Synthesis, Antitumor and Antimicrobial Testing of Some New Thiopyrimidine Analogues

Abstract

The synthesis of some new 4-chloro-pyrimidine-5-carbonitriles (3b-d), 4-substituted-amino-pyrimidine-5-carbonitriles (4a-g), trioxo and dioxo-thiazolo[3,2-a]pyrimidine-6-carbonitriles (5a-c and 6a-h) have been described. The obtained compounds were evaluated for their in-vitro antitumor activity. A single dose (10 µM) of the test compounds was used in the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 3c and 4f showed high inhibitory activity against leukemia, whereas, compounds 3b and 4d, g displayed moderate activity. On the other hand, all compounds were screened for their in-vitro antibacterial and antifungal activities. Compounds 3d and 4b exhibited significant antibacterial activity against Staphylococcus aureus. Compound 4e showed two folds inhibitory activity against Entrobacter aerogener compared with the reference drug Tobramycin.Key words thiopyrimidine derivative; synthesis; antitumor; antimicrobial activity Thiouracil, 5-Flurouracil 1) (A) and other pyrimidine compounds are important synthons in anticancer, antibacterial and antifungal chemotherapy.2-5) S-Alkylation (B) and N-alkylation (C) products of thiouracil analogues have been recently reported as novel antibacterial, and cytotoxic agents. 6,7)Thiazolopyrimidines (D), the bioisostere analogues of the anticancer purines such as Thioguanine 8,9) (Lanvis ® ) (E), are potentially bioactive molecules reported to display significant anticancer and antimicrobial activities [10][11][12][13] (Fig. 1). The development of potent and effective novel antineoplastic drugs is one of the most intensely persuaded goals of contemporary medicinal chemistry. In view of the biological significance of thiouracils and in continuation of our previous efforts in the synthesis of new thiouracils and uracil-related heterocycles, 7) we would like to report herein the synthesis of new thioxo-chloro-pyrimidines (3b-d), substituted-aminopyrimidines (4a-g) and thiazolopyrimidines (5a-c, 6a-h) and their antitumor, antimicrobial testing. Results and DiscussionChemistry The 6-chloro-pyrimidine derivatives 3a-d is used as a key precursor in the present study. They were synthesized using the reported method for compound 3a.14) (Chart 1). Thus compounds 1a-d was treated with alkyl halides to give the corresponding S-alkylated derivatives 2a-d followed by phosphoryl chloride treatment to afford 3a-d. The structure of the newly prepared compounds 3b-d was confirmed by elemental analyses and spectral data (IR, 1 H-NMR and MS). The IR spectra of these compounds showed the disappearance of both NH and C= O bands. 1 H-NMR spectra of compounds 3b-d showed the absence of NH signal. Moreover mass spectrum of compound 3c showed molecular ion peaks at m/z 307.05 (M + ) (33.17%) and 309.05 (M+ 2) (13.09%) in ratio 3 : 1 indicating the presence of chlorine atom.2-Alkylthio-6-aryl-4-substituted-aminopyrimidine-5-carbonitriles (4a-g) were prepared through direct reaction of 2-alkylthio-4-aryl-6-chloropyrimidine-5-carbonitrile with various amines, in the presence of potassiu...

Synthesis of Novel Substituted Tetrahydropyrimidine Derivatives and Evaluation of Their Pharmacological and Antimicrobial Activities

“…Anal. Calcd for C 14 (4). A mixture of pyrimidine 1 (0.01 mol, 2.59 g) and ethyl chloroacetate (0.01 mol, 1.22 mL) in acetone containing potassium carbonate anhydrous was heated under water steam for 7 h. The reaction mixture was allowed to cool and then acidified by HCl after pouring into water/ice.…”

“…Anal. Calcd for C 14 7-(4-Methoxyphenyl)-2,5-dioxo-2,3-dihydro-5H-thiazolo [3,2-a]pyrimidine-6-carbonitrile (21). A mixture of pyrimidine 1 (0.01 mol, 2.59 g), chloroacetyl chloride (0.01 mol, 11.2 mL) in ethanol (30 mL), and triethylamine were heated under reflux for 12 h. The reaction mixture was concentrated, was allowed to cool, and was poured onto ice/HCl.…”

“…Anal. Calcd for C 14 To-a solution of pyrimidine 1 (0.01 mol, 2.59 g) in ethanol (30 mL), chloroacetonitrile (0.01 mol, 0.75 mL) was added dropwise with continuous stirring during 30 min in the presence of drops of triethylamine, and then the mixture was heated under reflux for 14 h. The reaction mixture was neutralized by HCl after pouring onto ice/water. The formed precipitate was filtered, dried, and crystallized from ethanol to give 22.…”

“…Anal. Calcd for C 14 The samples were prepared by dissolving 2 mg in 2 mL of DMSO, and 100 μL (containing 100 μg) was used in this test. The antimicrobial activity of different samples was investigated by the agar cup plate method.…”

Synthesis, In Vitro Cytotoxicity and Bleomycin‐Dependent DNA Damage Evaluation of Some Heterocyclic‐Fused Pyrimidinone Derivatives

“…For example, Emivirine (EMV) is currently undergoing Phase III clinical trials in HIV‐1‐infected patients, HEPT displayed a powerful and selective activity toward HIV‐1, 5‐fluorouracil (5‐FU) as thymidylate synthase inhibitor, and Merbarone as DNA topoisomerase II (topoII) catalytic inhibitor (Figure ). They also possess a long range of biological properties, including antitumor, anti‐inflammatory, antifungal, and antitubercular activities. The construction of heterocycles and their fused derivatives has become a central issue in organic synthesis due to their structural diversity and potential pharmaceutical applications .…”