title: Design, Synthesis and Biological Evaluation of Novel Primaquine-Cinnamic Acid Conjugates of the Amide and Acylsemicarbazide Type.
abstract: In this paper design and synthesis of a scaffold comprising primaquine (PQ) motif and cinnamic acid derivatives (CADs) bound directly (compounds3a-k) or via a spacer (compounds7a-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 amides3a-kwere prepared by a simple one-step condensation reaction of PQ with a series of CAD chlorides (method A) or benzotriazolides2(method B). The synthesis of acylsemicarbazides7a-kincluded activation of PQ with benzotriazole, preparation of PQ-semicarbazide6and its condensation with CAD chlorides4. All synthesized PQ-CAD conjugates were evaluated for their anticancer, antiviral and antioxidative activities. Almost all compounds from series3were selective towards the MCF-7 cell line and active at micromolar concentrations. Theo-fluoro derivative3hshowed high activity against HeLa, MCF-7 and in particular against the SW 620 cell line, while acylsemicarbazide7fwith a benzodioxole ring and7c,7gand especially7jwith methoxy-, chloro- or trifluoromethyl-substituents in theparaposition 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,7jand 7kshowed 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 with7dand7g, while methoxy (compounds7c-e), benzodioxole (7f),p-Cl (7g) andm-CF₃ (7i) acylsemicarbazides and amide3fpresented the highest LP inhibition (83%-89%). The dimethoxy derivative7dwas 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.
authors.affiliation: Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10 000 Zagreb, Croatia. kpavic@pharma.hr.
authors.forename: Kristina
authors.initials: K
authors.lastname: Pavić
authors.affiliation: Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10 000 Zagreb, Croatia. iperkovic@pharma.hr.
authors.forename: Ivana
authors.initials: I
authors.lastname: Perković
authors.affiliation: Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10 000 Zagreb, Croatia. pgilja@student.pharma.hr.
authors.forename: Petra
authors.initials: P
authors.lastname: Gilja
authors.affiliation: Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10 000 Zagreb, Croatia. filip.kozlina@gmail.com.
authors.forename: Filip
authors.initials: F
authors.lastname: Kozlina
authors.affiliation: Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia. katja.ester@irb.hr.
authors.forename: Katja
authors.initials: K
authors.lastname: Ester
authors.affiliation: Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia. marijeta.kralj@irb.hr.
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. dominique.schols@rega.kuleuven.be.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: Faculty of Health Sciences, School of Pharmacy, Aristotles University of Thessaloniki, Thessaloniki 54 124, Greece. hadjipav@pharm.auth.gr.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Hadjipavlou-Litina
authors.affiliation: Faculty of Health Sciences, School of Pharmacy, Aristotles University of Thessaloniki, Thessaloniki 54 124, Greece. epontiki@pharm.auth.gr.
authors.forename: Eleni
authors.initials: E
authors.lastname: Pontiki
authors.affiliation: Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10 000 Zagreb, Croatia. bzorc@pharma.hr.
authors.forename: Branka
authors.initials: B
authors.lastname: Zorc
mesh_terms: D000256:Adenoviridae / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D017934:Coronavirus / Q000187:drug effects; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D011319:Primaquine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D014616:Vaccinia virus / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D000998:Antiviral Agents; D002934:Cinnamates; C029010:cinnamic acid; D011319:Primaquine
keywords: antioxidative activity; antiviral activity; cinnamic acid derivative; conjugate; cytostatic activity; primaquine