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.
Highlights
Compounds bearing α,β-unsaturated carbonyl groups are Michael acceptors capable of conjugate addition, known as Michael addition
Most of the bacteria, 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)
The antimicrobial screening was assessed against a panel of Gram-positive bacteria (S. pneumoniae MFBF 10373, S. aureus ATCC 6538, methicillin-resistant S. aureus methicillin-resistant Staphylococcus aureus (MRSA) 63718, SA 630 and SA 3202, E. faecalis ATCC 29212 and three vancomycin-resistant Enterococci vancomycin-resistant E. faecalis (VRE) 342 B, 365 and 725 B, B. cereus ATCC 11778, and B. subtilis ATCC 6633), Gram-negative species (P. aeruginosa ATCC 27853, E. coli ATCC 10536, S. marcescens ATCC 10905, P. mirabilis MFBF 10430, A. baumannii MFBF 10913, and S. enteritidis MFBF 11945), four Mycobacterium strains (M. tuberculosis H37Ra, M. smegmatis ATCC 700084, M. kansasii DSM 44162, and M. marinum CAMP 5644) and fungi
Summary
Compounds bearing α,β-unsaturated carbonyl groups are Michael acceptors capable of conjugate addition, known as Michael addition. Molecules 2018, 23, 1724 are α,β-unsaturated carbonyl compounds with exposed unsaturated β-carbon atoms, such as exomethylene ketones and lactones or vinyl ketones [1] These fragments are often used in the design of new anticancer drugs, together with others (6-methylhept-5-ene-1,4-dione, propiolamide, 4-(dimethylamino)but-2-enamide) (Figure 1). Taking literature data into account [22,23,24] and our previous experience with PQ derivatives [20,21,25,26,27,28], we have assumed that the designed compounds have a high pharmacological potential We report their synthesis, evaluation of antimicrobial activity on a wide spectrum of bacteria, fungi and viruses, their biofilm eradication ability, and cytostatic activity against several human tumor cell lines. All compounds are fully in agreement with the Lipinski and Gelovani rules for prospective small molecular drugs (MW ≤ 500, log P ≤ 5, number of H-bond donors ≤ 5, number of H-bond acceptors ≤ 10, TPSA < 140 Å2, MR within the range of 40 and 130 cm3/mol, the number of atoms 20–70), 4e,f and 5e,f have the highest permitted relative molecular masses
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