Search

In this study, novel phthalonitrile 3 and their corresponding metal-free 4 and metallophthalocyanine derivatives 5–7 bearing 2-isopropenyl-4-methoxy-1-methylbenzene groups were synthesized and characterized. 3,4-Dihydropyrimidinones have been synthesized by a modified Biginelli-type reaction with various metallophthalocyanines 5–7 as catalysts. Compared to the classical Biginielli reaction, the new method has the advantages of good yield and short reaction time. Among the various metallophthalocyanines studied, cobalt (II)-phthalocyanine was found to be most active for this transformation. The newly prepared compounds were characterized using elemental analyses, MS, IR, 1H/13C-NMR and UV-Vis spectroscopy. In addition; the 3,4-dihydropyrimidinones (DHPMs) 8–12 were investigated for antimicrobial activities and revealed good activity. The minimum inhibitory concentration (MIC) was determined by the microdilution technique in Mueller-Hinton broth. The MICs were recorded after 24 hours of incubation at 37 °C. These results are promising, showing these compounds are biologically active.

In this study, new derivatives of pyrazole, isoxazole, pyrazolylthiazole, and azolopyrimidine having a thiophene ring were synthesized under microwave irradiation. Their pharmacological activity toward bacteria and fungi inhibition was screened and compared to the references Chloramphenicol and Trimethoprim/sulphamethoxazole. The antimicrobial results of the investigated compounds revealed promising results and some derivatives have activities similar to the references used.

Herein we designed and synthesized three series of novel 8-morpholinoimidazo[1,2-a]pyrazine derivatives bearing phenylpyridine/phenylpyrimidine-carboxamides (compounds 12a–g, 13a–g and 14a–g). All the compounds were evaluated for their IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Most of the target compounds exhibited moderate cytotoxicity against the three cancer cell lines. Two selected compounds 14b, 14c were further tested for their activity against PI3Kα kinase, and the results indicated that compound 14c showed inhibitory activity against PI3Kα kinase with an IC50 value of 1.25 μM. Structure-activity relationships (SARs) and pharmacological results indicated that the replacement of the thiopyranopyrimidine with an imidazopyrazine was beneficial for the activity and the position of aryl group has a significant influence to the activity of these compounds. The compounds 13a–g in which an aryl group substituted at the C-4 position of the pyridine ring were more active than 12a–g substituted at the C-5 position. Moreover, the cytotoxicity of compounds 14a–g bearing phenylpyrimidine-carboxamides was better than that of the compounds 12a–g, 13a–g bearing phenylpyridine-carboxamides. Furthermore, the substituents on the benzene ring also had a significant impact on the cytotoxicity and the pharmacological results showed that electron donating groups were beneficial to the cytotoxicity.

Due to the innate ability of bacteria to develop resistance to available antibiotics, there is a critical need to develop new agents to treat more resilient strains. As a continuation of our research in this area, we have synthesized a series of racemic 2,4-diaminopyrimidine-based drug candidates, and evaluated them against Bacillus anthracis. The structures are comprised of a 2,4-diaminopyrimidine ring, a 3,4-dimethoxybenzyl ring, and an N-acryloyl-substituted 1,2-dihydrophthalazine ring. Various changes were made at the C1 stereocenter of the dihydrophthalazine moiety in the structure, and the biological activity was assessed by measurement of the MIC and K(i) values to identify the most potent drug candidate.

Novel 4-(4-substituted phenyl)-5-(3,4,5-trimethoxy/3,4-dimethoxy)-benzoyl-3,4-dihydropyrimidine-2(1H)-one/thione derivatives (DHP 1–9) were designed, synthesized, characterized and evaluated for antitumor activity against cancer stem cells. The compounds were synthesized in one pot. Enaminones E1 and E2 were reacted with substituted benzaldehydes and urea/thiourea in the presence of glacial acetic acid. The synthesized compounds were characterized by spectral analysis. The compounds were screened in vitro against colon cancer cell line (LOVO) colon cancer stem cells. Most of the compounds were found to be active against side population cancer stem cells with an inhibition of >50% at a 10 μM concentration. Compounds DHP-1, DHP-7 and DHP-9 were found to be inactive. Compound DHP-5 exhibited an in vitro anti-proliferative effect and arrested cancer cells at the Gap 2 phase (G2) checkpoint and demonstrated an inhibitory effect on tumor growth for a LOVO xenograft in a nude mouse experiment.

This study deals with a new and efficient metal-free regioselective synthesis of pyrimido-fused indazoles with nitrogen ring junction motifs. We have developed a metal-free domino type reaction between 3-aminoindazole, aryl aldehydes and aceotophenones in the presence of KOH/DMF that leads to pyrimido[1,2-b]indazole analogues. Response Surface Methodology (RSM) coupled with a Box-Behnken design (BBD) were utilized for exploring the effect of base used (A), temperature of reaction (B) and (C), reaction time. This approach can allow access to a variety of pyrimidoindazole fluorophores and related compounds. The compound N,N-dimethyl-4-(2-phenylpyrimido[1,2-b]indazol-4-yl)aniline (4e) displays the maximum fluorescence intensity at 518 nm and shows a fluorescence quantum yield of 0.068. The synthesized pyramido-fused indazoles have been evaluated for their free radical scavenging activity and compound 4f showed good antioxidant activity.

A new series of fused triazolo- and tetrazolopyrimidine derivatives 2–14 were synthesized and their anti-inflammatory and ulcerogenic activities were evaluated. The pharmacological screening showed that many of these obtained compounds have good anti-inflammatory activities, comparable to the reference drug. The toxicity of the compounds was also assayed via the determination of their LD50 values. The structures of newly synthesized compounds were confirmed by IR, 1H-NMR, MS spectral data and elemental analysis.

2-Amino-4,5-di-(2-furyl)furan-3-carbonitrile (1) reacted with triethyl orthoacetate to afford the corresponding 2-ethoxyimine derivative (2). The latter compound reacted with phenyl hydrazine, p-fluorobenzylamine and sodium hydrogen sulfide, respectively, to afford the corresponding furo[2,3-d]pyrimidine derivatives (3-5). Compound 1 also reacted with carbon disulfide and phenyl isocyanate to afford 5,6-di-(2-furyl)-1H-4H-furo[2,3-d]-[1,3-thiazin]-4-imino-2-thione (6) and 5,6-di-(2-furyl)-1H-3H-3-phenylfuro[2,3-d]pyrimidin-4-imine-2-one (7), respectively. Treatment of compound 2 with hydrazine hydrate at 0oC afforded compound 8, while on boiling 5,6-di-(2-furyl)-3H,4H-4-imino-2-methylfuro-[2,3-d]pyrimidin-3-amine (9) was isolated. Treatment of 9 with carbon disulfide, cyanogen bromide, ethyl cyanoacetate, diethyloxalate and triethyl orthoformate gave the corresponding furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines (10-14). Reaction of 9 with isatin and N-acetyl isatin gave the condensation products 15 and 16 respectively.

A novel series of 1,3,4-thiadiazoles, 5-arylazothiazoles and hexahydropyrimido-[4,5-d][1,2,4]triazolo[4,3-a]pyrimidines were synthesized via reaction of hydrazonoyl halides with each of alkyl carbothioates, carbothioamides and 7-thioxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidine-2,4(1H,3H)-diones in the presence of triethylamine. The structures of the newly synthesized compounds were established based on their spectral data, elemental analyses and alternative synthetic routes whenever possible. Also, the newly synthesized compounds were screened for their antimicrobial activity against various microorganisms.

Fatty Acid Amide Hydrolase (FAAH) is an intracellular serine enzyme involved in the biological degradation of the fatty acid ethanolamide family of signaling lipids, which exerts neuroprotective, anti-inflammatory, and analgesic properties. In the present study, a conjugated 2,4-dioxo-pyrimidine-1-carboxamide scaffold was confirmed as a novel template for FAAH inhibitors, based on which, a series of analogues had been prepared for an initial structure-activity relationship (SAR) study. Most of the synthesized compounds displayed moderate to significant FAAH inhibitory potency. Among them, compounds 11 and 14 showed better activity than others, with IC50 values of 21 and 53 nM. SAR analysis indicated that 2,4-dioxopyrimidine-1-carboxamides represented a novel class of potent inhibitors of FAAH, and substitution at the uracil ring or replacement of the N-terminal group might favor the inhibitory potency. Selected compounds of this class may be used as useful parent molecules for further investigation.

Salicylidene acylhydrazides are inhibitors of type III secretion in several Gram-negative pathogens. To further develop the salicylidene acylhydrazides, scaffold hopping was applied to replace the core fragment of the compounds. The novel 2-(2-amino-pyrimidine)-2,2-difluoroethanol scaffold was identified as a possible analog to the salicylidene acylhydrazide core structure. The synthesis of a library of 2-(2-amino-pyrimidine)-2,2-difluoro-ethanols is described in this paper.

Two novel organic–inorganic compounds based on tetrahexylammonium (THA) and tetraheptylammonium (THPA) ions and the Preyssler anion, [NaP5W30O110]14-, were synthesized and formulated as (THA)7.7H6.3 [NaP5W30O110] (A) and (THPA)7.5 H6.5[N aP5W30O110] (B). The synthesized compounds were characterized by IR, UV, and TGA and used for the catalytic synthesis of 4-aminopyrazolo[3,4,-d]pyrimidine derivatives 2a-2d. Our findings showed efficient catalytic activities for A and B.

The synthetic route for introduction of fluorophenylalkyl (compounds 5, 7, 14 and 15) and fluorophenylalkenyl (compounds 4E and 13) side chains at C-6 of the pyrimidine nucleus involved the lithiation of the pyrimidine derivatives 1, 2 and 11 and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with 2-fluorophenylacetone, 4-fluoroacetophenone or ethyl 4-fluorobenzoate as electrophiles. The structures of novel compounds were confirmed by (1)H-, (19)F- and (13)C-NMR and MS. Compounds 8 and 10 containing unsaturated fluorophenylalkyl side chains showed better inhibitory effect than their saturated fluorophenylalkylated pyrimidine counterparts 7 and 9. A conformational study based on NOE enhancements showed the importance of the double bond and substitution in the side chain for the conformational preferences in relation to inhibitory activity. Among all tested compounds, C-5 furyl (12) and phenyl (13 and 15) substituted pyrimidine derivatives showed significant cytostatic activities against all tested tumor cell lines.

A fast, general, environmentally friendly and facile method for preparation of five- and six-membered ring diazaheterocylic salts under microwave irradiation is presented. The N-alkylation reactions of imidazole, pyrimidine, pyridazine and phthalazine have been studied. The microwaves remarkably accelerated these N-alkylations, the reaction times decreased dramatically, the reaction conditions were milder, the consumed energy decreased considerably and the amount of solvents used was reduced substantially. Consequently, the microwave assisted alkylation of N-containing heterocycles could be considered eco-friendly. In some cases, under MW irradiation the yields are also higher. A comparative study of microwave vs. classical conditions (liquid solvents) has been done. Twelve new diazaheterocylic salts of potential practical interest were obtained.

A.B.A. El-Gazzar and N.A. Hassan *Photochemistry Department, National Research Center, Cairo, EgyptF ax: 002-02-3370931 , E-mail: nasserabdelhamid@hotmail.comReceived : 2 August 1999 ; revised form 6 June 2000 / Accepted : 13 June 2000 / Published : 25 June 2000Abstract: Reaction of 2-hydrazino-3-methyl-3,4-dihydrothieno[2,3-d]pyrimidin-4-one de-rivatives 2a ,b with aliphatic acids afforded the thienotriazolopyrimidinone derivatives 3a -d ,with nitrous acid yielded tetrazolothienopyrimidinone derivatives 4a ,b and with carbon disu l-phide furnished 3-mercaptothienotriazolopyrimidinone derivatives 5a ,b . Also, 2a ,b reactedwith aldehydes to afford the arylhydrazones 6a -f which cyclized into thienotriazolopyrimid i-none derivatives 7a -f. Furthermore, 2a ,b condensed with ethyl acetoacetate and ethyl cyan o-acetate to afford 2-(1-pyrazolyl) derivatives 9a ,b and 10a ,b , respectively. On the other hand,2-hydrazino derivatives 2a ,b condensed with α-halo-ketones to yield thienpyrimidotriazinonederivatives 11a ,b and with β-diketones, to form 2-(1-pyrazolyl) derivatives 12a -f.Keywords: Pyrimidines, α-haloketones, β-diketones, β-ketoesters, aliphatic acids, NMRspectra .IntroductionThe biological [1-5], bactericidal [6], and medicinal [7,8] activities of thieno[2,3-d]-pyrimidine de-rivatives have stimulated considerable research in this field [9-12]. In continuation of our work on thesynthesis of fused pyrimidine derivatives [13], we report here the utility of 3-methyl-2-methylthio-3,4-dihydrotheino[2,3- d]pyrimidine-4-one derivative

Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models. The validation of a dedicated high-throughput method using liquid chromatography–mass spectrometry is presented for the simultaneous analysis of IBR and its pharmacologically active metabolite dihydrodiol ibrutinib (DIB) in human plasma. The 6 h benchtop stability of IBR, DIB, and the active moiety (IBR + DIB) was assessed in whole blood and in plasma to identify any risk of degradation before samples reach the laboratory. In addition, four regression algorithms were tested to determine the optimal assay error equations of IBR, DIB, and the active moiety, which are essential for the correct estimation of the error of their future nonparametric pharmacokinetic models. The noncompartmental pharmacokinetic properties of IBR and the active moiety were evaluated in three patients diagnosed with chronic lymphocytic leukemia to provide a proof of concept. The presented methodology allows clinical laboratories to efficiently support pharmacokinetics-based precision pharmacotherapy with IBR.