Naslov
Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors

Autori
Rajić, Zrinka ; Beus, Maja ; Michnová, Hana ; Vlainić, Josipa ; Persoons, Leentje ; Kosalec, Ivan ; Jampílek, Josef ; Schols, Dominique ; Keser, Toma ; Zorc, Branka

Izvornik
Molecules (1420-3049) 23 (2018), 7; 1724, 18

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

Ključne riječi
fumardiamide ; primaquine ; succindiamide ; Michael acceptor ; biofilm eradication ; antibacterial screening ; antiviral activity ; cytostatic activity

Sažetak
Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4a–f, potential Michael acceptors, and their reduced analogues succindiamides 5a–f were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate (1a) or mono-methyl succinate (1b), hydrolysis of PQ-dicarboxylic acid mono-ester conjugates 2a, b to corresponding acids 3a, b, and a coupling reaction with halogenanilines. 1- [bis(Dimethylamino)methylene]-1H-1, 2, 3- triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate (HATU) was used as a coupling reagent along with Hünig′s base. Compounds 4 and 5 were evaluated against a panel of bacteria, several Mycobacterium strains, fungi, a set of viruses, and nine different human tumor cell lines. p-Chlorofumardiamide 4d showed significant activity against Staphylococcus aureus, Streptococcus pneumoniae and Acinetobacter baumannii, but also against Candida albicans (minimum inhibitory concentration (MIC) 6.1–12.5 µg/mL). Together with p-fluoro and p-CF3 fumardiamides 4b, f, compound 4d showed activity against Mycobacterium marinum and 4b, f against M. tuberculosis. In biofilm eradication assay, most of the bacteria, particularly S. aureus, showed susceptibility to fumardiamides. m-CF3 and m- chloroaniline fumardiamides 4e and 4c showed significant antiviral activity against reovirus- 1, sindbis virus and Punta Toro virus (EC50 = 3.1–5.5 µM), while 4e was active against coxsackie virus B4 (EC50 = 3.1 µM). m-Fluoro derivative 4a exerted significant cytostatic activity (IC50 = 5.7–31.2 μM). Acute lymphoblastic leukemia cells were highly susceptible towards m-substituted derivatives 4a, c, e (IC50 = 6.7–8.9 μM). Biological evaluations revealed that fumardiamides 4 were more active than succindiamides 5 indicating importance of Michael conjugated system.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Farmacija

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