Novel amphiphilic pyridinium ionic liquids-supported Schiff bases: ultrasound assisted synthesis, molecular docking and anticancer evaluation

(2018) 12:118 Al‑Blewi et al. Chemistry Central Journal https://doi.org/10.1186/s13065-018-0489-z RESEARCH ARTICLE Chemistry Central Journal Open Access Novel amphiphilic pyridinium ionic liquids‑supported Schiff bases: ultrasound assisted synthesis, molecular docking and anticancer evaluation Fawzia Faleh Al‑Blewi1, Nadjet Rezki1,2*, Salsabeel Abdullah Al‑Sodies1, Sanaa K. Bardaweel3, Dima A. Sabbah4, Mouslim Messali1 and Mohamed Reda Aouad1* Abstract Background: Pyridinium Schiff bases and ionic liquids have attracted increasing interest in medicinal chemistry. Results: A library of 32 cationic fluorinated pyridinium hydrazone-based amphiphiles tethering fluorinated coun‑ teranions was synthesized by alkylation of 4-fluoropyridine hydrazone with various long alkyl iodide exploiting lead quaternization and metathesis strategies. All compounds were assessed for their anticancer inhibition activity towards different cancer cell lines and the results revealed that increasing the length of the hydrophobic chain of the synthe‑ sized analogues appears to significantly enhance their anticancer activities. Substantial increase in caspase-3 activity was demonstrated upon treatment with the most potent compounds, namely 8, 28, 29 and 32 suggesting an apop‑ totic cellular death pathway. Conclusions: Quantum-polarized ligand docking studies against phosphoinositide 3-kinase α displayed that com‑ pounds 2–6 bind to the kinase site and form H-bond with S774, K802, H917 and D933. Keywords: Cationic, Amphiphilic, Pyridinium, Hydrazones, Ultrasound, Anticancer, QPLD docking Introduction Schiff bases have been widely investigated due to a broad spectrum of relevant properties in biological and pharmaceutical areas [1]. In addition, a number of molecules having azomethine Schiff base skeleton are the clinically approved drugs [2]. Meanwhile, carbohydrazide hydrazone and their derivatives an interesting class of Schiff bases, represented reliable and highly efficient pharmacophores in drug discovery and played a vital role in medical chemistry due to their potency to exhibit significant antimicrobial [3], anticancer [4, 5], anti-HIV [6], and anticandidal [7] activities. Azomethine hydrazone linkages (RCONHN=CR1R2) are one of the versatile and *Correspondence: ; 1 Department of Chemistry, Faculty of Science, Taibah University, Al‑Madinah Al‑Munawarah, Medina 30002, Saudi Arabia Full list of author information is available at the end of the article attractive functional groups in organic synthesis [8, 9]. Their ability to react with electrophilic and nucleophilic reagents make them valuable candidates for the construction of diverse heterocyclic scaffolds [10]. Some pyridine hydrazones have been reported to possess fascinating chemotherapeutic properties [11, 12]. On the other hand, biological and toxicity of pyridinium salts have been well documented due to their increasing applications. More specifically, pyridinium salts carrying long alkyl chains were found to be outstanding bioactive agents as antimicrobial [13], anticancer [14] and biodegradable [15] agents. Recently, we have reported a green ultrasound synthesis of novel fluorinated pyridinium hydrazones using a series of alkyl halides ranging from C2 to C7 [16]. The biological screening results revealed that the activity increased with increasing the length of the alkyl side chains, especially for hydrazones tethering fluorinated counteranions (PF6−, BF4− and CF3COO−). © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Al‑Blewi et al. Chemistry Central Journal (2018) 12:118 Encouraged by these findings and in continuation of our efforts in designing highly active heterocyclic hydrazones [17–19], we aim to introduce a lipophilic long alkyl chain to a hydrazone skeleton to develop a new class of bioactive molecules. In the present work, a series of novel cationic fluorinated pyridinium hydrazone-based amphiphiles tethering different fluorinated counteranions were designed, synthesized and screened for their anticancer activities against four different cell lines. Additionally, their activities were further characterized via investigating the Caspase-3 signaling pathway, a hallmark of apoptosis that is commonly studied to understand the mechanism of cellular death. Molecular quantum-polarized ligand docking (QPLD) studies were carried out employing MAESTRO [20] software against the kinase domain of phosphoinositide 3-kinase α (PI3Kα) [21] to identify their structural-basis of binding and ligand/receptor complex formation. Results and discussion Synthesis The methodology for affecting the sequence of reactions utilized ultrasound irradiations which have been widely used by our team as an alternative source of energy. Starting from fluorinated pyridine hydrazone 1, the quaternization of pyridine ring through its conventional alkylation with various long alkyl iodide with chain ranging from C8 to C 18, in boiling acetonitrile as well as under ultrasound irradiation and gave the desired cationic fluorinated pyridinium hydrazones 2–9 tethering lipophilic side chain and iodide counteranion in good yields (Scheme 1). Short reactions time were required (10–12 h) when the ultrasound irradiations were used as an alternative energy source (Table 1). The structure of newly designed pyridinium cationic surfactants 2–9 have been elucidated based on their spectral data (IR, NMR, Mass). Their IR spectra revealed the appearance of new characteristic bands at 2870– 2969 cm−1 attributed to the aliphatic C-H stretching which confirmed the presence of alkyl side chain in this structure. The 1H NMR analysis showed one methyl and Page 2 of 18 methylene groups resonating as two multiplets between δH 0.74–0.87 ppm and 1.16–1.32 ppm, respectively. The spectra also showed the presence of characteristic triplet and/or doublet of doublet ranging between δH 4.68– 4.78 ppm assigned to NCH2 protons. In addition, the imine proton (H–C=N) resonated as two set of singlets at δH 8.15–8.50 ppm with a 1:3 ratio. The presence of such pairing of signals confirmed that these compounds exist as E/cis and E/trans diastereomers. The 13C NMR data also confirmed the appearance of E/cis and E/trans diastereomers through the presence of two peaks at δH 58.60 and 62.74 ppm for NCH2. In the downfield region between δC 156.38–165.76 ppm, the carbonyl and the imine carbons of the hydrazone linkage resonated as two sets of signals. (...truncated)