Novel semicarbazides and ureas of primaquine with bulky aryl or hydroxyalkyl substituents: Synthesis, cytostatic and antioxidative activity

•Synthesis of aryl and hydroxyalkyl primaquine semicarbazides and ureas was presented.•Most compounds displayed potent cytostatic and antioxidative activity.•One hit displayed high selectivity towards MCF-7 cells.

Novel primaquine semicarbazides 7a–l and ureas 9a–g with modified benzhydryl, trityl, phenyl or hydroxyalkyl substituents were prepared and evaluated for cytostatic and antioxidative activities. Two synthetic approaches for preparation of the title semicarbazides were applied, both having certain advantages. In the first approach, the products grew from the semicarbazide side and the primaquine residue entered the molecule the last. In the second approach, semicarbazide grew from the primaquine side. This method was more convenient for synthesis of a series of semicarbazides: various products could be obtained from the same precursor N-(4-((6-methoxyquinolin-8-yl)amino)pentyl)hydrazinecarbox-amide (10). Primaquine ureas 9a–f were prepared from primaquine benzotriazolide 8 and corresponding amines and urea 9g directly from primaquine and 4-chloro-3-(fluoromethyl)phenyl isocyanate.All primaquine semicarbazide derivatives showed either prominent cytostatic activity towards all the tested cell lines (benzhydryl or trityl derivatives 7a–e) or high selectivity towards MCF-7 cells (hydroxyalkyl derivatives 7h–l), with IC50 values in the low micromolar range. The highest selectivity exerted symmetric bisprimaquine derivative 7f, with an IC50 0.2 μM against MCF-7 cells and practically no activity against other seven tested cancer cell lines. Urea derivatives 9a–f were generally less active than their semicarbazide analogues, but still selective towards MCF-7 cells. Urea 9g with the similar structure to cytostatic drug sorafenib, was the most active urea derivative.Semicarbazides 7g and 10 showed the best antioxidative activity as measured by DPPH (64% at 20 min and 90% at 60 min), while urea derivatives 9a–g, especially 9d, and semicarbazides 7a–g with lipophilic substituents exerted better LP antioxidant activity. Both semicarbazides and ureas with methoxy or chloro benzhydryl substituents and high Clog P values showed significant LOX inhibition.

Graphical abstractA series of primaquine semicarbazides 7a–l and ureas 9a–g with benzhydryl, trityl, phenyl and hydroxyalkyl substituents were prepared and evaluated for cytostatic and antioxidative activities.Figure optionsDownload full-size imageDownload as PowerPoint slide