Original scientific paper

https://doi.org/10.5562/cca3165

Synthesis, Cytostatic and Antibacterial Evaluations of Novel 1,2,3-Triazolyl-tagged Pyrimidine and Furo[2,3-d]pyrimidine Derivatives

Maja Stipković Babić ; Department of Organic Chemistry, Faculty of Chemical Engeneering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
Ana Ratković ; Department of Organic Chemistry, Faculty of Chemical Engeneering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
Marijana Jukić ; Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, J. J. Strossmayer University of Osijek, Huttlerova 4, HR-31000 Osijek, Croatia
Ljubica Glavaš-Obrovac ; Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, J. J. Strossmayer University of Osijek, Huttlerova 4, HR-31000 Osijek, Croatia
Domagoj Drenjančević ; Department of Microbiology and Parasitology, Faculty of Medicine, J. J. Strossmayer University of Osijek, Huttlerova 4, HR-31000 Osijek, Croatia
Silvana Raić-Malić ; Department of Organic Chemistry, Faculty of Chemical Engeneering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
Tatjana Gazivoda Kraljević ; Department of Organic Chemistry, Faculty of Chemical Engeneering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia

Abstract

C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reaction of 5-iodouracil in the presence of NaH, as a base, followed by Pd-catalyzed Sonogashira cross-coupling reaction of N-alkyl-5-iodouracil derivatives (1 and 2) with corresponding terminal alkynes. Intramolecular in situ O-heteroannulation ring closure of N-1-alkyl-C-5-alkynylpyrimidine derivatives (3 and 5) generated novel 6-substituted furo[2,3-d]pyrimidine derivatives (7 and 8). 1,4-Disubstituted 1,2,3-triazole tethered 5-alkynylpyrimidines (14–19) and 6-substituted furo[2,3-d]pyrimidines (20–22) were successfully prepared by the copper(I)-catalyzed click reaction of 5-iodo-N-1-propargylpyrimidine (2) using microwave irradiation, followed by Sonogashira cross-coupling reaction with corresponding terminal alkynes. In vitro antiproliferative activity of prepared compounds evaluated on human cancer cell lines cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji) revealed that pyrimidine (19) and furo[2,3-d]pyrimidine (22) derivatives with 3,5-difluorophenyl at pyrimidine and furo[2,3-d]pyrimidine as well as p-(trifluoromethyl)phenyl at 1,2,3-triazole exhibited marked and selective inhibitory effects on the growth of K562 and Raji tumor cells. Antibacterial evaluations showed that pyrimidine derivative 14 substituted with p-tolylethynyl at C-5 of pyrimidine and benzyl at 1,2,3-triazole moiety was the most active of all evaluated compounds on the Gram positive bacterial strains Enterococcus faecalis. Further structure optimization of compounds 14, 19 and 22 is foreseen in order to obtain lead structural analogs with efficient and selective antitumoral and antibacterial activities.

This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords

pyrimidine; furo[2; 3-d]pyrimidine; Sonogashira cross-coupling reaction; click chemistry; antiproliferative; antibacterial evaluations

Hrčak ID:

185003

URI

https://hrcak.srce.hr/185003

Publication date:

3.7.2017.

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