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Synthesis of new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives as anti-MRSA and anti-H. pylori agents

Abstract

In this work, we have synthesized twenty five new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing an aryl or heteroaryl methylene group on position 5 of thiazolidinone and evaluated their antimicrobial activity against Gram-positive and -negative bacteria as well as three metronidazole resistant Helicobacter pylori strains. Most of the compounds were very potent towards tested Gram-positive bacteria and showed an antibacterial efficacy substantially greater than ampicillin as the reference drug. However, no effectiveness was observed for the Gram-negative microorganisms. The compounds 9, 20 and 29 exhibited strong antimicrobial activity against Helicobacter pylori strains (inhibition zone > 30 mm) in 100 μg/disc and (inhibition zone > 20 mm) in 50 μg/disc. Taking these findings together, it seems that these potent antibacterial derivatives could be considered as promising agents for developing new anti-infectious drugs against microorganisms resistant to currently available antibiotics.

Graphical Abstract

Introduction

Treatment of infectious diseases remains one of the most important and challenging areas in global public health. Infections that are caused by microbes are a paramount cause of death worldwide, specifically in low-income countries. The World Health Organization (WHO) has mentioned three infectious diseases: lower respiratory infections, diarrheal diseases, and tuberculosis in the list of top ten causes of death worldwide in 2016 [1]. Although various antimicrobial and antifungal agents have been discovered in the last decades, the substantial need for finding new potent antimicrobials still remains of great concern owing to the rapid growth in microbial resistance and emergence of multi-drug resistant pathogens [2]. Designing new agents that utilize different targets and mechanisms of action can be a useful approach to deal with microbial resistance and particularly cross-resistance with conventional antimicrobial therapeutics.

Thiazolidinone ring is a promising pharmacophore that has possessed a broad spectrum of pharmacological actions such as antimicrobial (compound A) (Fig. 1) [3,4,5], antiviral [6], antiparasitic [7, 8], analgesic, anti-inflammatory [9], antioxidant [10], anticancer [6, 7, 11], antidiabetic [12], antihypertensive, anti-hyperlipidemic, anti-arrhythmic [13], anti-convulsant activities [14, 15]. In the last two decades, 4-thiazolidinone pharmacophore has received great attention for its inhibitory effect on MurB and various substituted 4-thiazolidinones were explored for their antibacterial activity. MurB is an essential enzyme in the bacterial peptidoglycan synthesis pathway. It reduces UDP-N-acetylglucosamine enolpyruvate to UDP-N-acetylmuramic acid, a crucial precursor in peptidoglycan biosynthesis process. Presence of MurB in both Gram positive and negative bacteria and its absence in eukaryotic cells makes it a potential target for designing new antibacterial agents [3, 16, 17]. It appears that 4-thiazolidinone moiety interacts with MurB active site by imitating diphosphate moiety of UDP-N-acetylglucosamine enolpyruvate; It was also observed that presence of aromatic rings bearing electron withdrawing groups and heterocyclic cores could improve antibacterial activity of 1,3-thiazolidin-4-ones [18].

Fig. 1
figure 1

The design of target compounds by incorporating 4-thiazolidinone, 1,3,4-thiadiazole and 5-nitrofuran rings

Thiadiazoles are nitrogen and sulfur-containing aromatic five-membered rings that have exhibited numerous biological activities [19, 20]. The presence of = N − C − S − moiety enables the 1,3,4-Thiadiazole heterocyclic core to actively interact with biomolecules and, at the same time the mesoionic character of thiadiazole ring grants good cell permeability for the compounds bearing it [19]. There are already many 1,3,4-thiadiazole nucleus containing drugs such as acetazolamide, methazolamide, megazol, cefozopram [13], cefazolin [19] in the market. Based on the literature, many of the 2-amino-1,3,4-thiadiazole derivatives have shown great antimicrobial activities against various pathogens (compound B) (Fig. 1) [13, 19,20,21]. In addition, several studies have revealed that derivatives containing thiadiazole ring attached to thiazolidinone moiety offer good antibacterial effects [3, 22].

Another interesting heterocyclic core is 5-nitrofuran that is used in several antibacterial agents already available in the market like nitrofurantoin, nifuroxazide, furazolidone, nitrofural, nifurtoinol, furazidin, difurazone, and nifurquinazol [23, 24]. Different nitroreductase enzymes, available in both aerobic and anaerobic bacteria, easily reduce 5-nitrofuran derivatives and form various nitro radical anions and cyano derivatives. Although, the exact toxic intermediate species as well as their cellular targets are still undiscovered, but it is supposed that these reduced reactive intermediates can interfere with diverse critical bacterial pathways through damaging both DNA and proteins [23, 25].

In our previous study, several new compounds bearing 5-nitrothiophen moiety in conjugation with 1,3,4-thiadiazole-2-ylimino-4-thiazolidinone scaffold have been found to exhibit notable antibacterial activities against S.aureus, S.epidermidis, B.cereus and B.subtilis as Gram-positive bacteria and H. pylori [3]. According to the former mentioned study and by means of molecular hybridization and incorporation of different mentioned active pharmacophores in a new structure, the target 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives 7–31 (Fig. 1) were designed, synthesized and their antibacterial activity against some strains of Gram-positive and Gram-negative bacteria as well as H. pylori was evaluated.

Results and discussion

Chemistry

The target 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives were synthesized according to the multistep reaction procedure indicated in our previous paper (Scheme 1) [3].

Scheme 1
scheme 1

Synthesis of 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives 7–31. Reagents and conditions: a) Thiosemicarbazide, Ethanol, Hydrochloric Acid, Reflux, 1.5 h, b) Ferric Ammonium Sulfate, Water, Reflux 24 h, c) Chloroacetyl Chloride, Toluene, 80–90 °C, 3 h, d) Ammonium thiocyanate, Ethanol, reflux, 3 h, e) ArCHO, Sodium Acetate, Acetic Acid, Reflux, 24 h

5-nitrofuran-2-carbaldehyde 1 and thiosemicarbazide 2 were commercially available and reacted in refluxing ethanol under acidic condition to yield 1-((5-nitrofuran-2-yl)methylene)thiosemicarbazide 3. The 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-amine 4 was obtained by oxidative cyclization of 3 in the presence of ferric ammonium sulfate (FAS). The thiazolidinone ring was formed through the reaction of 4 with chloroacetyl chloride in dry toluene at 80–90 °C to give intermediate 5, which was subsequently treated with ammonium thiocyanate in refluxing ethanol to afford 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one 6. To obtain the final compounds 7–31, compound 6 reacted with respective aromatic or heteroaromatic aldehydes in the acidic conditions.

The structures of newly synthesized compounds 7–31 were characterized by 1H-NMR, FT-IR, and mass spectra. In the 1H-NMR spectral data, the signal for thiazolidinone NH group was observed as a broad singlet at δ 12.84–13.25 ppm, and the singlet signal for = CH in the arylidene appeared at δ 7.63–7.83 ppm. The signals for two hydrogens of furan ring were found as two broad singlets at δ 7.73–8.07 and 7.53–7.61 ppm. In the FT-IR spectra, the characteristic signals for carbonyl moiety appeared at 1694–1743 cm−1. Additionally, the absorption bands of the NH group at 3072–3262 cm−1 and asymmetric and symmetric bands of NO2 group at 1518–1581 and 1347–1362 cm−1 confirmed the structures.

Biological activity

The antibacterial activity of the final compounds 7–31 was evaluated by determining their minimal inhibitory concentration (MIC) against the following strains: S. aureus ATCC 6538, MRSA ATCC 33591, S. epidermidis ATCC 12228, M. luteus ATCC 9341, B. subitilis ATCC 6633, B. cereus PTCC 1247, E. faecalis ATCC 11700, E. coli ATCC 8739, P. aeruginosa ATCC 9027, K. pneumonia ATCC 10031, S. typhimurium ATCC 14028. These compounds were also tested against three clinically isolate metronidazole resistant strains of H. pylori [26].

As shown in Table 1, most of the compounds showed significant antibacterial activity that was better than ampicillin as the reference drug against the rest of Gram-positive bacteria; however all the Gram-negative bacteria including E. coli, K. pneumonia, P. aeruginosa, and S. typhimurium (except H. pylori) were resistant to the target compounds (MIC > 200). According to the results, the most sensitive bacteria appeared to be S. aureus, MRSA, S. epidermidis, and B. cereus, while M. luteus was the most resistant. Compounds 17 and 28 showed the greatest antibacterial activity against S. aureus (MIC = 0.01 µg/ml), and S. epidermidis (MIC = 0.02 µg/ml); 8, 17, 28, 29 were the most active compounds on MRSA (MIC = 1.56 µg/ml), 18 and 28 were the most potent compounds toward B. cereus (MIC = 0.097 µg/ml) being almost 330 times more active than ampicillin. Most tested derivatives showed respectable activity toward E. faecalis; however they were less active than ampicillin as the reference drug, with the exception of 17 (MIC = 0.78 µg/ml), that was 2.5 times more potent than ampicillin (MIC = 2 µg/ml). Also, only compound 28 (MIC = 0.097 µg/ml) was more potent than the reference drug (MIC = 0.125 µg/ml) in terms of activity toward B. subitilis. Besides, although M. luteus was not resistant to the rest of the compounds, none of the target compounds was more potent than the reference drug against M. luteus. Unlike our previous study that had shown compounds bearing 2-, 3-pyridyl moiety on thiazolidinone ring were the most active compounds against S. aureus, S. epidermidis, B. cereus and B. subtilis, 3-pyridyl containing derivative 26 was only more potent than ampicillin against B. cereus.

Table 1 Antibacterial activities of compounds 7–31 and ampicillin against selected Gram-positive strains (MICs in µg ml−1)

Considering proper anti-H. pylori activity of similar derivatives in previous studies as well as good antibacterial activity of the title compounds against various Gram-positive bacteria, the anti-H. pylori activities of our target compounds were evaluated [3, 27]. The activity of compounds 7–31 was assessed by in vitro paper disk diffusion bioassay and measuring Inhibition Zone Diameters (IZDs) of compounds at 100, 50, 25, and 12.5 µg/disk concentrations against three metronidazole resistant strains of H. pylori. The inhibition zone diameters (IZDs) were recorded and the antimicrobial activity was expressed as mean ± SD IZDs (mm) produced by selected compound against three clinical H. pylori isolates. H. pylori strains were considered as susceptible when exhibited growth inhibition zones of ≥ 15 mm for each compound. Metronidazole was used as reference drug and no inhibition zone was found in all recruited doses.

As Table 2 shows, 12 synthesized compounds exhibited anti-H. pylori activity at recruited concentrations. MICs were deremined as 12.5 µg/disk for compounds 8, 9, 20 and 29, 25 µg/disk for compound 17 and 100 µg/disk for compound 71015161825 and 30. All the remanaing 13 compounds showed weak anti-H. pylori activity at 100 µg/disk conentration (7 < IZDs < 15 mm) which needs further studies.

Table 2 In vitro antibacterial activity and MIC of selected compounds against three clinical strains of H. pylori using disc-diffusion method. IZD cutoff value > 15 mm was used for MIC determination

In order to investigate the safety and cytotoxicity of the target compounds, the in silico toxicity evaluation was performed by means of osiris property explorer (OPE) (https://www.organic-chemistry.org/prog/peo/) which shows the probable mutagenic, tumorgenic, irritant and reproductive effects of compounds and vNN web server was used to study their cytotoxicity [28]. The results were shown in Additional file 1: Table S1. According to the results the mutagenic property of 28 and 29, the tumurgenic activity of 14 and 29 and reproductive effect of 20 are possible. The medium irritant and reproductive effects of 24 were predicted by OPE. The cytotoxicity results of vNN indicate that none of the compounds 7–31 were cytotoxic. The MTT test showed that the IC50 of compounds 8 and 18 was more than 50 µg/ml and the the IC50 of compounds 17 and 29 was 19.45 ± 1.09 and 32.93 ± 1.05 respectively. The comparison of their antibacterial concentrations with the related cytotoxic results depicted their acceptable selectivity index.

Structure–Activity Relationship (SAR)

As Table 1 shows, among five different aryl and heteroaryles introduced to position 5 of thizolidinone ring, attachment of 2-furyl ring 28 led to excellent activity against S. aureus, MRSA, S. epidermidis, B. subtilis and B. cereus. Replacement of 2-furyl with unsubstituted phenyl 7 and 2-thienyl 30 moieties resulted in a slight decrease in the activity, but the compounds were still very active. However, unlike the results from our previous study [3], the insertion of 3-pyridyl 26 moiety had a deteriorative effect on antibacterial activity.

The substitution of 4-Me group on phenyl ring improved activity, while 4-OMe and 4-SMe decreased the activity of 9 and 10. In addition, the introduction of the more polar electron-donating OH group on meta and para positions of phenyl ring, reduced antibacterial activity.

Introduction of non-polar electron-withdrawing halogens on the para position of phenyl ring affected the antimicrobial activity in the following order: 4-F > 4-H > 4-Cl > 4-Br. Also, the effect of positioning each halogen at the ortho, meta, and para sites of phenyl ring was as follows: 4-Cl > 3-Cl > 2-Cl and 2-Br > 3-Br > 4-Br. 2,6-dichloro substitution on the phenyl ring resulted in high antimicrobial activity in compound 17. Yet again, the introduction of polar electron withdrawing nitro substituent on both aryl and heteroaryl ring systems led to significant diminishing in antibacterial activity. Bulky substituents at meta and para positions of 24 and 25 seem unfavorable for antibacterial activity.

With these findings in mind, it seems that the presence of bulky polar substituents on the para position of the phenyl ring has a negative impact on antibacterial activity and 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing small aryl or heteroaryl groups with non-bulky and non-polar substituents, are favorable for antibacterial activity against Gram-positive bacteria.

Anti-H. pylori assay data, as shown in Table 2, revealed that the unsubstituted phenyl ring led to better anti-H. pylori activity in comparison to other unsubstituted heteroaryles. The sequence of their activity was in the following order: phenyl > 2-thienyl > 2-furyl > 2-indolyl > 3-pyridyl. Introduction of electron-donating groups on the para position of the phenyl ring, improved activity and compounds 8, 9 and 20 bearing 4-Me, 4-OMe and 4-OH showed strong anti-H. pylori activity [MIC (12.5 µg/disk)]. However, the displacement of the hydroxyl group to meta position reduced activity. Generally, it seems that presence of both polar and non-polar electron-withdrawing groups on the phenyl ring reduces the efficacy of compounds on H. pylori. The only exceptions were compound 17, having 2,6-dichloro substitution on the phenyl ring, and compound 29, bearing 5-nitro-2-furyl moiety, which showed stronger activities. These results indicate that small electron-donating substituent on the para position of aryl ring can lead to better anti-H. pylori activity.

Conclusions

In summary, new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing an aryl or heteroaryl methylene group on position 5 of thiazolidinone were synthesized and examined for their antimicrobial and anti-H. pylori activity. The in vitro Biological data illustrated that many of these derivatives were potent active growth inhibitors against Gram-positive bacteria as well as H. pylori whereas Gram-negative microorganisms were not susceptible to them.

The MIC determination results exhibited that most of the compounds showed better activity than ampicillin as the reference drug versus MRSA, S. epidermidis and B. cereus and Compounds 17 and 28 were the most active compounds. The anti-H. pylori assay showed that compounds 8, 9, 20 and 29 had strong growth inhibitory activity at 12.5 µg/disk concentrations against three metronidazole resistant strains. Based on these results, it seems that 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing small aryl or heteroaryl groups with non-bulky non-polar substituents, are favorable for antibacterial activity against Gram-positive bacteria. On the other hand, the small polar substituents on the para position of aryl or heteroaryl methylene group can lead to better anti-H. pylori activity.

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Experimental section

General procedure for the synthesis of compounds 7–31

To a well-stirred solution of 6 (0.2 g, 0.64 mmol) in glacial acetic acid (35 ml) buffered with anhydrous sodium acetate (1.83 mmol), the respective aryl aldehyde (1.28 mmol) was added. The solution was refluxed for 24–72 h and then poured into ice-cold water. The precipitate was filtered and recrystallized from ethanol to give compounds 7–31 (All the compounds were recrystallized from ethanol except compounds 11, 12, 13, 18, 19 and 20 that were recrystallized in ethyl acetate).

2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)-5-benzylidenethiazolidin-4-one (7). Yield: 90%. M.p. 292–293 °C. IR (KBr): 3164 (NH), 1712 (C = O), 1562, 1353 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.17 (bs, 1H, NH); 7.91 (bs, 1H, furan); 7.82 (s, 1H, = CH); 7.67–7.53 (m, 6H, aromatic, furan). MS (m/z, %): 399 (M+, 5), 368 (42), 236 (14), 212 (13), 134 (65), 111 (20), 97 (36), 83 (45), 69 (60), 57 (100). Anal. Calcd. For C16H9N5O4S2: C, 48.12; H, 2.27; N, 17.54, Found: C, 48.43; H, 2.06; N, 17.23.

5-(4-Methylbenzylidene)-2-[5-(5-nitro-furan-2-yl)-[1,3,4]thiadiazol-2-ylimino]-thiazolidin-4-one (8). Yield: 68%. M.p. 306–308 °C. IR (KBr): 3138 (NH), 1714 (C = O), 1562, 1349 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.08 (bs, 1H, NH); 7.89 (bs, 1H, furan); 7.75 (s, 1H, = CH); 7.56 (bs, 3H, aromatic, furan); 7.38 (bs, 2H, aromatic); 2.36 (s, 3H, CH3). MS (m/z, %): 413 (M+, 18), 148 (100), 82 (16), 69 (12), 57 (18). Anal. Calcd. For C17H11N5O4S2: C, 49.39; H, 2.68; N, 16.94, Found: C, 49.71; H, 2.97; N, 16.60.

5-(4-methoxybenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (9). Yield: 72%. M.p. 284–286 °C. IR (KBr): 3097 (NH), 1696 (C = O), 1563, 1351 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.14 (bs, 1H, NH); 7.93 (bs, 1H, furan); 7.83 (s, 1H, = CH); 7.64 (bs, 2H, aromatic); 7.56 (bs, 1H, furan); 7.15 (bs, 2H, aromatic); 3.84 (s, 3H, OCH3). MS (m/z, %): 429 (M+, 6), 212 (81), 164 (100), 149 (52), 138 (34), 121 (29), 110 (19), 97 (32), 82 (61), 69 (54), 57 (71). Anal. Calcd. For C17H11N5O5S2: C, 47.55; H, 2.58; N, 16.31, Found: C, 47.89; H, 2.27; N, 16.43.

5-(4-(methylthio)benzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (10). Yield: 70%. M.p. 305–307 °C. IR (KBr): 3080 (NH), 1710 (C = O), 1560, 1352 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.03 (bs, 1H, NH); 7.89 (bs, 1H, furan); 7.75 (bs, 1H, = CH); 7.57 (bs, 3H, aromatic, furan); 7.43 (bs, 2H, aromatic); 2.5 (s, 3H, CH3). MS (m/z, %): 445 (M+,18), 368 (14), 180 (100), 165 (42), 121 (19), 97 (25), 83 (31), 69 (43), 57 (63). Anal. Calcd. For C17H11N5O4S3: C, 45.83; H, 2.49; N, 15.72, Found: C, 46.11; H, 2.20; N, 15.37.

5-(2-bromobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (11). Yield: 78%. M.p. 293–295 °C. IR (KBr): 3120 (NH), 1716 (C = O), 1561, 1352 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.20 (bs, 1H, NH); 7.90 (bs, 1H, furan); 7.82–7.44 (m, 6H, = CH, furan, aromatic). MS (m/z, %): 478 (M+ + 2, 23), 476 (M+, 22), 214 (100), 212 (99), 97 (42), 69 (54), 57 (76). Anal. Calcd. For C16H8BrN5O4S2: C, 40.18; H, 16.71; N, 14.64, Found: C, 40.52; H, 16.36; N, 14.28.

5-(3-bromobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (12). Yield: 78%. M.p. 293–295 °C. IR (KBr): 3072 (NH), 1720 (C = O), 1571,1354 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.22 (bs, 1H, NH); 7.90 (bs, 1H, furan); 7.87–7.55 (m, 6H, = CH, furan, aromatic). MS (m/z, %): 478 (M+ + 2, 28), 476 (M+, 27), 214 (100), 212 (99), 97 (51), 82 (39), 57 (74). Anal. Calcd. For Anal. Calcd. For C16H8BrN5O4S2: C, 40.18; H, 16.71; N, 14.64, Found: C, 39.97; H, 16.93; N, 14.29.

5-(4-bromobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (13). Yield: 91%. M.p. 336–338 °C. IR (KBr): 3095 (NH), 1716 (C = O), 1569, 1352 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.17 (bs, 1H, NH); 7.89 (bs, 1H, furan); 7.76 (bs, 3H, = CH, aromatic); 7.58 (bs, 3H, furan, aromatic). MS (m/z, %): 478 (M+ + 2, 40), 476 (M+, 39), 214 (100), 212 (99), 133 (30), 89 (38). Anal. Calcd. For Anal. Calcd. For C16H8BrN5O4S2: C, 40.18; H, 16.71; N, 14.64, Found: C, 39.91; H, 16.99; N, 14.83.

5-(2-chlorobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (14). Yield: 68%. M.p. 304–306 °C. IR (KBr): 3092 (NH), 1719 (C = O), 1579, 1362 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.21 (bs, 1H, NH); 7.94–7.52 (m, 7H, = CH, furan, aromatic). MS (m/z, %): 435 (M+ + 2, 4), 433 (M+, 12), 170 (33), 168 (100), 69 (35), 57 (44). Anal. Calcd. For C16H8ClN5O4S2: C, 44.30; H, 1.86; N, 16.14, Found: C, 44.39; H, 2.01; N, 16.02.

5-(3-chlorobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (15). Yield: 75%. M.p. 288–290 °C. IR (KBr): 3092 (NH), 1718 (C = O), 1518, 1356 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.20 (bs, 1H, NH); 7.89 (bs, 1H, furan); 7.79–7.58 (m, 6H, = CH, furan, aromatic). MS (m/z, %): 435 (M+ + 2, 5), 433 (M+, 15), 170 (33), 168 (100), 139 (44), 111 (22), 85 (20), 69 (38), 57 (48). Anal. Calcd. For C16H8ClN5O4S2: C, 44.30; H, 1.86; N, 16.14, Found: C, 44.59; H, 1.69; N, 16.10.

5-(4-chlorobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (16). Yield: 90%. M.p. 284–286 °C. IR (KBr): 3115 (NH), 1711 (C = O), 1564, 1351 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.17 (bs, 1H, NH); 7.89 (bs, 1H, furan); 7.79 (s, 1H, = CH); 7.66–7.58 (m, 5H, furan, aromatic). MS (m/z, %): 435 (M+ + 2,6), 433 (M + ,2), 170 (33), 168 (100), 139 (47), 111 (21), 85 (25), 69 (24), 57 (35). Anal. Calcd. For C16H8ClN5O4S2: C, 44.30; H, 1.86; N, 16.14, Found: C, 44.48; H, 1.76; N, 16.02.

5-(2,6-dichlorobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (17). Yield: 86%. M.p. 237–239 °C. IR (KBr): 3128 (NH), 1710 (C = O), 1581, 1348 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.20 (bs, 1H, NH); 7.89 (bs, 1H, furan); 7.98–7.56 (m, 5H, = CH, furan, aromatic). MS (m/z, %): 471 (M+ + 4, 10), 469 (M+ + 2, 7), 467 (M+, 1), 432 (90), 206 (100), 204 (66), 202 (11), 167 (21), 123 (19), 82 (28), 69 (10),53 (10). Anal. Calcd. For C16H7Cl2N5O4S2: C, 41.04; H, 1.51; N, 14.96, Found: C, 41.14; H, 1.74; N, 14.33.

5-(4-fluorobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (18). Yield: 75%. M.p. 269–271 °C. IR (KBr): 3137 (NH), 1715 (C = O), 1575, 1349 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.18 (bs, 1H, NH); 7.92 (bs, 1H, furan); 7.25 (s, 1H, = CH); 7.75 (bs, 2H, aromatic); 7.61 (bs, 1H, furan); 7.45 (bs, 2H, aromatic). MS (m/z, %): 417 (M+,18), 152 (100), 85 (13), 71 (12), 57 (20). Anal. Calcd. For C16H8FN5O4S2: C, 46.04; H, 1.93; N, 16.78, Found: C, 46.33; H, 1.80; N, 16.92.

5-(3-Hydroxybenzylidene)-2-[5-(5-nitro-furan-2-yl)-[1,3,4]thiadiazol-2-ylimino]-thiazolidin-4-one (19). Yield: 75%. M.p. 319–320 °C. IR (KBr): 3202 (OH), 3098 (NH), 1718 (C = O), 1562, 1350 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.14 (bs, 1H, NH); 10.01 (bs, 1H, OH); 7.91 (bs, 1H, furan); 7.72 (bs, 1H, = CH); 7.59 (bs, 1H, furan); 7.36(bs, 1H, aromatic); 7.11 (bs, 1H, aromatic); 7.06 (s, 1H, aromatic); 6.91 (bs, 1H, aromatic). MS (m/z, %): 415 (M+,5), 311 (100), 238 (84), 173 (47), 150 (22), 121 (58), 82 (80). Anal. Calcd. For C16H9N5O5S2: C, 46.26; H, 2.18; N, 16.86, Found: C, 45.99; H, 2.08; N, 17.05.

5-(4-Hydroxybenzylidene)-2-[5-(5-nitro-furan-2-yl)-[1,3,4]thiadiazol-2-ylimino]-thiazolidin-4-one (20). Yield: 94%. M.p. 258–260 °C. IR (KBr): 3133 (OH), 3116 (NH), 1717 (C = O), 1569, 1351 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.02 (bs, 1H, NH); 10.41 (bs, 1H, OH); 7.73 (bs, 1H, furan); 7.72 (bs, 1H, = CH); 7.58 (bs, 2H, aromatic); 7.55 (bs, 1H, furan); 6.97 (bs, 2H, aromatic). MS (m/z, %): 415 (M+,3), 311 (100), 238 (88), 212 (14), 173 (29), 150 (24), 121 (54), 110 (21), 99 (25), 82 (86), 60 (83). Anal. Calcd. For C16H9N5O5S2: C, 46.26; H, 2.18; N, 16.86, Found: C, 46.39; H, 2.29; N, 16.69.

5-(2-nitrobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (21). Yield: 56%. M.p. 302–304 °C. IR (KBr): 3131 (NH), 1738 (C = O), 1580, 1342 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.21 (bs, 1H, NH); 8.22 (bs, 1H, aromatic); 8.06 (bs, 1H, aromatic); 7.95 (bs, 1H, furan); 7.89–7.76 (m, 3H, aromatic, = CH); 7.57 (bs, 1H, furan). MS (m/z, %): 444 (M+,22), 179 (63), 97(55), 69(75), 57(100). Anal. Calcd. For C16H8N6O6S2: C, 43.24; H, 1.81; N, 18.91, Found: C, 43.48; H, 1.70; N, 18.69.

5-(3-nitrobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (22). Yield: 70%. M.p. 285–287 °C. IR (KBr): 3262 (NH), 1743 (C = O), 1572, 1354 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.23 (bs, 1H, NH); 8.52 (s, 1H, aromatic); 8.31 (bs, 1H, aromatic); 8.08 (bs, 1H, aromatic); 7.97–7.91 (m, 3H, furan, aromatic, = CH); 7.61 (bs, 1H, furan). MS (m/z, %): 444 (M+,28), 179 (66), 97 (51), 86 (43), 69 (72), 57 (100). Anal. Calcd. For C16H8N6O6S2: C, 43.24; H, 1.81; N, 18.91, Found: C, 43.13; H, 1.23; N, 18.80.

5-(4-nitrobenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (23). Yield: 88%. M.p. 344–346 °C. IR (KBr): 3215 (NH), 1727 (C = O), 1562, 1352 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.2 (bs, 1H, NH); 8.37 (bs, 2H, aromatic); 7.89 (bs, 4H, aromatic, furan, = CH); 7.59 (bs, 1H, furan). MS (m/z, %): 444 (M+, 20), 268 (16), 211 (17), 179 (58), 163 (10), 149 (28), 133 (21), 111 (24), 97 (43), 84 (68), 69 (70), 57 (100). Anal. Calcd. For C16H8N6O6S2: C, 43.24; H, 1.81; N, 18.91, Found: C, 42.91; H, 1.68; N, 19.09.

5-(4-(dimethylamino)benzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (24). Yield: 81%. M.p. 349–351 °C. IR (KBr): 3135 (NH), 1703 (C = O), 1573, 1303 (NO2). 1H-NMR (400 MHz, DMSO-d6): 12.84 (bs, 1H, NH); 7.88 (bs, 1H, furan); 7.63 (bs, 1H, = CH); 7.53 (bs, 1H, furan); 7.46 (bs, 2H, aromatic), 6.83 (bs, 2H, aromatic), 3.01 (bs, 6H, CH3). MS (m/z, %): 442 (M+, 12), 262 (11), 177 (100), 163 (22), 97 (19),83 (21), 69 (29), 57 (48). Anal. Calcd. For C18H14N6O4S2: C, 48.86; H, 3.19; N, 18.99, Found: C, 48.57; H, 3.02; N, 19.11.

5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (25). Yield: 62%. M.p. 217–219 °C. IR (KBr): 3613 (OH, non-bonded), 3789 (OH, bonded), 3130 (NH), 1698, 1668 (C = O), 1575, 1348 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.02 (bs, 1H, NH), 9.81, 8.03 (bs, 1H, OH, Z/Eisomers), 7.92 (bs, 1H, Furan), 7.87 (s, 1H, = CH, Z-isomer), 7.79 (s, 1H, furan), 7.67 (s, 1H, aromatic), 7.64 (s, 1H, = CH, E-isomers), 7.48 (s, 1H, aromatic), 1.44, 1.41 (s, 18H, CH3, Z/E-isomers). MS (m/z, %): 442 (M+, 12), 262 (11), 177 (100), 163 (22), 97 (19),83 (21), 69 (29), 57 (48). Anal. Calcd. For C24H25N5O5S2: C, 54.64; H, 4.78; N, 13.27, Found: C, 54.31; H, 4.65; N, 13.06.

2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)-5-((pyridin-3-yl)methylene)thiazolidin-4-one (26). Yield: 97%. M.p. 299–301 °C. IR (KBr): 3116 (NH), 1719 (C = O), 1569, 1349 (NO2). 1H-NMR (400 MHz, DMSO-d6) 12.96 (bs, 1H, NH); 8.91 (bs, 1H, pyridine); 8.67 (bs, 1H, pyridine); 8.07 (bs, 1H, pyridine); 7.90 (s, 1H, furan); 7.85 (bs, 1H, pyridine); 7.65 (s, 1H, = CH); 7.57 (bs, 1H, furan). MS (m/z, %): 400 (M+,40), 368 (13), 135 (100), 97 (14), 82 (22), 69 (24), 57 (29). Anal. Calcd. For C15H8N6O4S2: C, 45.00; H, 2.01; N, 20.99, Found: C, 45.28; H, 2.18; N, 21.16.

5-((1H-indol-2-yl)methylene)-2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one (27). Yield: 78%. M.p. 359–361 °C. IR (KBr): 3112 (NH), 1694 (C = O), 1572, 1351 (NO2). 1H-NMR (400 MHz, DMSO-d6): 12.95 (bs, 1H, NH); 12.22 (bs, 1H, NH); 8.07 (bs, 1H, furan); 7.89–7.22 (m, 7H, aromatic, furan, = CH). MS (m/z, %): 438 (M+,59), 212 (54), 173 (100), 97 (39), 82 (48), 69 (24), 57 (78). Anal. Calcd. For C18H10N6O4S2: C, 49.31; H, 2.30; N, 19.17, Found: C, 49.62; H, 2.56; N, 19.02.

2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)-5-((furan-2-yl)methylene)thiazolidin-4-one (28). Yield: 96%. M.p. 324–326 °C. IR (KBr): 3130 (NH), 1704 (C = O), 1565, 1358 (NO2). 1H-NMR (400 MHz, DMSO-d6): 12.98 (bs, 1H, NH); 8.16 (bs, 1H, furan); 7.91 (bs, 1H, nitrofuran); 7.65 (bs, 1H, = CH); 7.59 (bs, 1H, furan); 7.17 (bs, 1H, nitrofuran); 6.78 (bs, 1H, furan). MS (m/z, %): 389 (M+,34), 212 (49), 124 (100), 97 (36), 83 (31), 69 (71), 57 (84). Anal. Calcd. For C14H7N5O5S2: C, 43.19; H, 1.81; N, 17.99, Found: C, 42.97; H, 1.95; N, 17.08.

5-(5-Nitro-furan-2-ylmethylene)-2-[5-(5-nitro-furan-2-yl)-[1,3,4]thiadiazol-2-ylimino]-thiazolidin-4-one (29). Yield: 93%. M.p. 259–261 °C. IR (KBr): 3140 (NH), 1714 (C = O), 1580, 1347 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.25 (bs, 1H, NH); 7.93 (bs, 1H, furan); 7.83 (bs, 1H, furan); 7.69–7.64 (m, 2H, = CH, furan); 7.37 (bs, 1H, furan). MS (m/z, %): 434 (M+, 52), 388 (68), 238 (21), 169 (100), 139 (19), 111 (29), 95 (78), 82 (24), 69 (14). Anal. Calcd. For C14H6N6O7S2: C, 38.71; H, 1.39; N, 19.35, Found: C, 38.36; H, 1.20; N, 19.52.

2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)-5-((thiophen-2-yl)methylene)thiazolidin-4-one (30). Yield: 85%. M.p. 314–316 °C. IR (KBr): 3102 (NH), 1727 (C = O), 1545, 1351 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.06 (bs, 1H, NH); 8.05 (bs, 2H, furan, thiophen); 7.89 (bs, 1H, thiophen); 7.71 (s, 1H, = CH); 7.57 (bs, 1H, furan); 7.29 (bs, 1H, thiophen). MS (m/z, %): 405 (M+, 34), 140 (100), 96 (25), 82 (13), 69 (10). Anal. Calcd. For Found: C14H7N5O4S3: C, 41.48; H, 1.74; N, 17.27, Found: C, 41.66; H, 1.52; N, 17.10.

2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)-5-((5-nitrothiophen-2-yl)methylene)thiazolidin-4-one (31). Yield: 79%. M.p. 301–303 °C. IR (KBr): 3132 (NH), 1720 (C = O), 1530, 1359 (NO2). 1H-NMR (400 MHz, DMSO-d6): 13.14 (bs, 1H, NH); 8.22 (bs, 1H, thiophen); 8.08 (bs, 1H, thiophen); 7.90 (bs, 1H, furan); 7.71 (s, 1H, = CH); 7.60 (bs, 1H, furan). MS (m/z, %): 450 (M+, 3), 368 (33), 313 (29), 264 (18), 236 (34), 185 (19), 109 (27), 97 (55), 83 (60), 69 (69), 57 (100). Anal. Calcd. For C14H6N6O6S3: C, 37.33; H, 1.34; N, 18.66, Found: C, 37.62; H, 1.19; N, 18.39.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Anal. Calcd:

Analytical calculated

ATCC:

American Type Culture Collection

B. cereus :

Bacillus cereus

B. subitilis :

Bacillus subtilis

E. coli :

Escherichia coli

E. faecalis :

Enterococcus faecalis

FAS:

Ferric ammonium sulfate

FT-IR:

Fourier transform infrared

1H-NMR:

Proton nuclear magnetic resonance

H. pylori :

Helicobacter pylori

IZD:

Inhibition zone diameter

K. pneumonia :

Klebsiella pneumonia

M. luteus :

Micrococcus luteus

MIC:

Minimal inhibitory concentration

MRSA :

Methicillin-resistant Staphylococcus aureus

MS:

Mass spectrometry

P. aeruginosa :

Pseudomonas aeruginosa

PTCC:

Persian type culture collection

S. aureus :

Staphylococcus aureus

S. epidermidis :

Staphylococcus epidermidis

S. typhimurium :

Salmonella typhimurium

WHO:

World Health Organization

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Acknowledgements

We would like to show our gratitude to Dr. Mona Salimi and Raheleh Tahmasvand, Pasteur Institute of Iran for providing MTT assay. Authors would like to thank the late professor Abbas Shafiee for his considerable help that made this work possible.

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Contributions

AT: Synthesis of compounds, RE: Synthesis of compounds and preparation of first minute of the manuscript, AM: Performed the anti-bacterial activity evaluation, PS: Carried out the anti-H. pylori test, AF: Collaboration in interpretation of the structures of target compounds, AD: In silico toxicity evaluation of compounds, AA: Design of target compounds and the synthesis experiments. All authors read and approved the final manuscript.

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Correspondence to Ali Almasirad.

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Supplementary Information

Additional file 1.

The Synthetic procedures and spectral data of intermediates of 3-6. Antimicrobial susceptibility assay. Assessment of anti-H. pylori activity. The MTT assay of selected compounds 7, 17, 18 and 29. The in silico toxicity evaluation results of target compounds. Table S1 insilico toxicity risk assessment of synthesized commpounds.

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Tabei, A., Ejtemaei, R., Mahboubi, A. et al. Synthesis of new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives as anti-MRSA and anti-H. pylori agents. BMC Chemistry 16, 38 (2022). https://doi.org/10.1186/s13065-022-00829-7

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Keywords

  • Nitrofuran
  • Thiadiazole
  • 4-Thiazolidinone
  • Gram-positive
  • Helicobacter pylori
  • Antibacterial activity