -
European Journal of Medicinal Chemistry Aug 2013Some novel pyrimidine-5-carbonitrile derivatives bearing various substituent have been synthesized. The structures of target compounds were confirmed by elemental...
Some novel pyrimidine-5-carbonitrile derivatives bearing various substituent have been synthesized. The structures of target compounds were confirmed by elemental analysis and spectral data. Some selected members of the newly synthesized compounds were investigated for their cytotoxic potency against certain human tumor cell lines. Five representative active anticancer compounds 6a, 6c, 6d, 17a and 18a were subjected to docking using MOE program on the 3D structure of two enzymes, namely; thymidylate synthase and dihydrofolate reductase. The antimicrobial activities of the synthesized compounds were tested against Staphylococcus aureus, Pseudomonas aeruginosa, Shigella flexneri and Candida albicans. Compounds 2c, 7a and 9c showed broad spectrum antimicrobial activity.
Topics: Anti-Infective Agents; Antineoplastic Agents; Bacteria; Candida albicans; Catalytic Domain; Cell Line, Tumor; Chemistry Techniques, Synthetic; Humans; Molecular Docking Simulation; Pyrimidines; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase
PubMed: 23811090
DOI: 10.1016/j.ejmech.2013.05.028 -
The Journal of Organic Chemistry Feb 2006A convenient and efficient synthesis of highly functionalized dihydropyrido[2,3-d]pyrimidines via a double [5 + 1] annulation strategy starting from easily available...
A convenient and efficient synthesis of highly functionalized dihydropyrido[2,3-d]pyrimidines via a double [5 + 1] annulation strategy starting from easily available alpha-alkenoyl-alpha-carbamoyl ketene-(S,S)-acetals 1 and cheap reagents (NH4OAc, DMF, and POCl3) has been developed. In the first step of the double annulation route, 2-amino-3-carbamoyl-5,6-dihydro-4-pyridones 2 were created in high to excellent yields by a formal [5C + 1N] annulation reaction of ketene-(S,S)-acetals 1 with ammonia (from ammonium acetate). In the second step of the double annulation strategy, the highly functionalized dihydropyrido[2,3-d]pyrimidine derivatives, 7,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-ones 3 (when R1 = aryl) and 7,8-dihydropyrido[2,3-d]pyrimidines 4 (when R1 = H), were constructed, respectively, in fair to good yields by reacting 2 with excessive Vilsmeier reagent (DMF/POCl3). A mechanism involved in the second [5 + 1] annulation step, including a formal [5 + 1] annulation and accompanied chlorovinylation, chloroformylation, amination, and aromatization reactions, is proposed.
Topics: Acetals; Alkenes; Ethylenes; Hydrogen; Ketones; Molecular Structure; Pyrimidines
PubMed: 16438526
DOI: 10.1021/jo0522106 -
Drug Design, Development and Therapy 2019Tyrosinase (EC 1.14.18.1) is responsible for enzymatic browning in fruits and vegetables. Its inhibitors may be applied to efficiently treat hyperpigmentation and are...
BACKGROUND AND AIM
Tyrosinase (EC 1.14.18.1) is responsible for enzymatic browning in fruits and vegetables. Its inhibitors may be applied to efficiently treat hyperpigmentation and are widely used in pharmaceutical and cosmetic products, food supplements and insecticides. Previous studies have shown that heterocyclic compounds with an amino group can inhibit tyrosinase activity. The present study aims to evaluate the inhibitory effect of some novel 2,6-diamino-4-chloropyrimidine derivatives (1a-e) and 2,4,6-triaminopyrimidine (2a-e) including bioactive aniline moiety on the activity of the mushroom tyrosinase.
METHODS
In practice, the azo salt was initially synthesized from aniline derivatives and combined subsequently with the 2,4,6-triaminopyrimidine and 2,6-diamino-4 chloropyrimidine followed by crystallization. The structures of resulting compounds were confirmed by FT-IR, C NMR, and H NMR. The derivatives (0-100 µM) were evaluated for their inhibitory effect on tyrosinase activity using l-3,4-dihydroxyphenylalanine (l-DOPA) as substrate.
RESULTS
All compounds showed inhibitory effects against the activity of the enzyme. About 23.72-55.08% inhibition was observed in the presence of 30 µM of each compound. The IC values of the synthesized compounds were measured, and their inhibition properties were also visualized by zymography. Based on the results, the compounds 1a-e and 2a-e showed moderate inhibitory activities. Notably, pyrimidine derivatives 1a (IC=24.68) and 1d (IC=24.45) also exhibited similar inhibitory activities when compared with the positive control, kojic acid (IC=25.24 µM). Kinetic studies indicated that the type of inhibition was noncompetitive.
CONCLUSION
All results suggest that pyrimidine derivatives, especially 1d and 1a, can be considered as safe and efficient tyrosinase inhibitors.
Topics: Agaricales; Dose-Response Relationship, Drug; Enzyme Inhibitors; Molecular Docking Simulation; Molecular Structure; Monophenol Monooxygenase; Pyrimidines; Structure-Activity Relationship
PubMed: 31371919
DOI: 10.2147/DDDT.S209324 -
Journal of Mass Spectrometry : JMS Jun 2009Electrospray ionization mass spectrometry/mass spectrometry (ESI/MS/MS) and multiple stage mass spectrometry (MSn, n > 2) were used in the positive ion mode, with two...
Electrospray ionization mass spectrometry/mass spectrometry (ESI/MS/MS) and multiple stage mass spectrometry (MSn, n > 2) were used in the positive ion mode, with two different types of mass spectrometers, a quadrupole time-of-flight and an ion trap, to characterize two sets of different types of C60-aminopyrimidine exohedral derivatives. In one set, the pyrimidine moiety bears an amino acid methyl ester residue, and in the other the pyrimidine ring is part of a nucleoside-type moiety, the latter existing as two separated diastereoisomers.We have found that retro-cycloaddition processes occur for the closed shell protonated species formed by electrospraying C60 derivatives synthesized by Diels-Alder reactions, whereas for the C60 derivatives synthesized via 1,3-dipolar cycloadditions, these processes did not occur. Formation of diagnostic ions allowed the differentiation between the two groups of fullerene derivatives, and between the diastereoisomers of C60 derivatives with a nucleoside-type moiety. In general, the fragmentation processes are strongly dependent on the protonation sites and on the structure of the exohedral moieties.
Topics: Formic Acid Esters; Fullerenes; Molecular Structure; Protons; Pyrimidines; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 19194997
DOI: 10.1002/jms.1564