New Series Of Pyrimidine Derivatives Research Articles

Synthesis of new sulfapyrimidine and pyrazolo[1,5-a]pyrimidine derivatives

A series of new pyrimidine derivatives were synthesized, including sulfapyrimidines and pyrazolo[1,5-a]pyrimidines. In basic medium, pyrimidine compounds were produced by reacting sulfa guanidine with either 2-cyano-3-(dimethylamino)-N-acrylamides or N-(4-chlorophenyl)-2-cyano-3-(4-aryl)-acrylamides. The reaction of 5-amino-1H-pyrazole-4-carboxamides with either 2-cyano-3-(dimethylamino)-N-acrylamides or N-(4-chlorophenyl)-2-cyano-3-(4-aryl)acrylamides resulted in the synthesis of pyrazolo[1,5-a]pyrimidine compounds.

New Potential Antitumor Pyrimidine Derivatives: Synthesis and Cytotoxicity Evaluation

A new series of pyrimidine derivatives are reported here as antitumor agents such as pyrimidine carboxamide linked to thiophene, pyrazole, and thiazole moieties have been synthesized from the readily available (2-cyano-N-(5-cyano-2-phenyl-6-arylpyrimidin-4-yl)acetamide (6a,b). All the new compounds were screened for their antitumor activity in vitro against a panel of three human tumor cell lines namely, hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, and mammary gland breast MCF-7. Compounds 9b, 10b, 11b, and 19b displayed a significant therapeutic activity. All the synthesized new compounds were established their structures by means of spectroscopic analysis.

Synthesis and anticancer activity of some pyrimidine derivatives with aryl urea moieties as apoptosis-inducing agents

A new series of pyrimidine derivatives containing aryl urea moieties was designed and synthesized. The anticancer activities of all compounds were evaluated in vitro against colon and prostat cancer cell lines by MTT assay. Among these compounds, 4b exhibited the highest cytotoxic activity against SW480 cancer cell line with IC50 value of 11.08 µM. Mechanistic studies showed that compound 4b arrested cell cycle at G2/M phase and induced apoptosis through upregulating Bax, Ikb-α and cleaved PARP and downregulating Bcl-2 expression levels. Moreover, compound 4b induced loss of mitochondrial membrane potential in SW480 cells. These results suggest that pyrimidine with urea moieties could be a template for designing new anticancer agents.

Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells

A new series of pyrimidine derivatives as human carbonic anhydrases (CA, EC 4.2.1.1) inhibitors is here designed by including a 5-fluorouracil (5-FU) moiety, broadly used anticancer medication, in nitrogenous base modulators of the tumor-associated CAs. Most sulfonamide derivatives efficiently inhibit the target CA IX (KIs in the range 0.47–44.7 nM) and CA XII (KIs in the range 2.9–83.1 nM), while the 5-FU coumarin derivatives showed a potent and totally selective inhibitory action against the target CA IX/XII over off-target CA I/II. The X-ray solved crystal structure of CA II in adduct with a representative uracil derivative provided insights on the binding mode to the target of such pyrimidine derivatives. On the basis of potency and selectivity inhibition profiles, coumarin 12a, the sulfonamide CAIs showing the greatest II/IX specificity (4e, 6b and 6d) and the unique subnanomolar CA IX inhibitor 10a were tested in vitro for their antiproliferative action against a panel of eight cancer cell lines. The breast cancer cell lines MDA-MB-231 and T47D were the most susceptible with IC50 values in low to medium micromolar ranges (2.45 ± 0.07–18.86 ± 0.72 μM and 6.86 ± 0.31–40.92 ± 1.59 μM, respectively). A cell cycle analysis showed that 4e and 6d arrest T-47D cells mainly in the G2/M phase. Using an annexin V-FITC apoptosis assay, 4e and 6d were shown to induce an approximately 23.6-fold and 34.8-fold total increase in apoptosis compared to the control, corroborating the concrete potential of 5-FU CAIs for the design of new effective anticancer strategies.

Synthesis and Plant Growth Stimulating Action of 2-Amino-6-methylpyrimidine-4(3H)-thione Derivatives

A series of new pyrimidine derivatives, including those containing an azole or azine heterocycle linked through a sulfur atom or a thiomethylene group, was synthesized based on 2-amino-6-methylpyrimidine-4(3H)-thione. The synthesized compounds exhibited a pronounced stimulating effect on plants growth in the range of 43–96% compared to heteroauxin.

Eco‐friendly synthesis of novel pyrimidine derivatives as potential anticancer agents

AbstractHerein, a rapid and highly efficient method for the synthesis of a new series of pyrimidine derivatives was demonstrated. The strategy was emanated from the reaction of hydrazinyl pyrimidine derivative (1) with different electrophilic species such as ethyl acetoacetate, ethyl 4,4,4‐trifluoro acetoacetate, and phenyl isothiocyanate following cyclocondensation mechanism to afford the corresponding derivatives (2‐6). Furthermore, condensation of hydrazine derivative (1) with different carbonyl compounds via conventional heating and microwave irradiation conditions was employed as a source of Schiff base derivatives bearing pyrimidine moiety (7‐12). The structural features of all newly synthesized compounds were characterized by elemental and spectroscopic evidences. Some of the synthesized compounds were evaluated for in vitro cytotoxicity. The preliminary screening results showed that most of the tested compounds have moderate cytotoxic activity against HepG2 and HCT‐116 cell lines. Finally, a molecular docking study was conducted to reveal the probable interaction with the thymidylate synthase enzyme.

Luminescent non-traditional π-gels fabricated from pyrimidine derivatives bearing carbazole for the detection of acid vapors

A series of new pyrimidine derivatives modified with carbazole (CM, CMH, CMCl and CMBr) and tert-butyl carbazole (TCM, TCMH, TCMCl and TCMBr) were synthesized. It was found that CM, CMCl, CMBr, TCM, TCMCl and TCMBr without traditional gelation groups could self-assemble into organogels with intense emission. It was found that V-shaped π-conjugated skeleton and π-π interactions were essential for the organogelation. It was interesting that the organogels could be destroyed by adding TFA (trifluoroacetic acid), accompanied with the quenching of the emission on account of the protonation of pyrimidine unit. In particular, the xerogel-based film of TCM emitting strong bluish green light could be used as fluorescent sensor to detect TFA vapor with the decay time and detection limit of 0.6 s and 95 ppb, respectively. Such high performance of the xerogel-based film in fluorescent responsive ability was originated from the high surface-to-volume ratios of nanomaterials and the large space in 3D networks, which were favorable for the adsorption and diffusion of the analytes. We provided new strategy for the design of non-traditional π-gelators and the fabrication of fluorescent sensory materials with high performance to detect gaseous analytes.

Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists

The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78–90%). In the second series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77–84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10−15–10−9M) significantly increased insulin secretion compared to that of the control cells in both the absence and presence of 2.8mM glucose; compound 8b only demonstrated significance in the absence of glucose. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally.

Antibacterial activity and mechanism of action of the benzazole acrylonitrile-based compounds: In vitro, spectroscopic, and docking studies

A new series of pyrimidine derivatives 5, 9a-d and 12a-d was synthesized by an efficient procedure. The antibacterial activity of the new compounds was studied against four bacterial strains. Compound 5 was found to exhibit the highest potency, with = 1.0 μg/ml, against both Escherichia coli and Pseudomonas aeruginosa when compared with amoxicillin (MIC = 1.0–1.5 μg/mL). Transmission electron microscope results confirmed that activities against bacteria occurred via rupturing of the cell wall. Molecular modeling results suggested that compounds 5, 9a-d and 12a-d have the potential to irreversibly bind to the penicillin-binding protein (PBP) Ser62 residue in the active site and were able to overcome amoxicillin resistance in bacteria by inhibiting the β-lactamase enzyme. Docking studies showed that compounds 5, 9a-d and 12a-d inhibit the β-lactamase enzyme through covalent bonding with Ser70. The synergistic effect with amoxicillin was studied. The newly synthesized compounds reported in this study warrant further consideration as prospective antimicrobial agents.

Synthesis of a new series of pyrimidine derivatives: exploration of anti-proliferative activity on EAT cells and molecular docking

A new series of pyrimidine derivatives was designed and synthesized from 2-thiouracil via multicomponent, Biginelli-type reactions and structurally characterized by all spectral means. Synthesized compounds were evaluated for antiproliferative activity against Ehrlich ascites tumour (EAT) cells. A molecular docking study was carried out to establish the binding mode of these compounds into human casein kinase-2 inhibitor (CK2). The established binding modes of these compounds into human CK2 were in very good agreement with the in vitro antiproliferative activity. Compound 4-(2-(1H-indol-2-yl)ethylamino)-2-(2-(diethylamino)ethylthio)-6-(4-fluorophenyl)pyrimidine-5-carbonitrile 4h exhibited stronger cytotoxic activity against EAT cells with an IC50 value of 5.2 µM which was the nearest cytotoxic activity compared with the standard drug methotrexate (MTX) that showed an IC50 value of 3.6 µM. Compound 4h has the maximum cytotoxicity against EAT cell, the lowest binding energy (−8.7 kcal/mol) and good ligand efficiency with CK2 compared to all other compounds.

A concise Pd catalyzed cross coupling reaction along with deprotection for the synthesis of a new series of pyrimidine derivatives

A new series of 2-amino, 4-azepanone, 5-aryl substituted derivatives of pyrimidine compounds were synthesized for the first time from the commercially available 2-amino-4-hydroxypyrimidine. The key step in the reaction is a conceptually new single step palladium catalyzed cross coupling along with the deprotection of N,N-diisopropylformimidamide using bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2).

Abstract A284: Anaplastic lymphoma kinase (ALK) inhibitors for cancer treatment.

Abstract Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, has been recently elucidated as a potential target for various cancers due to its implications of tumorigenesis by ALK gene mutations, overexpressions, and amplifications. ALK was first identified in 1994 as a part of nucleophosmin NPM-ALK fusion gene in 60% of anaplastic large-cell lymphoma (ALCL). In late 2007, EML4-ALK fusion gene was found in 3∼7% of non-small cell lung cancer (NSCLC), and a kind of ALK fusion genes are found one by one in various cancers such as DLBCL, inflammatory myofiblastic tumor (IMT), plasmacytoma, esophageal cancer, and ovarian cancer. More over mutated ALK is much implicated in neuroblastoma and thyroid carcinoma. Crizotinib (Xalkori) was the first small molecule inhibitor which was approved as a treatment of NSCLC including ALK fusion gene by FDA in 2011. Crizotinib, a potent inhibitor of both c-Met and ALK tyrosine kinases is a 3-benzyloxy-2-aminopyridine derivative derived from c-Met inhibitors and surprisingly its overall clinical benefit was 57 %. However, its clinical efficacy is limited by drug-resistance mutations, particularly the gatekeeper L1196M mutation. Unlike their aminopyridine-based core scaffold, a pyrimidine-based inhibitor has been identified for the ALK-related inhibition and shown a potent activity to EML4-ALK wild type and other mutants including EML4-ALK L1196M. In this paper, we designed and synthesized a new series of pyrimidine derivatives to discover a new ALK inhibitor which is well-matched with crizotinib and LDK378 in docking study. KRCA-0008 has been identified as a highly potent and selective ALK inhibitor with potency profiles (ALK wt, IC50=12 nM). It has excellent activities both ALK mutants (L1196M, C1156Y, F1174L, R1275Q) and BaF3 ALK L1196M cell line. PK profiles were excellent and KRCA-0008 was safe in Ames test, chromosomal aberration assay, micronucleus asssay, and acute toxicity. Also, we observed KRCA-0008 is chemically and metabolically very stable and no CYP and hERG inhibitions. In vivo xenograft mouse model (H3122 NSCLC) model study, KRCA-0008 shows moderate tumor growth inhibition without significant body weight change. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A284. Citation Format: Kwangho Lee, Hyoung Rae Kim, Sung Yun Cho, Hee Jung Jung, Jae Du Ha, Chang-Soo Yun, Pilho Kim, Chi Hoon Park, Chong Ock Lee. Anaplastic lymphoma kinase (ALK) inhibitors for cancer treatment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A284.

New Pyrimidine Derivatives possessing ALK Inhibitory Activities

Anaplastic lymphoma kinase (ALK), a family of tyrosine kinases has been recently elucidated as a potential target for various cancers due to its implications of tumorigenesis by ALK gene mutations, overexpressions, and amplifications. ALK was first identified in 1994 as a part of nucleophosmin NPM-ALK fusion gene in 60% of anaplastic large-cell lymphoma (ALCL), in late 2007 EML4-ALK fusion gene was found in 3-7% of non-small cell lung cancer, and a kind of ALK fusion genes are found one by one in various cancers such as DLBCL, inflammatory myofibroblastic tumor (IMT), plasmacytoma, esophageal cancer, renal cell carcinoma, breast cancer, colon cancer, and ovarian cancer. Moreover mutated ALK is much implicated in neuroblastoma and thyroid carcinoma. Crizotinib (Xalkori) was the first small molecule inhibitor which was approved as a treatment of NSCLC including ALK fusion gene by FDA in 2011. Crizotinib, a potent inhibitor of both c-Met and ALK tyrosine kinases is a 3-benzyloxy-2-aminopyridine derivative derived from c-Met inhibitors and surprisingly its overall clinical benefit was 87%. Many pharmaceutical companies have been looking forward to finding better ALK inhibitors and among them, CH-5424802 by Chugai Pharm., LDK378 by Novartis/GNF, and AZD-3463 by Astrazeneca are showing excellent progress. 2-Aminopyrimidine derivatives have been massively studied as various kinase inhibitors such as for ALK, EGFR, Aurora kinase, JAK, CK1, LRR2, etc. Especially, imatinib and nilotinib for BCR-ABL, dasatinib for BCR-ABL/Src/c-Kit/etc., fostamatinib for Syk, and pazopanib for VEGFR2/PDGFR/c-Kit had approved as new chemical entities by US FDA. We designed a new series of pyrimidine derivatives to discover a new ALK inhibitor, and among them 4-{4-(piperazin-1-)yl-2-methoxy-phenyl}amino-2-(methoxy-substitutedphenyl)aminopyrimidines were well-matched with crizotinib and LDK378 in docking study. We synthesized those pyrimidine derivatives and evaluated ALK inhibitory activities. 5-Substituted-2,4-dichloropyrimidine 1 (X=F, Cl) was reacted with 4-(N-acetylpiperazin-1-yl)-2-methoxyaniline 2 in DMF at 80 C overnight to predominantly afford 4-substituted-pyrimidine 3 in good yield and it was reacted with various methoxyanilines in 0.08 M HCl solution of ethoxyethanol at 110 C overnight to afford 5 in moderate to good yields (Scheme 1). In case of 2,4-dichloro-5-trifluoromethylpyrimidine, reaction of 6 with aniline (2) in the presence of base in DMF gave a mixture of 2-substituted and 4-substituted pyrimidines with a trace of 2,4-disubstituted pyrimidine, and the regioisomers could hardly been separated by TLC. Fortunately, 6 reacted with 4-(N-Boc-piperazin-1-yl)-2-methoxyaniline 7 in the presence of diisopropylethylamine as a base at room

Synthesis of some new pyrimidine derivatives and evaluation of their anticancer and antibacterial activities

Starting from the reaction of ethyl cyanoacetate with thiourea and the appropriate aldehydes, a series of new pyrimidine derivatives were prepared. Ten selected pyrimidine derivatives were subjected to a screening system for the investigation of their antitumor potency against liver (HEPG2) cell line. The antitumor activity results indicated that most of the selected pyrimidine derivatives showed moderate growth inhibition activity against the tested cell line, but with varying intensities in comparison to the known anticancer drugs: 5-fluorouracil and doxorubicin. Some of the synthesized compounds were also tested for their antimicrobial activity against bacteria as well as fungal isolates.

Synthesis and Antifungal Activities of Some Novel Pyrimidine Derivatives

Three series of new pyrimidine derivatives were synthesized and their antifungal activities were evaluated in vitro against fourteen phytopathogenic fungi. The results indicated that most of the synthesized compounds possessed fungicidal activities and some of them are more potent than the control fungicides. Preliminary SAR was also discussed.

Synthesis and Evaluation of 5‐HT2A and 5‐HT2C Receptor Binding Affinities of Novel Pyrimidine Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and evaluation of 5-HT 2A and 5-HT 2C receptor binding affinities of novel pyrimidine derivatives

In an effort to find potential anxiolytic and/or antipsychotic agents with selective 5-HT 2C affinity a series of new pyrimidine derivatives was prepared and the binding affinities for 5-HT 2A and 5-HT 2C receptors were determined.