Abstract
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 7k 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.
Highlights
The molecular hybridization approach based on the combination of the pharmacophoric moieties of different compounds was used to produce new hybrid molecules with cinnamic acid derivatives (CADs) and primaquine (PQ) motifs
We have shown that PQ derivatives of urea and acylsemicarbazide type possess strong antiproliferative effects against a number of tumor cell lines and/or high selectivity towards the breast cell line MCF-7 [43,44,45,46,47]
The present study reports the synthesis and characterization of PQ-CAD conjugates and their evaluation as potential anticancer and antiviral agents
Summary
The molecular hybridization approach based on the combination of the pharmacophoric moieties of different compounds was used to produce new hybrid molecules with cinnamic acid derivatives (CADs) and primaquine (PQ) motifs. Cinnamic acid (CA, trans-3-phenylacrylic acid, trans-3-phenyl-2-propenoic acid) and its derivatives are naturally occurring substances found in various plants. They are important intermediates in biosynthetic pathways of secondary metabolites, which play key roles in plant growth, development, reproduction and disease resistance [1]. Numerous research papers report various pharmacological activities of CADs [2,3]. First of all, they exhibit strong antimicrobial, antifungal and antiviral activity [4,5,6,7,8].
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