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Starting from 6-aryl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4a-d), a series of mono-and dialkyl derivatives 5a-j and 6a, b was synthesized. Hydrazinolysis of 4a, b, d and 5d afforded the hydrazino derivatives 7a-c which were cyclised to give the triazolopyrimidinones 8a-c and the pyrimidotriazinones 9a-c through the reaction with formic acid and chloroacetyl chloride, respectively. Most of the newly synthesized compounds were evaluated for their in-vitro antitumor activity. Compounds 6a and b displayed promising anticancer activity against leukaemia, non-small cell lung, melanoma, and renal cancer. On the other hand, all compounds prepared were screened for their in-vitro antibacterial and antifungal activities. Compounds 5h and j showed significant activity against Staphylococcus aureus, while compounds 5e, 7c and 8c displayed moderate inhibitory activity against Candida albicans.Key words pyrimidinone; synthesis; antitumor activity; antimicrobial activity Nowadays, cancer is the highly striking disease worldwide. It represents the second leading cause of human mortality after cardiovascular diseases. During the search for developing more potent anticancer agents, several nitrogen heterocycles were synthesized and evaluated for their anticancer activity.

Aim: Design and synthesis of novel morpholinopyrimidine-5-carbonitriles as antitumor agents. Materials & methods: New series of morpholinopyrimidine-5-carbonitriles have been synthesized. 19 derivatives (3b, 4a, 5–6, 9–12, 13a–e, 14a–c and 15–17) were evaluated for their in vitro antitumor activity by the National Cancer Institute (NCI; MD, USA). Moreover, compound 13e was evaluated against PI3K (α, β and δ) and the mechanism of its cytotoxic activity on leukemia SR was studied. Results: Compound 13e possessed remarkable broad spectrum antitumor activity with GI50 (median growth inhibition) and TGI (total growth inhibition) values of 6.15 and 28.66 μM, respectively, caused cell cycle arrest at G2-M phase and significant increase in the percentage of annexin V-FITC – positive apoptotic cells, also increased the level of active caspase-3. Moreover, 13e revealed good safety profile against transformed human liver epithelial-2 (THLE2).

A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N -containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound 7f was promising more than 4d with IC 50 = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚβ. Furthermore, in-vivo toxicity study indicated good safety profile for 7f . These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.

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...