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Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors

Rajić, Zrinka; Beus, Maja; Michnová, Hana; Vlainić, Josipa; Persoons, Leentje; Kosalec, Ivan; Jampílek, Josef; Schols, Dominique; Keser, Toma; Zorc, Branka (2018) Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors. Molecules, 23 (7). ISSN 1420-3049

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: fumardiamide ; primaquine ; succindiamide ; Michael acceptor ; biofilm eradication ; antibacterial screening ; antiviral activity ; cytostatic activity
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Division of Molecular Medicine
Projects:
Project titleProject leaderProject codeProject type
Dizajniranje, sinteza i evaluacija derivata primakina, vorinostata i sorafeniba kao potencijalnih citostatika-PVSderivativesUNSPECIFIEDIP-2014-09-1501HRZZ
Depositing User: Sofija Konjević
Date Deposited: 04 Sep 2018 12:28
Last Modified: 04 Sep 2018 12:28
URI: http://fulir.irb.hr/id/eprint/4164
DOI: 10.3390/molecules23071724

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