Naslov
Synthesis, in vitro anticancer and antibacterial activities and in silico studies of new 4-substituted 1,2,3-triazole–coumarin hybrids

Autori
Gazivoda Kraljević, Tatjana ; Harej, Anja ; Sedić, Mirela ; Kraljević Pavelić, Sandra ; Stepanić, Višnja ; Drenjančević, Domagoj ; Talapko, Jasminka ; Raić-Malić, Silvana

Izvornik
European journal of medicinal chemistry (0223-5234) 124 (2016); 794-808

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
1, 2, 3-triazole–coumarin hybrids ; click chemistry ; cytostatic activity ; antibacterial activity ; 5-lipoxygenase (5-LO) ; acid ceramidase (ASAH)

Sažetak
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 IC50 value 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 found 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 a model skeleton 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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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