Novel 1-acyl-4-substituted semicarbazide derivatives of primaquine − synthesis, cytostatic, antiviral and antioxidative studies

Abstract

A series of novel 1,4-substituted semicarbazides 5a–g with a primaquine moiety bridged by a carbonyl group at position 1 and a cycloalkyl, aryl, benzyloxy or hydroxy substituent at position 4 were prepared and biologically evaluated. The synthetic pathways applied for preparation of the title compounds involved benzotriazole as synthetic auxiliary. Primaquine semicarbazides 5a–g and their synthetic precursors benzotriazolecarbonyl semicarbazides 4 were evaluated for cytostatic, antiviral and antioxidative activities. All compounds of the series 5 showed high selectivity towards MCF-7 cells (breast carcinoma) with IC₅₀ values in the low micromolar range and the most active was benzyl derivative 5c (IC₅₀ 1 ± 0.2 µM). The benzhydryl derivative 5e showed significant cytostatic activities towards all the tested cell lines (IC₅₀ 4–18 µM). The same compound was the strongest lipoxygenase inhibitor as well (51%). The highest antioxidant activity was demonstrated for the hydroxy derivative 5g and benzotriazolecarbonyl semicarbazides 4b,c (61.2–68.5%). No antiviral activity was observed against a wide variety of DNA and RNA viruses.

Keywords::

• Primaquine
• semicarbazide
• benzotriazole
• antitumoural activity
• antioxidative activity
• antiviral evaluation

Acknowledgement

We thank Dr. C. Hansch, Dr. A. Leo, and Biobyte Corp., Claremont, California, for free access to the C-QSAR program and Mrs. Leentje Persoons, Frieda De Meyer, Leen Ingels, Lizette van Berckelaer for excellent technical assistance.

Declaration of interest

The authors report no conflicts of interest. This study is supported by the Ministry of Science, Education and Sports of the Republic of Croatia (Projects No. 006-0000000-3216 and 098-0982464-2514) and the K.U. Leuven (GOA 10/014).