Design Synthesis and Biological Evaluation of Novel Primaquine-Cinnamic Acid Conjugates of the Amide and Acylsemicarbazide Type

摘要

In this paper design and synthesis of a scaffold comprising primaquine (PQ) motif and cinnamic acid derivatives (CADs) bound directly (compounds >3a–>k) or via a spacer (compounds >7a–>k) are reported. In the first series of compounds, PQ and various CADs were connected by amide bonds and in the second series by acylsemicarbazide functional groups built from the PQ amino group, CONHNH spacer and the carbonyl group originating from the CADs. PQ-CAD amides >3a–>k were prepared by a simple one-step condensation reaction of PQ with a series of CAD chlorides (method A) or benzotriazolides >2 (method B). The synthesis of acylsemicarbazides >7a–>k included activation of PQ with benzotriazole, preparation of PQ-semicarbazide >6 and its condensation with CAD chlorides >4. All synthesized PQ-CAD conjugates were evaluated for their anticancer, antiviral and antioxidative activities. Almost all compounds from series >3 were selective towards the MCF-7 cell line and active at micromolar concentrations. The o-fluoro derivative >3h showed high activity against HeLa, MCF-7 and in particular against the SW 620 cell line, while acylsemicarbazide >7f with a benzodioxole ring and >7c, >7g and especially >7j with methoxy-, chloro- or trifluoromethyl-substituents in the para position showed high selectivity and high inhibitory activity against MCF-7 cell line at micromolar (>7c, >7f, >7g) and nanomolar (>7j) levels. Acylsemicarbazide derivatives with trifluoromethyl group(s) >7i, >7j and 7>k showed specific activity against human coronavirus (229E) at concentrations which did not alter the normal cell morphology. The same compounds exerted the most potent reducing activity in the DPPH test, together with >7d and >7g, while methoxy (compounds >7c–>e), benzodioxole (>7f), p-Cl (>7g) and m-CF3 (>7i) acylsemicarbazides and amide >3f presented the highest LP inhibition (83%–89%). The dimethoxy derivative >7d was the most potent LOX inhibitor (IC50 = 10 μΜ). The performed biological tests gave evidence of acylsemicarbazide functional group as superior binding group in PQ-CAD conjugates.