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Molecules 2018, 23(7), 1724; https://doi.org/10.3390/molecules23071724

Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors

1
Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, 10000 Zagreb, Croatia
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojárov 10, 83232 Bratislava, Slovakia
3
Laboratory for Advanced Genomics, Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
4
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
*
Authors to whom correspondence should be addressed.
Academic Editor: Michal Szostak
Received: 3 July 2018 / Revised: 10 July 2018 / Accepted: 11 July 2018 / Published: 14 July 2018
(This article belongs to the Special Issue Amide Bond Activation)
Full-Text   |   PDF [1200 KB, uploaded 14 July 2018]   |  

Abstract

Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides 4af, potential Michael acceptors, and their reduced analogues succindiamides 5af 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. View Full-Text
Keywords: fumardiamide; primaquine; succindiamide; Michael acceptor; biofilm eradication; antibacterial screening; antiviral activity; cytostatic activity fumardiamide; primaquine; succindiamide; Michael acceptor; biofilm eradication; antibacterial screening; antiviral activity; cytostatic activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Rajić, Z.; Beus, M.; Michnová, H.; Vlainić, J.; Persoons, L.; Kosalec, I.; Jampílek, J.; Schols, D.; Keser, T.; Zorc, B. Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors. Molecules 2018, 23, 1724.

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