Chinese Chemical Letters  2017, Vol. 28 Issue (7): 1369-1374   PDF    
Novel potentially antibacterial naphthalimide-derived metronidazoles: Design, synthesis, biological evaluation and supramolecular interactions with DNA, human serum albumin and topoisomerase Ⅱ
Jie Kanga, Vijai Kumar Reddy Tangadanchua,1, Lavanya Gopalaa,2, Wei-Wei Gaoa, Yu Chenga, Han-Bo Liua, Rong-Xia Genga, Shuo Lib, Cheng-He Zhoua    
a Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China;
b School of Chemical Engineering, Chongqing University of Technology, Chongqing 400054, China
Abstract: A series of novel naphthalimide-derived metronidazoles as new type of antimicrobial agents were for the first time designed, synthesized and characterized by NMR, IR and HRMS spectra. Experimental results revealed that most of them displayed moderate to good antibacterial activity towards Gram-positive and negative bacteria. Especially, compound 7b was able to not only exhibit effective inhibition towards the growth of P. vulgaris (MIC=0.002 μmol/mL) and S. dysenteriae (MIC=0.01 μmol/mL), but also have rapidly killing effect and prevent the development of bacterial resistance. Further research revealed that the highly active molecule 7b could not only intercalate into calf thymus DNA to form a steady supramolecular complex and thus might block DNA replication to exert the powerful bioactivities, but also be effectively transported by human serum albumin (HSA) via the formation of the 1:1 supramolecular complex, in which hydrogen bonds and hydrophobic effect played important roles in the association of compound 7b with HSA. Molecular docking indicated that the supramolecular interactions between 7b and topoisomerase Ⅱ were driven by hydrogen bonds.
Key words: Metronidazole     Naphthalimide     Antibacterial     Supramolecular     DNA    
1. Introduction

Metronidazole is a widely used clinical drug for the treatment of infectious diseases. Despite of its long term clinical use, there is less report about the incidence of its resistance. Therefore, much research has been directing towards its derivatives, so far many metronidazole derivatives as drugs like ornidazole, secnidazole, tinidazole and nimorazole have been successfully developed and extensively used in clinic [1]. This encourages continuous exploration to investigate metronidazole derivatives with potential medicinal application. It has been found that the formed reactive intermediates in microorganisms via the reduction of nitro group in metronidazole can covalently bind with DNA and trigger the adverse effects [2], so the sterical protection of nitro group is necessary to improve the metabolism and physicochemical property [3]. Our previous work revealed the introduction of a large structural fragment such as berberine and quinolone into metronidazole nucleus can not only exhibit good antimicrobial activities, but also broaden the antimicrobial spectrum [4]. However, to our best knowledge, the combination of metronidazole with napthalimide skeleton was seldom reported.

Naphthalimides have large π-deficient aromatic backbone with cyclic double imides and a naphthalene framework. The special structure makes naphthalimides readily interact with biological active sites via supramolecular interactions such as π-π stacking, cation-π, coordination bonds, hydrogen bonds, ion-dipole, hydrophobic effect, van der Waals and so on, thus exhibiting various biological activities [5]. In particular, some naphthalimide-based compounds like amonafide, mitonafide, elinafide and bisnafide have already shown large potentiality in the treatment of cancers by supramolecular interactions with biological molecule DNA or topoisomerase Ⅱ (Top Ⅱ) [6]. Recently, much literature showed that naphthalimides should also have quite large possibility as new type of antimicrobial agents [7]. Imidazolyl, 1, 2, 3-triazolyl and benzimidazolyl naphthalimides were found to display comparable or even superior antimicrobial activities to the standard drugs Norfloxacin, Chloromycin and Fluconazole [8]. Therefore, it is worth further studying naphthalimide derivatives as new antimicrobial agents.

In view of the above observations, as an extension of our research on metronidazole-based derivatives as new antimicrobial agents, herein a series of novel naphthalimide-derived metronidazoles were designed for the first time (Fig. 1). The introduction of large structural fragment might not only be beneficial to the sterical protection of nitro group to produce the reactive intermediates in microorganisms via the reduction of nitro group in metronidazole, and to avoid triggering the adverse effects, thus overcoming drug resistance, but also be helpful to excellent antimicrobial activity via multiple binding of supramolecular interactions with DNA or Top Ⅱ by the use of π-π stacking, hydrophobic effect, hydrogen bonds and so on. Furthermore, the amino group at the C-4 position of naphthalimide was capable to improve the affinity and water solubility of the target molecules by forming hydrogen bonds and coordination interaction etc. The aliphatic chain was reported to be capable of regulating physicochemical properties, so a series of alkyl substituents were incorporated into the target compounds in order to investigate their effect on biological activities [9].

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Fig. 1. Design of novel naphhtalimide-derived metronidazoles.

All the prepared compounds would be screened against Grampositive bacterial, Gram-negative bacterial and fungal strains including Methicillin-resistant Staphylococcus aureus (MRSA). To further evaluate the prospective of the most active compound as new antibacterial drug, time-kill kinetic assay, and bacterial resistance development research would be done. Moreover, with an aim to explore the possible antibacterial mechanism of the prepared target compounds, the supramolecular interactions with DNA and Top Ⅱ, which are the targets of many antibacterial drugs, would be performed towards the highly active compound. The supramolecular transportation behavior of the highly active compound by HSA would also be investigated to understand the distribution, deposition, metabolism and efficacy.

2. Results and discussion 2.1. Chemistry

The target compounds 7a–g were synthesized via multi-step reactions from commercially available 4-bromo-1, 8-naphthalic anhydride 1. The synthetic process was outlined in Scheme 1. Commercial naphthalic anhydride 1 was treated with aqueous ammonia to produce intermediate 2 in excellent yield of 92%, and was further reacted with chloroacetone in DMF under the presence of potassium carbonate as base to afford compound 3 with a yield of 62%. The latter was brominated to generate the corresponding compound 4 in the yield of 53%. The prepared bromide 4 was coupled with 2-methyl-5-nitroimidazole in DMF at 40 ℃ using potassium carbonate as base to give the desired nitroimidazole 5 in the 64% yield. The reduction of compound 5 by sodium borohydride afforded the metronidazole derivative 6 in moderate yield. The further N-alkylation of compound 6 with various alkyl amines in dimethyl sulphoxide using potassium carbonate as base and copper(Ⅰ) oxide as catalyst under nitrogen atmosphere produced a series of amino type of substituted naphthalimide metronidazoles 7a–g in the moderate yields ranging from 40% to 60%. All the new compounds were confirmed by NMR, IR and HRMS spectra.

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Scheme 1. Synthetic route of naphthalimide-derived metronidazoles. Reagents and conditions: (ⅰ) aqueous ammonia, 45 ℃, 8 h; (ⅱ) chloroacetone, potassium carbonate, DMF, 100 ℃, 7 h; (ⅲ) bromine, acetic acid, 60 ℃, 3 h; (ⅳ) 2-methyl-5-nitroimidazole, potassium carbonate, DMF, 40 ℃, 5 h; (ⅴ) sodium borohydride, ethanol, 60 ℃, 6 h; (ⅵ) amines, copper(Ⅰ) oxide, potassium carbonate, DMSO, 90 ℃, 4 h.

2.2. Biological activity

As shown in Table S1 in Supporting information, most of the prepared compounds gave moderate to good antibacterial activity against the tested strains in vitro. The amino type of target compounds 7a–g possessed the better antibacterial efficacy than intermediates 5 and bromo-substituted naphthalimide metronidazole 6, which demonstrated that positive effect of amino group on biological activity. Especially, ethylamino deriavtive 7b showed relatively good broad-spectrum and efficient antibacterial activities in comparison with other compounds. The anti-P. vulgaris potency of compound 7b among the target compounds was the strongest with an excellent MIC value of 0.002 μmol/mL, which was 95-fold, 50-fold and 10-fold more potent than reference drugs Metronidazole, Chloromycin and Norfloxacin, respectively. Furthermore, S. dysenteriae and E. coli (DH52) were more sensitive to compound 7b (MIC = 0.01 and 0.04 μmol/mL, respectively) than Chloromycin (MIC = 0.05 and 0.10 μmol/mL, respectively). Moreover, compound 7b also exhibited better activity against MRSA, S. aureus and B. typhi than Chloromycin. Notably, derivative 7b showed 5-fold inhibition potency against MRSA than Metronidazole with a MIC value of 0.04 μmol/mL. These indicated that naphthalimide metronidazole 7b had large potentiality as a lead compound in the development of more effective board-spectrum antimicrobial agents. Continual studies found that the length of the alkyl chain also had a certain effect on the antibacterial efficacy. The replacement of ethyl group by dodecyl fragment, which yielded compound 7e, resulted in low activity towards the tested strains. Moreover, the antibacterial activities of compounds 7a, 7c and 7d were also weaker than those of the highly active molecule 7b. These results suggested that the appropriate alkyl chain was beneficial for the biological activity of the target compounds. In comparison with compound 7b, the introduction of hydroxyl group into the alkyl chain, which yielded hydroxyethyl amino compound 7f, did not improve inhibition potency. The ethylation of secondary amino group in compound 7b gave compound 7g which also did not increase antibacterial potency, except for against B. typhi with the MIC value of 0.04 μmol/mL, which was 2.5-fold more potent than Chloromycin (MIC = 0.10 μmol/mL). The antifungal results (Table S2 in the Supporting information) showed that most of the target compounds had similar inhibitory tendency and intensity to their antibacterial activity. The antifungal activity of compound 7b was stronger than other target compounds against all tested fungi with MICs between 0.01 and 0.04 μmol/mL. Particularly, compound 7b showed 5-fold more active potency against B. yeast (MIC = 0.01 μmol/mL) than Fluconazole, and stronger activity against C. utilis (MIC = 0.02 μmol/mL) than Fluconazole. All naphthalimide-derived metronidazoles possessed better anti-A. flavus (MIC = 0.04–0.29 μmol/mL) efficiency than Fluconazole (MIC = 0.84 μmol/mL).

2.3. Resistance study

MRSA has been challenging the effectiveness of antibiotics including Norfloxacin [10]. Herein, the ability of MRSA to develop drug resistance against the most active compound 7b was tested and clinical drug Norfloxacin was chosen as a positive control. As can be seen from Fig. 2, it indicated that the MIC for compound 7b showed no obvious change, whereas that of Norfloxacin began to significantly increase after 5 passages against MRSA. It demonstrated that MRSA was more difficult to develop resistance against compound 7b than clinical Norfloxacin.

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Fig. 2. Evaluation of resistance development against compound 7b in bacterial strain MRSA.

2.4. Bactericidal kinetic assay

To determine the bactericidal potency of the synthesized compounds, the viability of exponentially growing MRSA against the most active 7b was investigated by time–kill kinetics experiment [11]. The data revealed more than 3 log (CFU/mL) reduction in the number of viable bacteria in one hour at a concentration of 4 × MIC (refer to Fig. S1 in Supporting information). The experimental result manifested that compound 7b had rapidly killing effect against MRSA.

2.5. Cytotoxicity

The in vitro cytotoxic activity of compound 7b was evaluated in MCF-7 (human breast adenocarcinoma) cells by Cell Counting Kit-8 (CCK8) method. As shown in Fig. S2 in Supporting information, when the concentration of compound 7b was 6.25 μg/mL, the cell viability was 70.4%. With the increasing concentration of compound 7b, the toxicity gradually became high and the IC50 value was 8.51 μg/mL, which suggested that it might be a promising candidate to treat cancer.

2.6. Supramolecular interactions with calf thymus DNA

The investigation of supramolecular interactions is a prevalent active field, especially in developing supramolecular drugs [12]. DNA is a main cellular target for antimicrobial agents. There is considerable attention in investigating the supramolecular interactions of small molecules with DNA for the rational design of new and efficient DNA targeting drugs [13]. To explore the preliminary mechanism of antimicrobial action, calf thymus DNA was often employed as DNA model [14]. Neutral Red (NR) is a convenient planar phenazine dye which has been demonstrated that the binding mode of NR with DNA is intercalation [15]. Therefore, NR was selected as a spectral probe to explore the binding model between the biological active compound 7b and calf thymus DNA on molecular level in vitro by UV–vis spectroscopy (Supporting information).

The absorption spectra of supramolecular interactions of the most active compound 7b with DNA were shown Fig. 3. With the increasing concentration of 7b, an apparent intensity increase was observed in the developing band around 460 nm. In comparison to the absorption around 460 nm of free NR in the presence of the increasing concentrations of DNA (Fig. S4 in Supporting information), the absorbance at the same wavelength exhibited the reverse process (inset of Fig. 3). The results suggested that compound 7b should intercalate into the double helix of DNA by substituting for NR in the DNA–NR complex. In addition, the increase of absorbance at 276 nm provided evidence for intercalation of compound 7b into DNA.

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Fig. 3. UV absorption spectra of supramolecular interactions of the active compound 7b with DNA. c(DNA) = 4.32 × 10-5 mol/L, c(NR) = 2 × 10-5 mol/L, and c (compound 7b) = 0 -2.25 × 10-5 mol/L for curves a -i, respectively, at increment 0.25 × 10-5.

2.7. Supramolecular interactions of compound 7b with HSA

HSA is a main carrier protein for a variety of endogenous and exogenous substances in the body, therefore assists in their distribution and deposition [16]. It has been well accepted that the overall distribution, metabolism, and efficacy of drugs can be changed by their affinity to HSA. So the investigation of supramolecular interactions with HSA can provide a better understanding of the absorption, transportation, distribution, metabolism and excretion properties of drug molecules [17]. The experimental results (Table 1) indicated that compound 7b could spontaneously interact with HSA to form 1:1 stable supermolecular complex via hydrophobic effect and hydrogen bonds (Supporting information).

Table 1
Binding constants and sites of 7b–HSA supramolecular system.

2.8. Supramolecular interactions of compound 7b with topoisomerase Ⅱ

To rationalize the observed antibacterial activity and understand the possible mechanism, the supramolecular docking investigation of compound 7b with topoisomerase Ⅱ receptor (PDB code: 1ZXN) was undertaken [18]. The mimetic results showed that compound 7b possessed a high total score (9.02) against topoisomerase Ⅱ. Supramolecular interactions of compound 7b with topoisomerase Ⅱ receptor was shown in Fig. 4, the amido groups could interact with Ser149 and Lys418 residues of Top Ⅱ through hydrogen bonds with the distance of 2.4 Å and 2.7 Å, respectively. Furthermore, the hydroxyl group could form hydrogen bonds with Ala167 and Asn91 residues in nearly 2.1 Å distance. There were also hydrogen bonds between nitro group and residues of Tyr165 and Asn163 with the distance of 1.7 Å and 2.8 Å, respectively. These multi-site bindings might be favorable to stabilize the compound 7b–topoisomerase Ⅱ supramolecular complex, which might be responsible for the good inhibitory efficacy of compound 7b against the tested strains.

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Fig. 4. Stereoview of conformation of compound 7b–topoisomerase Ⅱ supramolecular complex.

3. Conclusion

A series of novel naphthalimide-derived metronidazoles were for the first time designed and successfully synthesized as potential antibacterial agents through a convenient and efficient procedure. All the target compounds were confirmed by NMR, IR and HRMS spectra. The in vitro antimicrobial evaluation revealed that some of the target compounds could effectively inhibit the growth of some tested strains. Structure–activity relationship suggested that aliphatic chains at the C-4 position of naphthalimide exerted a certain impact on biological activity. The most active compound 7b with the ethylamino group could effectively inhibit the growth of P. vulgaris and S. dysenteriae with MIC values of 0.002 and 0.01 μmol/mL, respectively. Importantly, compound 7b had the ability to rapidly kill the tested strains and did not trigger development of bacterial resistance. Moreover, the most active molecule 7b could not only intercalate into calf thymus DNA to form a steady supramolecular complex which might block DNA replication to display the antibacterial activity, but also be effectively transported by HSA via the formation of the 1:1 biological supramolecular complex, in which hydrogen bonds and hydrophobic effect played important roles in the association of compound 7b with HSA. Molecular docking indicated that the supramolecular interactions between 7b and topoisomerase Ⅱ were driven by hydrogen bonds. Additionally, compound 7b showed concentration-dependent toxicity to MCF-7 cells. Further research studies including in vivo bioactivities, structural modification alicyclic amines (morpholine, pyrrolidine, piperidine and piperazine, etc.) and heterocyclic azole rings (triazole, benzimidazole, their derivatives, etc.) into the naphthalimide backbone as well as their corresponding metal supramolecular complexes are now in progress. All these will be discussed in the full paper.

4. Experimental 4.1. General procedures for synthesis of compounds

General procedures for synthesis of compounds 2–6 have been provided in Supporting information.

4.2. Synthesis of 6-(ethylamino)-2-(2-hydroxy-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propyl)-1H-benzo[de] isoquinoline-1, 3(2H)-dione (7b)

A mixture of compound 6 (4.59 g, 10 mmol), ethylamine (4.51 g, 100 mmol), copper(Ⅰ) oxide (0.29 g, 2 mmol), potassium carbonate (0.69 g, 5 mmol) in dimethyl sulfoxide (10 mL) was stirred at 90 ℃ for 4h (monitored by TLC, eluent, chloroform/methanol, 40:1, v/v). After the solvent was evaporated under reduced pressure, and the resulting residue was extracted with chloroform (3 ×30 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with chloroform/methanol (50:1, V/V) to give the compound 7b (2.46 g) as the yellow solid. Yield: 58%; mp: > 250 ℃; IR (KBr, cm-1) ν: 3377 (O-H), 3137 (N-H), 1675 (C=O), 1637, 1580, 1500, 1456 (aromatic frame); 1H NMR (600MHz, DMSO-d6): δ 8.70 (d, 1H, J=8.1Hz, NAPH-H), 8.45 (d, 1H, J=7.0Hz, NAPH-H), 8.28 (d, 2H, J=8.5Hz, NAPH-H, Im-4-H), 7.69 (dd, 2H, J=17.4, 9.7Hz, NAPH-H, -NHCH2), 6.78 (d, 1H, J=8.3Hz, NAPH-H), 5.45 (d, 1H, J=4.3Hz, OH), 4.13 (tdd, 4H, J=17.1, 11.8, 5.4Hz, NAPH-CH2, Im-CH2), 3.95 (dd, 1H, J=13.7, 8.9Hz, OH-CH), 3.43 (m, 2H, -NHCH2), 2.35 (s, 3H, Im-CH3), 1.31 (t, 3H, J=6.6Hz, -CH2CH3); 13C NMR (151MHz, DMSO-d6): δ 164.7, 163.8, 151.1, 146.1, 145.7, 134.8, 131.2, 130.2, 129.0, 124.7, 123.1, 122.6, 120.7, 108.3, 104.2, 68.1, 51.3, 43.5, 38.0, 14.1, 13.4; HRMS (ESI) calcd. for C21H21N5O5 [M+Na]+, 446.1440; found, 446.1443.

Synthesis of compounds 7a and 7c–g according to the procedure described for compound 7b.

4.3. General methods for biological assays

The antimicrobial activity in vitro for all the target compounds were evaluated for four Gram-positive bacteria (Staphylococcus aureus ATCC25923, Methicillin-Resistant Staphylococcus aureus N315 (MRSA), Bacillus subtilis ATCC6633 and Micrococcus luteus ATCC4698), six Gram-negative bacteria (Escherichia coli DH52, Escherichia coli JM109, Pseudomonas aeruginosa ATCC27853, Shigella dysenteriae, Proteus vulgaris and Bacillus typhi) and five fungi (Candida albicans ATCC76615, Candida mycoderma, Candida utilis, Aspergillus flavus and Beer yeast) using two folds serial dilution technique in 96–well micro-test plates recommended by National Committee for Clinical Laboratory Standards (NCCLS) with the positive control of clinically antimicrobial drugs Chloromycin, Norfloxacin, Metronidazole and Fluconazole.

General methods for resistance, bactericidal kinetic assays have been provided in Supporting information.

General methods for supramolecular interactions with DNA, HSA, and topoisomerase Ⅱ have been provided in Supporting information.

Acknowledgments

This work was partially supported by National Natural Science Foundation of China (Nos. 21372186, 21672173), the Research Fund for International Young Scientists from International (Regional) Cooperation and Exchange Program (No. 81650110529) and Chongqing Special Foundation for Postdoctoral Research Proposal (No. Xm2016039).

Appendix A. Supplementary data

Supplementary data associatedwith this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2017.04.002.

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