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Synthesis, and antibacterial activities of novel 1,3,4a,9-tetraza-4H-fluoren-2-amines incorporating phenoxy-N-arylacetamide, pyrazole, and 2-(4-(1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamide moieties

BMC Chemistry volume 19, Article number: 61 (2025) Cite this article

Abstract

A ring annelation reaction was used to successfully prepare benzo[4,5]imidazo[1,2-a][1,3,5]triazines (Systematic Name: 1,3,4a,9-tetraza-4H-fluoren-2-amines) tethered to phenoxy-N-arylacetamide, pyrazole, and 2-(4-(1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamide moieties utilizing 1-(1H-benzo[d]imidazol-2-yl)guanidine and the proper aldehydes as precursors. 2-(Phenylamino)ethyl fragment of compound 7 was cleaved off and compound 8 was formed. The constitutions of the novel compounds were confirmed based on spectral data. The antibacterial activity was evaluated for the prepared compounds against two gram-negative and two gram-positive bacteria. Among them, compound 12b (inhibition zone 16 ± 0.7 mm) was the most promising against S. aureus compared to Gentamycin (15 ± 0 mm). Also, compounds 5a and 5d exerted comparable antibacterial activity (inhibition zones 13 ± 1.4 and 13 ± 2.1 mm), respectively to Gentamycin against S. aureus. Minimum inhibitory concentration (MIC) evaluation against S. aureus showed that compound 12b had the lowest MIC value (78.1 µg/mL).

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Introduction

Benzimidazoles are the fundamental component of a wide range of biochemical and medicinal substances with varying chemical and pharmacological properties. Numerous derivatives of benzimidazoles have a variety of biological characteristics, including antitumor [1,2,3,4,5,6], antifungal [7, 8], antiviral [9,10,11], antihistaminic [12,13,14] antibacterial [15, 16], and anticonvulsant activity [17, 18]. Representative examples of drugs containing benzimidazole moiety are depicted in Fig. 1 (compounds I [19,20,21], II [22,23,24], III [25,26,27]).

Fig. 1
figure 1

Some drugs containing benzimidazole or [1,3,5]triazine cores

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Moreover, triazines are benzene-like six-membered planar structures having three nitrogen atoms [28]. The triazine scaffold is the most well-known heterocycle, with a wide spectrum of biological activity [28,29,30,31]. There are three triazine isomers, namely, 1,2,4-triazine, 1,2,3-triazine, and 1,3,5-triazine. 1,3,5-Triazine is the most studied due to its distinct chemical structure and medicinal capabilities [30, 31]. For example, 1,3,5-triazine-thiazolidine-dione IV [30] has been reported as a DPP-4 inhibitor with antibacterial activity targeting the S1 pocket for the treatment of type 2 diabetes [30] (Fig. 1). Also, triazine dimer V [31] has been reported as an antileishmanial agent (Fig. 1) [31].

Besides, it was noted that compounds with acetamide linkages as core structures have drawn a lot of interest because of their possible therapeutic applications, including anticancer [32, 33], haemolytic [34], antioxidant [35], antitubercular [36], antiurease [34], antimicrobial [34, 37, 38], anti-inflammatory [39], anticonvulsant [40], analgesic [38, 39], anti-COVID-19 [41], and antituberculosis [42].

Moreover, pyrazoles, a five-membered heterocycle with two neighboring nitrogen atoms, are the fundamental structures found in a variety of compounds with diverse biological activities such as anticancer [43, 44], anti-inflammatory [45, 46], antimicrobial [46, 47], antioxidant [48, 49], and anticonvulsant [50] activities. Furthermore, bis-heterocycles, which consist of two bioactive heterocycles linked by a flexible linker, have been reported to possess plant growth regulative, anticancer, antibacterial, and fungicidal properties [51,52,53,54,55]. They can also be used as chelating agents, electrical conducting compounds [56], and metal ligands [57].

Fluorene is one example of a polyaromatic hydrocarbon (PAH), an essential precursor used in manufacturing as a component of plastics, insecticides, resins, dyes, and medications [58,59,60]. It was found that replacing one or more carbon atoms with heteroatoms results in significant alterations of its biological activity [61, 62]. Thus, in continuation of our interest in the synthesis of bioactive heterocycles [63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87], we aim to prepare hybrid heterocycles based on 1,3,4a,9-tetraza-4H-fluoren-2-amines tethered phenoxy-N-arylacetamide, and pyrazole moiety.

Results and discussion

According to the preceding general procedure, the reaction of o-phenylenediamine 1 with cyanoguanidine 2 in a refluxing water-HCl mixture produces 1-(1H-benzo[d]imidazol-2-yl)guanidine 3 (Scheme 1).

Scheme 1
scheme 1

Synthesis of 1-(1H-benzo[d]imidazol-2-yl)guanidine 3

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The reaction of 1-(1H-benzo[d]imidazol-2-yl)guanidine 3 with 2-(4-formylphenoxy)-N-arylacetamides 4a-d in ethanol in the presence of piperidine as a basic catalyst leads to the formation of 2-(4-(2-amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)phenoxy)-N-phenylacetamides 5a-d in which the benzo[4,5]imidazo[1,2-a][1,3,5]triazine moiety is linked to phenoxy-N-arylacetamide moieties (Scheme 2).

Scheme 2
scheme 2

Synthesis of 2-(4-(dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)phenoxy)-N-arylacetamides 5a-d

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The constitution of the formed products was proved based on spectral data. For example, the mass spectrum of 5a revealed a molecular ion peak at m/z 412. The IR spectrum of compound 5a showed characteristic N-H stretching bands at \(\:\stackrel{-}{\nu\:\:}\)3449 and 3325 cm− 1 and a strong absorption band at \(\:\stackrel{-}{\nu\:}\:\)1674 cm− 1 for the carbonyl group. The 1H NMR spectrum displayed a singlet at δ 4.69 ppm for OCH2 protons besides a multiplet at δ 6.68–7.62 ppm integrated for 14 protons corresponding to the aromatic protons and H-4. It also demonstrated three singlet signals (exchangeable with D2O) at δ 6.39 (2 H), 7.98 (1H), and 10.06 (1H) ppm assigned to NH2 and 2 NH protons. In addition, the 13C NMR showed peaks at δ 65.6 and 67.1 ppm for aliphatic carbons OCH2 and C-4 as well as a characteristic peak at δ 166.4 for the amide group. Peaks of the aromatic carbons appear at their appropriate position.

Compounds 5 can be seen as 1,3,4a,9-tetraza-4H-fluoren-2-amines, as illustrated in Fig. 2. It has been observed that replacing one or more carbon atoms of a carbocyclic molecule with heteroatoms results in significant alterations of its biological activity [88,89,90,91].

Fig. 2
figure 2

Structures of 9H-fluorene and1,3,4a,9-tetraza-4H-fluoren-2-amines 5

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However, the formed dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazine could exist in three tautomeric structures, namely 3,4-dihydro- 5, 1,4-dihydro- 5(I), and 4,10-dihydro- 5(II) tautomeric forms, the 3,4-dihydro- isomer is predominant in the crystal form, as indicated in related work [92] (Fig. 3).

Fig. 3
figure 3

Isomeric structures of [4,5]imidazo[1,2-a][1,3,5]triazines 5

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On the other hand, trials to prepare the benzo[4,5]imidazo[1,2-a][1,3,5]triazines 7 which are linked to benzoyloxyacetamide via the direct reaction of 3 with 2-oxo-2-(phenylamino)ethyl 4-formylbenzoate derivatives 6a-d under the same condition of absolute ethanol at reflux in presence of a catalytic amount of piperidine did not succeed. Instead, in all these examples, only ethyl 4-(2-amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)benzoate 8 was obtained as the sole product (Scheme 3).

Scheme 3
scheme 3

Synthesis of ethyl 4-(2-amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)benzoate 8

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Compound 8 was formed due to the transesterification of the initially formed 7a-d as indicated in the following mechanism. The nucleophilic attack of ethanol to the carbonyl ester of 7 leads to the tetrahedral intermediate 9 that was deprotonated in the presence of a basic catalyst (piperidine) into the intermediate 10 that affords the final isolable product 8 (Scheme 4).

Scheme 4
scheme 4

Unexpected formation of ethyl 4-(2-amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)benzoate 8

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The chemical constitution of compound 8 was undoubtedly confirmed by the aid of spectral tools and elemental analysis. The mass spectrum showed a molecular ion peak at m/z 335, consistent with the proposed structure. The IR spectrum revealed the presence of a characteristic absorption band at \(\:\stackrel{-}{\nu\:}\) 1713 cm− 1 for the ester carbonyl stretch, and broad absorption bands at \(\:\stackrel{-}{\nu\:}\) 3418 and 3248 cm− 1 for NH2 and NH group. The 1H NMR further confirmed the transesterification as it showed the absence of any peaks for OCH2 and amide NH protons. Instead, ethoxy protons appeared as a characteristic triplet and quartet at δ 1.26 and 4.25 ppm (pJ = 7.2 Hz). NH2 and NH protons gave peaks at δ 6.42 (2 H) and 8.09 (1H) ppm, respectively. Other peaks for aromatic protons and H-4 exist in their expected position. 13C NMR spectrum showed peaks for carbons of ethoxy group at δ 14.2 and 61.1 ppm. It revealed also peaks at δ 65.4 ppm for C-4, and at δ 165.3 ppm for ester carbonyl. Peaks of other aromatic carbons appeared as expected.

To achieve the concept of molecular hybridization, we attempt to introduce the biologically active pyrazole ring into the structure of 1,3,4a,9-tetraza-4H-fluoren-2-amines (benzo[4,5]imidazo[1,2-a][1,3,5]triazines). For this purpose, 1-phenyl-3-aryl-1H-pyrazole-4-carbaldehydes 11a-c were chosen as starting materials and were allowed to react with 3 in ethanol at reflux in the presence of a few drops of piperazine. Interestingly, benzo[4,5]imidazo[1,2-a][1,3,5]triazines 12a-c which are linked to a pyrazole moiety at position-4 has been generated in good yields (Scheme 5).

Scheme 5
scheme 5

Synthesis of pyrazole-containing 1,3,4a,9-tetraza-4H-fluoren-2-amines 12a-c

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The chemical composition of the products was verified by the different spectral tools. For example, the mass spectrum of 12b (Ar = 4-MeC6H4) demonstrated a molecular ion peak at m/z 419 which fits with the proposed structure. The IR spectrum of compound 12 showed absorption bands at \(\:\stackrel{-}{\nu\:}\) 3546 and 3325 cm− 1 for NH2 and NH stretching vibration. The 1H NMR indicated the presence of a signal at δ 2.24 ppm for methyl protons, a doublet at δ 6.57 ppm for H-4, a characteristic signal at δ 9.03 ppm for pyrazole-H5, and two singlet signals at δ 7.04 (2 H), 9.48 (1H) ppm for NH2 and NH, respectively. Signals for the aromatic protons appear at their appropriate position. The 13C NMR spectrum showed characteristic peaks at δ 20.9 and 59.9 ppm for methyl and C-4, respectively. Peaks for other carbons appear in their expected position.

Stimulated by the previously mentioned results, we broadened the scope of this reaction to include the synthesis of 1,3,4a,9-tetraza-4H-fluoren-2-amines 14a-d that are linked to 2-(4-(1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamide moieties at position-4 in good yields by the direct reaction of the appropriate 2-(4-(4-formyl-1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamides 13a-d with the corresponding mole equivalent of 3 (Scheme 6).

Scheme 6
scheme 6

Synthesis of 1,3,4a,9-tetraza-4H-fluoren-2-amines 14a-d that are linked to 2-(4-(1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamide moieties

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The chemical structure of the resulting compounds 14a-d was confirmed based on spectral analyses. For instance, the mass spectrum of 14a indicated a molecular-ion peak at m/z 554 which is relative to the proposed structure. The IR spectrum showed characteristic absorption bands at \(\:\stackrel{-}{\nu\:}\) 3549, 3325, 1674 cm− 1 for NH2, NH, and amide C = O, respectively. The 1H NMR spectrum displayed two characteristic singlets at δ 4.79 and 9.08 ppm for OCH2 and pyrazole-H5, respectively. It showed further multiplets at δ 6.93–7.99 ppm integrated for 21 protons for the amino group, H-4, and aromatic protons, as well as two D2O-exchangeable singlets at δ 8.67 and 10.12 ppm for the two NH groups. The 13C NMR spectrum shows peaks at δ 67.1 and 166.5 ppm for OCH2 and amide C = O. Other peaks are present in close agreement with the proposed structure.

Antibacterial activity

Agar well diffusion assay was used to assess the antibacterial activity of all the prepared compounds against Staphylococcus aureus (S. aureus) and Bacillus subtilis (B. subtilis) (gram-positive bacteria), Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) (gram-negative bacteria). The results showed that compounds 5a, 5d, and 12b were promising against S. aureus with the inhibition zones of 13 ± 1.4, 13 ± 2.1, and 16 ± 0.7 mm, respectively, and the most effective one was compound 12b compared to Gentamycin (15 ± 0 mm) (Table 1). Concerning B. subtilis, compounds 5a, 5d, 12a, and 12b showed moderate activity with the inhibition zones of 14 ± 0, 16 ± 0.7, 14 ± 0, and 14 ± 1.4 mm, respectively, compared to Gentamycin (20 ± 1.4). Compound 5d had the strongest action against P. aeruginosa (16 ± 0.7 mm), compared to Gentamycin (21 ± 0 mm). Compounds 5a, 5c, and 12b had moderate activity, whereas compound 14d had the lowest activity (10 ± 0 mm) against P. aeruginosa compared to Gentamycin. All the synthesized compounds had no action against E. coli. So, the most promising results were shown against S. aureus compared to Gentamycin. Therefore, S.aureus strain was chosen for further MIC evaluation. Tables 2 and 3; Fig. 4 showed the results of MIC determination. It was found that compound 12b had the lowest MIC value (78.1 µg/mL).

Table 1 Antibacterial activity of the synthesized compounds at a concentration of 10 mg/mL. The data was mean ± standard deviation (SD) of two separate experiments performed in triplicats
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Table 2 The effect of different concentrations (10-0.0195 mg/mL) of 5a, 5c, 5d, 8, and 12b on S. Aureus. The data was the mean of duplicate results ± standard deviation (SD)
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Table 3 Minimum inhibitory concentration (MIC) of compounds 5a, 5c, 5d, 8, and 12b against S. Aureus
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Fig. 4
figure 4

Agar well diffusion assay for estimating the MIC of compounds 5a, 5c, 5d, 8 and 12b against S. aureus. The range of serial dilution concentrations was 1 = 10 mg/mL to 10 = 0.0195 mg/mL. CN10 means Gentamycin positive control

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Structure-activity relationship

Figure 5 shows a design for the prepared series of benzo[4,5]imidazo[1,2-a][1,3,5]triazines 5,12, and 14.

Fig. 5
figure 5

A general structure of the prepared benzo[4,5]imidazo[1,2-a][1,3,5]triazines 5,12, and 14

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The structure-activity relationship demonstrated that the derivatives 5a-d and 12a-c performed better than the derivatives 14a-d. Compound 5d, which included a 4-methoxyphenyl group (an electron-donating group), had the highest antibacterial activity against S. aureus,P. aeuroginosa, and B. subtilis among the 5a-d derivatives. Compound 5a, which included an unsubstituted phenyl group, had a moderate action against S. aureus,P. aeruginosa and B. subtilis. The p-tolyl group (electron-donating group) in derivative 5c demonstrated modest antibacterial activity against S. aureus and P. aeruginosa. On the other hand, derivative 5b with 4-chlorophenyl moiety (electron-withdrawing group) reduced antibacterial efficacy against the tested bacterial strains. The unsubstituted phenyl group in 12a demonstrated moderate activity against B. subtilis, whereas derivative 12b with p-tolyl group exhibited promising action against S. aureus and moderate activity against B. subtilis and P. aeruginosa, respectively. Compound 12c, on the other hand, had decreased activity against all the strains tested. Among compounds 14a-d, only 14d containing a 4-methoxyphenyl group was effective. It showed limited efficacy against P. aeruginosa.

Conclusion

We have described an effective method for creating novel annelated 1,3,4a,9-tetraza-4H-fluoren-2-amines ring systems incorporating phenoxy-N-arylacetamide, and pyrazole moieties. The reaction involves reacting one-mole equivalent of 1-(1H-benzo[d]imidazol-2-yl)guanidine with one-mole equivalent of the appropriate aldehydes. We concluded that compound 5d’s promising action against S. aureus and P. aeruginosa, as well as its modest activity against B. subtilis, might be attributed to its inhibition of the MurG enzyme, as indicated by our molecular docking studies. Furthermore, the promising efficacy of compounds 5a and 5c against S. aureus might be attributed to their inhibitory action on bacterial tyrosyl tRNA synthetase and MurG.

Supplementary file

Compounds 5a is represented here as a representative example. Full experimental details of all compounds and spectral data are represented in the supplementary file.

“Experimental

“Melting points were measured with using a Stuart melting point apparatus and were uncorrected. The IR spectra were recorded using Vector 22 FTIR-spectrophotometer (Brucker, Germany) as KBr pellets. The 1H and 13C NMR spectra were recorded in DMSO-d6 as a solvent with Mercury VXR-300 NMR spectrometer (Varian, USA) operating at 300 MHz and 75 MHz, using TMS as an internal standard. Chemical shifts were reported as δ values in ppm. Mass spectra were recorded with GCMS-QP-1000 EX mass spectrometer (Shimadzu, Japan) in EI (70 eV) model. The elemental analyses were performed using CHNS-932 Vario elemental analyzer (LECO, USA) at the Micro Analytical Centre, Cairo University”.

General method for the synthesis of compounds 5a-d, 8, 12a-c and 14a-d

“A solution of 1-(1H-benzo[d]imidazol-2-yl)guanidine (3) (175 mg, 1 mmol) and the appropriate aldehyde (4a-d), (6a-d), (11a-c), or (13a-d) (1 mmol) in ethanol (10 mL) containing piperidine (2 drops) was heated at reflux for 3 h. The reaction mixture is allowed to cool to ambient temperature. A precipitate is formed which is subsequently filtered, washed with ethanol, and recrystallized from EtOH\dioxane (3:1, v/v) mixture to give the titled compound”.

2-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)phenoxy)-N-phenylacetamide (5a)

Colorless powder (350 mg, 85%); Mp 235–237 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3449 (NH2), 3325 (2NH), 1674 (C = O), 1605 (C = N), 1520 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 4.69 (s, 2 H, OCH2), 6.39 (s, 2 H, NH2, D2O exchangeable), 6.70 (d, J = 6.9 Hz, 2 H, Ar-H), 6.78 (t, J = 7.5 Hz, 1H, Ar-H), 6.93 (t, J = 7.5 Hz, 1H, Ar-H), 7.02 (d, J = 8.6 Hz, 2 H, Ar-H), 7.08 (d, J = 8.4 Hz, 1H, H4), 7.22 (d, J = 8.0 Hz, 1H, Ar-H), 7.26–7.36 (m, 4 H, Ar-H), 7.61 (d, J = 8.6 Hz, 2 H), 7.98 (br s, 1H, NH, D2O exchangeable), 10.06 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6): δ 65.6, 67.1, 108.4, 115.0, 115.9, 119.0, 119.8, 120.9, 123.7, 127.8, 128.8, 131.2, 133.2, 138.4, 143.1, 153.5, 155.4, 158.4, 166.4 ppm; MS (EI, 70 eV): m/z (%) 412 ]M+[; Anal. Calcd for C23H20N6O2: C, 66.98; H, 4.89; N, 20.38. Found: C, 66.83; H, 4.70; N, 20.18%.

2-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)phenoxy)-N-(4-chlorophenyl)acetamide (5b)

Pale yellow powder (370 mg, 83%); Mp 200–202 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3448 (NH2), 3320 (2NH), 1670 (C = O), 1600 (C = N), 1519 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 4.69 (s, 2 H, OCH2), 6.34 (s, 2 H, NH2, D2O exchangeable), 6.69 (d, J = 7.2 Hz, 2 H, Ar-H), 6.76 (t, J = 7.2 Hz, 1H, Ar-H), 6.91 (t, J = 7.5 Hz, 1H, Ar-H), 7.01 (d, J = 8.7 Hz, 2 H, Ar-H), 7.22 (d, J = 7.7 Hz, 1H, H4), 7.32 (d, J = 8.8 Hz, 2 H, Ar-H), 7.36 (d, J = 8.9 Hz, 2 H, Ar-H), 7.65 (d, J = 8.9 Hz, 2 H, Ar-H), 7.92 (s, 1H, NH, D2O exchangeable), 10.20 (s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6) δ 65.9, 67.3, 108.3, 114.6, 116.0, 118.6, 120.1, 120.7, 121.1, 128.1, 129.7, 131.7, 132.6, 133.4, 135.2, 143.4, 154.9, 158.8, 166.6 ppm; MS (EI, 70 eV): m/z (%) 446 ]M+[ Anal. Calcd for C23H19ClN6O2: C, 61.82; H, 4.29; N, 18.81. Found: C, 61.66; H, 4.11; N, 18.64%.

2-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)phenoxy)-N-(p-tolyl)acetamide (5c)

Colorless powder (354 mg, 83%); Mp 204–206 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3448 (NH2), 3328 (2NH), 1677 (C = O), 1609 (C = N), 1520 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 2.25 (s, 3 H, CH3), 4.66 (s, 2 H, OCH2), 6.38 (s, 2 H, NH2, D2O exchangeable), 6.69 (d, J = 6.6 Hz, 2 H, Ar-H), 6.76 (t, J = 7.3 Hz, 1H, Ar-H), 6.92 (t, J = 7.1 Hz, 1H, Ar-H), 7.01 (d, J = 8.1 Hz, 2 H, Ar-H), 7.11 (d, J = 7.6 Hz, 2 H, Ar-H), 7.21 (d, J = 7.6 Hz, 1H, H4), 7.33 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 7.8 Hz, 2 H, Ar-H), 7.96 (br s, 1H, NH, D2O exchangeable), 9.96 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6): δ 20.5, 65.5, 67.1, 108.3, 115.0, 115.9, 118.9, 119.9, 120.5, 120.8, 127.7, 129.1, 131.3, 132.7, 133.2, 135.9, 143.4, 155.4, 158.4, 166.1 ppm; MS (EI, 70 eV): m/z (%) 426 ]M+[ Anal. Calcd for C24H22N6O2: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.39; H, 5.02; N, 19.53%.

2-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)phenoxy)-N-(4-methoxyphenyl)acetamide (5d)

Grey powder (380 mg, 86%); Mp 240–242 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3448 (NH2), 3330 (2NH), 1678 (C = O), 1608 (C = N), 1522 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 3.72 (s, 3 H, OCH3), 4.65 (s, 2 H, OCH2), 6.37 (s, 2 H, NH2, D2O exchangeable), 6.69 (d, J = 6.2 Hz, 2 H, Ar-H), 6.77 (t, J = 7.5 Hz, 1H, Ar-H), 6.88 (d, J = 8.2 Hz, 2 H, Ar-H), 6.93 (d, J = 7.5 Hz, 1H, Ar-H), 7.02 (d, J = 7.9 Hz, 2 H, Ar-H), 7.21 (d, J = 7.7 Hz, 1H, H4), 7.33 (d, J = 8.1 Hz, 2 H, Ar-H), 7.51 (d, J = 8.7 Hz, 2 H, Ar-H), 7.95 (s, 1H, NH, D2O exchangeable), 9.91 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6) δ 58.1, 65.5, 69.1, 108.3, 115.0, 115.5, 116.0, 119.8, 120.1, 120.8, 129.1, 131.7, 132.3, 133.4, 135.9, 144.3, 154.5, 158.4, 160.3, 167.4 ppm; MS (EI, 70 eV): m/z (%) 442 ]M+[ Anal. Calcd for C24H22N6O3: C, 65.15; H, 5.01; N, 18.99. Found: C, 64.97; H, 4.87; N, 18.82%.

Ethyl 4-(2-amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)benzoate (8)

Wite powder (295 mg, 88%); Mp 208–210 ºC; IR (KBr): h\(\:\stackrel{-}{\nu\:}\) 3418 (NH2), 3248 (NH), 1713 (C = O), 1628 (C = N), 1528 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J = 7.2 Hz, 3 H, COOCH2CH3), 4.29 (q, J = 7.2 Hz, 2 H, COOCH2CH3), 6.42 (s, 2 H, NH2, D2O exchangeable), 6.74 (d, J = 7.5 Hz, 1H, H4), 6.79 (t, J = 7.4 Hz, 1H, Ar-H), 6.84 (s, 1H, H4), 6.94 (t, J = 7.4 Hz, 1H, Ar-H), 7.24 (d, J = 7.8 Hz, 1H, Ar-H), 7.48 (d, J = 7.9 Hz, 2 H, Ar-H), 7.96 (d, J = 7.7 Hz, 2 H, Ar-H), 8.09 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6): δ 14.2, 61.1, 65.4, 108.5, 116.1, 119.3, 121.4, 126.6, 128.7, 130.0, 130.7, 131.1, 143.2, 145.3, 155.2, 165.3 ppm; MS (EI, 70 eV): m/z (%) 335 ]M+[. Anal. Calcd for C18H17N5O2: C, 64.47; H, 5.11; N, 20.88. Found: C, 64.33; H, 4.95; N, 20.70%.

4-(1,3-Diphenyl-1H-pyrazol-4-yl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amine (12a)

Colorless powder (352 mg, 87%); Mp 280–282 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3540 (NH2), 3325 (NH), 1604 (C = N), 1520 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 6.40 (d, J = 7.9 Hz, 1H, H4), 6.51(s, 2 H, NH2, D2O exchangeable), 6.69 (t, J = 7.6 Hz, 1H, Ar-H), 6.88 (d, J = 7.2 Hz, 2 H, Ar-H), 7.15 (d, J = 7.8 Hz, 1H, Ar-H), 7.33 (t, J = 7.4 Hz, 1H, Ar-H), 7.41 (d, J = 6.6 Hz, 2 H, Ar-H), 7.50 (t, J = 7.7 Hz, 3 H, Ar-H), 7.65 (d, J = 7.6 Hz, 2 H, Ar-H), 7.90 (d, J = 8.0 Hz, 2 H, Ar-H), 8.25 (br s, 1H, NH, D2O exchangeable), 8.76 (s, 1H, pyrazole-H5) ppm; 13C NMR (75 MHz, DMSO-d6): δ 62.6, 111.2, 118.1, 118.5, 119.2, 122.9, 123.8, 127.0, 128.0, 128.2, 128.9, 129.2, 129.4, 129.6, 130.2, 137.6, 139.5, 150.5, 151.4, 157.7 ppm; MS (EI, 70 eV): m/z (%) 405 ]M+[ Anal. Calcd for C24H19N7: C, 71.09; H, 4.72; N, 24.18. Found: C, 70.96; H, 4.56; N, 24.04%.

4-(1-Phenyl-3-(p-tolyl)-1H-pyrazol-4-yl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amine (12b)

Wite powder (369 mg, 88%); Mp 295–297 ºC; IR (KBr): h\(\:\stackrel{-}{\nu\:}\) 3546 (NH2), 3325 (NH), 1604 (C = N), 1525 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3 H, CH3), 6.58 (d, J = 7.9 Hz, 1H, H4), 7.04 (s, 2 H, NH2, D2O exchangeable), 7.17 (d, J = 7.8 Hz, 1H, Ar-H), 7.23 (d, J = 7.6 Hz, 2 H, Ar-H), 7.33 (d, J = 7.9 Hz, 3 H, Ar-H), 7.43 (d, J = 8.0 Hz, 2 H, Ar-H), 7.52 (t, J = 7.7 Hz, 3 H, Ar-H), 7.89 (d, J = 8.2 Hz, 2 H, Ar-H), 9.03 (s, 1H, pyrazole-H5), 9.48 (br s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6): δ 20.9, 59.9, 110.2, 111.7, 118.5, 119.2, 122.9, 123.8, 127.0, 128.0, 128.2, 128.9, 129.2, 129.4, 129.7, 130.1, 138.2, 139.0, 150.8, 151.2, 156.7 ppm; MS (EI, 70 eV): m/z (%) 419 ]M+[ Anal. Calcd for C25H21N7: C, 71.58; H, 5.05; N, 23.37. Found: C, 71.43; H, 4.95; N, 23.18%.

4-(3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-2-amine (12c)

Colorless powder (374 mg, 86%); Mp 287–289 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3549 (NH2), 3325 (NH), 1674 (C = O), 1605 (C = N), 1528 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 3.78 (s, 3 H, OCH3), 6.50 (d, J = 7.6 Hz, 1H, H4), 6.92 (s, 2 H, NH2, D2O exchangeable), 6.97 (d, J = 8.3 Hz, 2 H, Ar-H), 7.07 (d, J = 7.5 Hz, 1H, Ar-H), 7.13 (s, 2 H, Ar-H), 7.27 (d, J = 7.8 Hz, 1H, Ar-H), 7.35 (d, J = 8.1 Hz, 1H, Ar-H), 7.50 (d, J = 6.1 Hz, 4 H, Ar-H), 7.88 (d, J = 8.1 Hz, 2 H, Ar-H), 8.37 (s, 1H, NH, D2O exchangeable), 8.87 (s, 1H, pyrazole-H5) ppm; 13C NMR (75 MHz, DMSO-d6): δ 55.4, 61.8, 110.5, 111.9, 118.4, 119.2, 122.9, 123.8, 127.2, 128.16, 128.18, 128.9, 129.3, 129.4, 129.7, 138.0, 138.6, 150.6, 151.2, 156.7, 159.4 ppm; MS (EI, 70 eV): m/z (%) 435 ]M+[ Anal. Calcd for C25H21N7O: C, 68.95; H, 4.86; N, 22.51. Found: C, 68.79; H, 4.69; N, 22.39%.

2-(4-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)-1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-phenylacetamide (14a)

White powder (415 mg, 75%); Mp 240–242 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3549 (NH2), 3325 (NH), 1674 (C = O), 1605 (C = N), 1528 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6): δ 4.79 (s, 2 H, OCH2), 6.92 (s, 1H, H4), 7.09–7.18 (m, 3 H, NH2, Ar-H), 7.35 (s, 4 H, Ar-H), 7.54 (s, 4 H, Ar-H), 7.67 (d, J = 18.5 Hz, 5 H, Ar-H), 7.99 (s, 4 H, Ar-H), 8.67 (s, 1H, NH, D2O exchangeable), 9.08 (s, 1H, pyrazole-H5), 10.12 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6): δ 67.2, 71.5, 110.5, 115.1, 115.7, 116.3, 119.0, 119.8, 120.6, 122.5, 123.9, 124.9, 127.3, 128.6, 128.9, 129.8, 130.0, 130.3, 138.4, 139.0, 142.8, 152.7, 153.6, 158.4, 160.2, 166.5.ppm; MS (EI, 70 eV): m/z (%) 554 ]M+[ Anal. Calcd for C32H26N8O2: C, 69.30; H, 4.73; N, 20.20. Found: C, 69.12; H, 4.57; N, 20.01%.

2-(4-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)-1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-(4-chlorophenyl)acetamide (14b)

Yellow powder (430 mg, 73%); Mp 180–182 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3549 (NH2), 3325 (NH), 1670 (C = O), 1604 (C = N), 1525 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6): δ 4.79 (s, 2 H, OCH2), 6.59 (d, J = 8.8 Hz, 1H, H4), 7.12 (t, J = 8.9 Hz, 3 H, NH2, Ar-H), 7.39 (td, J = 12.3, 8.3 Hz, 5 H, Ar-H), 7.55 (d, J = 7.9 Hz, 2 H, Ar-H), 7.58–7.66 (m, 2 H, Ar-H), 7.69 (d, J = 8.8 Hz, 2 H, Ar-H), 7.95 (dd, J = 12.7, 8.6 Hz, 5 H, Ar-H), 9.27 (s, 1H, pyrazole-H5), 9.97 (s, 1H, NH, D2O exchangeable), 10.28 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6): δ 66.9, 70.7, 108.9, 114.86, 114.93, 115.4, 115.9, 118.3, 118.9, 119.2, 119.9, 121.1, 125.0, 126.6, 129.1, 129.4, 129.5, 130.3, 131.1, 133.5, 135.8, 138.6, 143.3, 150.3, 158.1, 166.3 ppm;.MS (EI, 70 eV): m/z (%) 589 ]M+[ Anal. Calcd for C32H25ClN8O2: C, 65.25; H, 4.28; N, 19.02. Found: C, 65.05; H, 4.15; N, 18.86%.

2-(4-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)-1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-(p-tolyl)acetamide (14c)

Colorless powder (454 mg, 80%); Mp 193–195 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3549 (NH2), 3325 (NH), 1672 (C = O), 1604 (C = N), 1527 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3 H, CH3), 4.72 (s, 2 H, OCH2), 6.29 (s, 2 H, NH2, D2O exchangeable), 6.41 (d, J = 7.8 Hz, 1H, H4), 6.79–6.92 (m, 3 H, Ar-H), 7.06–7.20 (m, 5 H, Ar-H), 7.30–7.35 (m, 1H, Ar-H), 7.46–7.55 (m, 5 H, Ar-H), 7.64 (d, J = 7.2 Hz, 1H, Ar-H), 7.90 (d, J = 9.1 Hz, 2 H, Ar-H), 8.70 (s, 1H, NH, D2O exchangeable), 9.15 (s, 1H, pyrazole-H5), 10.02 (s, 1H, NH, D2O exchangeable) ppm; 13C NMR (75 MHz, DMSO-d6): δ 20.5, 67.2, 70.7, 108.4, 114.8, 114.9, 115.9, 118.3, 119.0, 119.2, 119.8, 120.8, 125.2, 126.6, 129.1, 129.5, 129.6, 129.7, 130.1, 131.5, 132.7, 135.8, 139.1, 143.3, 150.4, 158.0, 166.1 ppm; MS (EI, 70 eV): m/z (%) 568 ]M+[ Anal. Calcd for C33H28N8O2: C, 69.70; H, 4.96; N, 19.71. Found: C, 69.59; H, 4.81; N, 19.58%.

2-(4-(4-(2-Amino-3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazin-4-yl)-1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-(4-methoxyphenyl)acetamide (14d)

Grey powder (450 mg, 77%); Mp 182–184 ºC; IR (KBr): \(\:\stackrel{-}{\nu\:}\) 3549 (NH2), 3325 (NH), 1674 (C = O), 1605 (C = N), 1528 (C = C) cm− 1; 1H NMR (300 MHz, DMSO-d6) δ 3.72 (s, 3 H, OCH3), 4.70 (s, 2 H, OCH2), 6.30 (s, 2 H, NH2, D2O exchangeable), 6.41 (d, J = 7.3 Hz, 1H, H4), 6.70 (d, J = 7.6 Hz, 1H, Ar-H), 6.88 (t, J = 4.5 Hz, 4 H, Ar-H), 7.04–7.11 (m, 2 H, Ar-H), 7.44–7.68 (m, 8 H, Ar-H), 7.89 (d, J = 8.2 Hz, 2 H, Ar-H), 8.70 (s, 1H, NH, D2O exchangeable), 9.28 (s, 1H, pyrazole-H5), 9.95 (s, 1H, NH, D2O exchangeable) ppm; MS (EI, 70 eV): m/z (%) 584 ]M+[ Anal. Calcd for C33H28N8O3: C, 67.80; H, 4.83; N, 19.17. Found: C, 67.61; H, 4.67; N, 18.99%.

Antibacterial assay

The antibacterial activity of the prepared compounds was assessed by using the agar well diffusion assay. The antibacterial activity was screened against two gram-positive bacteria Staphylococcus aureus (ATCC 6538) and Bacillus subtilis (DSM 1088) as well as two gram-negative bacteria Pseudomonas aeruginosa (ATCC 10145) and Escherichia coli (ATCC 8739). Dimethyl sulfoxide (DMSO) was used to make a solution of 10 mg/mL of each synthesized compound. The nutrient agar medium was poured on the plates and let to be cooled to 45 °C. 105-106 colony forming unit (CFU) per mL from an overnight bacterial culture was cultured on nutrient agar plates. Then, 6 mm wells were created in the nutritional medium using sterile metallic bores. After that, 20 µL of each tested compound (10 mg/mL) was added to the prepared well. Herein, the negative control was 5% DMSO and the results were compared to standard Gentamycin (10 µg/disc) and Clindamycin (2 µg/disc) (positive controls). The inhibition zone diameter in (mm) was measured using a calliper after the incubation of the plates at 37 °C for (18–24) hours. The experiment was repeated twice and in each time was done in triplicates. The minimum inhibition concentration (MIC) of compounds 5a, 5c, 5d, 8 and 12b was determined against S. aureus. A serial dilution method with concentrations ranging from 10 to 0.0195 mg/mL was utilized. The MIC is the lowest concentration of the target drug that can inhibit the growth of the studied bacteria.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information file. Data available at request (Ismail A. Abdelhamid, ismail_shafy@yahoo.com, ismail_shafy@cu.edu.eg).

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Acknowledgements

This paper is based upon work supported by the Science, Technology, and Innovation Funding Authority (STDF) under grant 48572.

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Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).

This paper is based upon work supported by Science, Technology & Innovation Funding Authority (STDF) under grant 48572.

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Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt

    Reham E. Abdelwahab, Ahmed H. M. Elwahy, Amr M. Abdelmoniem & Ismail A. Abdelhamid

  2. Department of Chemistry (Biochemistry Division), Faculty of Science, Cairo University, Giza, 12613, Egypt

    Nada S. Ibrahim

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  1. Reham E. Abdelwahab
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Contributions

R.E.A. suggested the research plan, carried out the laboratory work, participated in data analysis, shared in writing the original draft of the manuscript, and followed up the experimental work. A.H.M.E., A.M.A., and I.A.A. suggested the research plan, and shared in writing the original draft of the manuscript. N.S.I carried out the biological activity work, participated in data analysis, and shared in writing the original draft of the manuscript. All authors gave final approval for publication.

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Abdelwahab, R.E., Elwahy, A.H.M., Ibrahim, N.S. et al. Synthesis, and antibacterial activities of novel 1,3,4a,9-tetraza-4H-fluoren-2-amines incorporating phenoxy-N-arylacetamide, pyrazole, and 2-(4-(1-phenyl-1H-pyrazol-3-yl)phenoxy)-N-arylacetamide moieties. BMC Chemistry 19, 61 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13065-025-01421-5

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BMC Chemistry

ISSN: 2661-801X

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