Synthesis and cytotoxic evaluation of some Pyrimidine derivatives (original) (raw)
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Liebigs Annalen der Chemie, 1987
Tlic Scyano-6-aryl-2-thiourHciIs la-d were prepared '-3 for the syntheses of several other pyrimidine derivatives. In basic medium 1x1 reacted with picryl chloride yielding the unexpected benzothiazolo-pyrimidine 2. Heating a mixture of i and t.2dibromoctbanc in DMF in basic medium gave the thiazolopyrimidines 3a. d, while chc reaction of 1 with 1.3dibromopropane and 1.3-dibromo-2-propanol under similar conditions yielded the pyrimido-thiazine 3 b, c, e. Alkylation of 1 with alkyl ldides in alkaline medium in 1 : 2 and 1 : 1 ratios gave the diand monoaikyl dcrivatjves 4 and 5, respectiveIy. With hydrazine hydrate. 4s yielded the 2-hydrazi~opyrimidine 6 which cyclized to give the triazolo-pyrimidine 7 on refluxing in formic acid Similar reaction conditions were maintained for attempts to cydize 6 with acetic and propionic acid, but always the acylhydrazino derivatives 8a, b were isolated. Reaction of 6 with methyl 2cyano-3,3-bis(metbylthio)ate
Utility of 6-amino-2-thiouracil as a precursor for the synthesis of bioactive pyrimidine derivatives
Bioorganic & Medicinal Chemistry, 2007
The condensation of 6-amino-2-thiouracil 1 with aromatic aldehydes afforded azomethine derivatives 3a,b. The formed azomethines underwent [4+2] cycloaddition with enaminones 4a-c and enaminonitrile 9 to form the corresponding condensed pyrimidines 8a-f and 11a,b, respectively. On the other hand, the interaction of 3a,b with acetylene derivatives 12a,b, 14 afforded the corresponding pyrido[2,3-d]pyrimidines 13a-d and 16a,b, respectively. The newly synthesized 2-azadiene 18 reacted with ortho-aminophenol and ortho-aminothiophenol 19a,b to yield the amidines 21a,b. The in vitro antimicrobial activity of some of the newly synthesized compounds was examined. All the tested compounds proved to be active as antibacterial and antifungal agents. Also the in vivo antitumor activity of compounds 8a, 11b, 13a,d, and 16b against lung (H460) and liver (HEPG2) carcinoma cells was examined. Compounds 8a, 16b showed moderate activity against lung carcinoma cell line (H460).
Design, synthesis of new pyrimidine derivatives as anticancer and antimicrobial agents
2017
A new series of 6-aryl-5-cyano thiouracil derivatives were synthesized. Cyanouracil 1 was condensed with monochloroacetic acid and different aldehydes to give thiazolopyrimidine 2. On the other hand, treatment of cyanouracil 1 with 2-chloro-N-substituted-phenylac etamide afforded 4. Hydrazinolysis of 6 afforded the hydrazino derivatives 7 which upon reaction with different electrophilic reagents such as acetic anhydride, benzoyl chloride, and carbon disulfide yielded pyrimidine derivatives 8–15. Some of the new derivatives were explored for their antimicrobial activities. Compounds 7 and 9 have a promising activity, relatively equipotent to the reference drug. All of the new synthesized compounds were tested in vitro for their antiproliferative activities against HePG-2 and MCF-7 cell lines. Compounds 7, 9, and 2d displayed potent growth inhibitory effect toward the two cell lines more than the standard drug 5-FU. Furthermore, a docking study of the most active compounds was performed with thymidylate synthase enzyme.
Pharmaceutical Chemistry Journal, 2014
The aim of this study was to describe the synthesis of four new 2-(3,4-diphenyl-3H-thiazol-2-ylidene)amino-4,6-dimethylpyrimidine derivatives, which were screened for their anticandidal activity and cytotoxicity. The title compounds (2a -2d) were synthesized via the reaction of 1-phenyl-3-(4,6-dimethylpyrimidin-2-yl)thiourea with phenacyl bromides. Anticandidal activity of the synthesized compounds was evaluated using microbroth dilution method. All compounds were also investigated for their cytotoxic effects on A549 and NIH3T3 cell lines. Compound 2c can be considered as the most promising anticandidal agent due to its inhibitory effects on Candida albicans, C. glabrata, C. tropicalis with a MIC value of 125 mg/mL and low toxicity to NIH3T3 cells (IC 50 = 193.32 mg/mL). Although compound 2a was the most effective derivative against A549 cells with an IC 50 value of 0.0623 mM, it is not a good candidate for cancer treatment because of its high toxicity against NIH3T3 cells (IC 50 = 0.00316 mM).
Design, Synthesis of Novel Thiourea and Pyrimidine Derivatives as Potential Antitumor Agents
Journal of the Chinese Chemical Society, 2015
1,3-Bis-(arylidene)thiourea derivatives (11a-c) were prepared by reacting thiourea (9) with bezaldehyde, p-chlorobenzaldehyde or p-anisaldehyde (10a-c) respectively. Further reaction of (11b) with acetyl acetone, ethyl acetoacetate, malononitrile and acetic anhydride gave tetrahydropyrimidine-2-thiones (12-14) and 1,3-diacetyl thiourea (15). Compound (11b) reacted with chloroacetyl chloride to give the corresponding pyrimidin-4-one derivative (16). Reaction of (12-14) with acetic acid in aqueous sodium nitrite yielded the corresponding oxime derivatives (17-19). The triazole (20) was achieved via refluxing of (19) in dimethylformamide. Reaction of (16) with mercaptoacetyl chloride gave the sulfanyl-acetic acid (21) which afforded the dihydrazinyl (22) up on treatment with hydrazine hydrate. Newly synthesized compounds ware characterized by elemental analyses and spectral data (IR, 1 H-NMR, 13 C-NMR and mass spectra). The investigated compounds were screened for their cytotoxicity, i.e. compounds 19, 20 and 22 exhibited highly potential antitumor activity.
Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2- a]pyrimidines
European Journal of Medicinal Chemistry, 2011
New series of sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]pyrimidine were synthesized and investigated as antitumor agents. Some of the newly prepared compounds were tested for their in vitro and in vivo antitumor activities. Preliminary biological studies revealed that compounds 4c, 4f, and 4j exhibited the highest affinity to DNA, while compounds 4h,i, 6a–c, 8 and 12–14 exhibited moderate activity. Also, compounds 4j, 4f and 4c showed the highest percentage increase in lifespan of mice inoculated with Ehrlich ascites cells over 5-flurouracil (positive control). The detailed synthesis, spectroscopic and biological data are reported.New series of sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]pyrimidine have been synthesized and screened for antitumor activity.► Sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a]pyrimidines have been synthesized. ► They were investigated for DNA-binding affinity and antitumor activity. ► Compounds 4c, 4f, and 4j exhibited the highest antitumor activity.
European Journal of Medicinal Chemistry, 1991
Eur J Med Chem (1991) 26,557-562 0 Elsevier, Paris 557 Short communication rnthesis and cytotoxic activity of 5(l-hydroxy-2-haloethyl)-, S-oxiranyland (IS)-5(2-iodovi nyl)-2,4-dichloro (or dimethoxy) pyrimidines Summary -A series of 5-(1-hydroxy-2-haloethyl) 6, 7, 13, 14a, 5-oxiranyl 8, 9 and (E)-5-(2-iodovinyl)-2,4-dichloro(or dimethoxy)pyrimidines 11, 12 were synthesized for evaluation as cytotoxic agents. The nuclear C-2 and C-4 substituents were determinants of activity since the 2,4-dichloro compounds 6, 8 and 11 were more potent (EDSo = 0.2-0.3 pg/ml) than the corresponding 2,4-dimethoxypyrimidine analogues 7, 9 and 12 (ED,, = 4-28 pg/ml), relative to melphalan (ED 5,, = 0.15 l.tg/ml), in the in vitro L1210 screen. Within the 2,4-dichloro series of compounds 6, 8 and 11, the C-5 substituent was not a determinant of activity. In contrast, in the 2,4dimethoxypyrimidine series, the C-5 substituents influenced activity significantly where the relative potency order was oxiranyl 9 > -CH(OH)CH*I 7 > (E)-CH = CHI 12 > CH(OH)CHI, 13, CH(OH)CHBr(I) 14a and CH(Br)CHOH(I) 14b. The most active compound (E)-5-(2-iodovinyl)-2,4-dichloropyrimidine 11 exhibited weak activity in the in vivo P388 screen (% T/C = 116 for a 10 mg/kg ip dose) relative to the reference drug 5-fluorouracil (% T/C = 135 for a 20 mg/kg dose).
Anticancer Activities of Some New Synthesized Thiazolo[3,2-a]Pyrido[4,3-d]Pyrimidine Derivatives
American Journal of Biochemistry and Biotechnology, 2011
Problem statement: This study describes the synthesis and anticancer activities of a new series of thiazolo[3,2-a]pyrimidines derivatives (2-7) using 3,5-bisarylmethylene-1-methyl-4piperidone and 4-aryl-8-arylmethelene-6-methylpyrido[4,3-d]pyrimidine-2(1H)thiones as a starting materials. Approach: The antitumor activities of the newly synthesized compounds 4-7 were evaluated utilizing 60 different human tumor cell lines, representing leukemia, melanoma, lung, colon, brain, ovary, breast and prostate as well as kidney. Results: Some of the tested compounds exhibited better in vitro antitumor activities at low concentration (log10 GI 50 = -4.7) against the used human tumor cell lines. Conclusion: From the obtained results, we can conclude that pyrimidine moieties fused to N-methylpipredine ring are essential for antitumor activities. In the present work, we can suggest that the anticancer activity is due to the presence of nitrogen heterocyclic rings and the presence of sulfur atom generally enhancing the activity.
Research on Chemical Intermediates, 2013
6-Amino-2-thiouracil (1) was condensed with benzenesulfonyl chloride and p-toluenesulfonyl chloride in presence of pyridine as an acid binder to give sulfonamides 2a, b, which could be methylated in basic medium to give methylmercapto derivatives 3a, b, which in turn reacted with bromine in glacial acetic acid to yield 5-bromo derivatives 4a, b. On the other hand, compounds 2a, b were cyclocondensed with monochloroacetyl chloride, p-tolualdehyde in glacial acetic acid/ pyridine, and ethyl bromoacetate to give the corresponding thiazolopyrimidines 5a, b, 6a, b, and 7a, b, respectively; also compounds 2a, b were hydrazinolyzed to compounds 8a, b, which could be cyclized to triazolopyrimidines 9a, b in presence of formic acid. They could also be condensed with p-anisaldehyde to give hydrazones 10a, b. In another pathway, compounds 2a, b were reacted with monochloroacetic acid in basic medium to give acetic acid derivatives 11a, b. It can be deduced from the preliminary screening results that the cell lines most sensitive to the antiproliferative activity of tested compounds are human liver HEPG2 and colon cancer HT-29. All selected compounds exhibited moderate to strong growth inhibition activity against the HEPG2 cell line with 50 % inhibitory concentration (IC 50 ) ranging between 1 and 10 lg/ml. The most active compounds, which revealed antiproliferative activity also against human colon HT-29 and breast MCF-7 cell lines, were 3a, 3b, 4a, and 10a.