title: Synthesis, in vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole-coumarin hybrids.
abstract: The 4-substituted 1,2,3-triazole core in designed coumarin hybrids (4-35) with diverse physicochemical properties was introduced by eco-friendly copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition under microwave irradiation. Coumarin-1,2,3-triazole-benzofused heterocycle hybrids emerged as the class of compounds exhibiting the highest antiproliferative activity. The strong relationship between lipophilicity and antiproliferative activities was observed indicating that lipophilic 1,2,3-triazole-coumarin hybrids containing phenylethyl (13), 3,5-difluorophenyl (14), 5-iodoindole (30) and benzimidazole (33 and 35) subunits showed the most potent cytostatic effects. The 7-methylcoumarin-1,2,3-triazole-2-methylbenzimidazole hybrid 33 can be highlighted as a lead that exerted the highest cytotoxicity against hepatocellular carcinoma HepG2 cells with IC50value of 0.9 μM and high selectivity (SI = 50). This compound induced cell death, mainly due to early apoptosis. Strong antiproliferative effect of 33 could be associated with its inhibition of 5-lipoxygenase (5-LO) activity and perturbation of sphingolipid signaling by interfering with intracellular acid ceramidase (ASAH) activity. Outlined considerable effect of lipophilicity on antiproliferative activity was not observed for antibacterial activity. The compounds with p-pentylphenyl (17), 2-chloro-4-fluorobenzenesulfonamide (23) and dithiocarbamate (27) moiety were endowed with high selectivity against Enterococcus species. Moreover, these compounds were found to be superior in inhibiting the growth of clinically isolated vancomycin-resistant Enterococcus faecium, while the reference antibiotics exhibited the lack of activity. Our findings indicate that coumarin-1,2,3-triazole could be used as the scaffold for structural optimization to develop more potent and selective anticancer agents and encourage further development of novel structurally related analogs of 33 as more effective 5-LO inhibitors.
authors.affiliation: University of Zagreb, Faculty of Chemical Engineering and Technology, Department of Organic Chemistry, Marulićev trg 20, HR-10000, Zagreb, Croatia.
authors.forename: Tatjana Gazivoda
authors.initials: TG
authors.lastname: Kraljević
authors.affiliation: Universiy of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000, Rijeka, Croatia; University of Rijeka, Centre for High-throughput Technologies, Radmile Matejčić 2, HR-51000, Rijeka, Croatia.
authors.forename: Anja
authors.initials: A
authors.lastname: Harej
authors.affiliation: Universiy of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000, Rijeka, Croatia; University of Rijeka, Centre for High-throughput Technologies, Radmile Matejčić 2, HR-51000, Rijeka, Croatia.
authors.forename: Mirela
authors.initials: M
authors.lastname: Sedić
authors.affiliation: Universiy of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000, Rijeka, Croatia; University of Rijeka, Centre for High-throughput Technologies, Radmile Matejčić 2, HR-51000, Rijeka, Croatia.
authors.forename: Sandra Kraljević
authors.initials: SK
authors.lastname: Pavelić
authors.affiliation: Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, HR-10002, Zagreb, Croatia.
authors.forename: Višnja
authors.initials: V
authors.lastname: Stepanić
authors.affiliation: Osijek University Hospital, Department of Transfusion Medicine, Josipa Huttlera 4, HR-31000, Osijek, Croatia; University of Osijek, Faculty of Medicine, Department of Microbiology and Parasitology, Cara Hadrijana 10/E, HR-31000, Osijek, Croatia.
authors.forename: Domagoj
authors.initials: D
authors.lastname: Drenjančević
authors.affiliation: University of Osijek, Faculty of Medicine, Department of Microbiology and Parasitology, Cara Hadrijana 10/E, HR-31000, Osijek, Croatia.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Talapko
authors.affiliation: University of Zagreb, Faculty of Chemical Engineering and Technology, Department of Organic Chemistry, Marulićev trg 20, HR-10000, Zagreb, Croatia. Electronic address: sraic@fkit.hr.
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001419:Bacteria / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D003374:Coumarins; D014230:Triazoles
keywords: 1,2,3-triazole–coumarin hybrids; 5-Lipoxygenase (5-LO); Acid ceramidase (ASAH); Antibacterial activity; Click chemistry; Cytostatic activity