One of the biggest risks to world health today is antimicrobial resistance. Numerous processes contribute to the evolution of bacterial resistance, including as mutations and horizontal gene transfer, which result in the acquisition of resistance genes [1]. Furthermore, the overuse and abuse of antibiotics without a prescription hastens the development and dissemination of bacteria that are resistant to multiple drugs [2]. Numerous bacterial strains have developed complex defenses that enable them to withstand the harsh effects of antibiotics. As an example, several isolated strains of Staphylococcus aureus have acquired inherent resistance to a variety of antibiotics, such as fluoroquinolones, β-lactams, glycopeptides, and aminoglycosides [3,4]. By preventing the messenger RNA from elongating, rifampicin was one of the best antibiotics for treating Mycobacterium tuberculosis. Genetic alterations that greatly inhibit Rifampicin's binding to the β-subunit of the RNA polymerase have led to the development of bacterial resistance to the drug [5,6]. Due to the great adaptability of these microorganisms to develop a diverse and effective array of resistance strategies and mechanisms, such as degrading beta-lactam rings present in many antibiotics,  limiting the entry of antibiotics used to vital and effective sites in the bacterial or fungal target, and there are other mechanisms that these microscopic organisms depend on, which is changing the bacterial targets by causing a genetic mutation, as certain types of Acinetobacter baumannii have shown great resistance to the antibiotics used and currently available in the markets [7]. The capacity of Pseudomonas aeruginosa to live in aggregates and produce biofilms, which have a high level of antibiotic resistance, is one of its defining characteristics [8]. Therefore, the creation and develop of new antimicrobial medications with entirely distinct chemical structures and modes of action should receive particular attention. A variety of pharmacological activities, such as antimycobacterial [9,10], antitubercular [11], anticancer [12], antiviral [13], antidiabetic [14,15], antifungal [16,17], anti-HIV [18], anti-inflammatory [19], antimalarial [20], anti-oxidant [21], and anti-proliferative [22] properties, are linked to the 1,2,3-triazole heterocycle derivatives, which can be synthesized through the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Carbamidotriazole (CAI) (I), cefatrizine (II), and tazobactum (III) are only a few of the pharmaceutical medications whose main constituent is the 1,2,3-triazole heterocycle. High product yield, stability, and chemo selectivity are just a few benefits of using the CuAAC click method to synthesize molecular structures comprising 1,2,3-triazole heterocycles [23, 24]. More significantly, click reactions are easy to perform with high yields and under mild reaction conditions that are not affected by oxygen or water. Because of their beneficial effects on increasing solubility and biological activity, 1,2,3-triazoles associated with carbohydrates have garnered a lot of attention [25,26]. In the current research, we report using a click chemistry strategy method for the synthesis, design, identification, and antibacterial evaluation of six novel 1,2,3-triazole carbazole, which builds on our earlier work on the synthesis of biologically active chemical structures using the heterocycle 1,2,3-triazole [27–29].

Experimental section 

The uncorrected melting points were determined using a Fischer-Johns melting point equipment. At 25 °C, optical rotations were captured using a JASCO P2000 polarimeter. Compounds' 1H NMR spectra bands were obtained as pure liquids or KBr pellets, and the reported absorptions are in cm^-1. Using TMS as an internal standard, all produced compounds were recorded at 300 MHz and 75 MHz for ¹³CNMR in the proper solvents. The d scale was used to display the chemical changes. S stands for (single), d for (doublet), t for (triplet), and q for (quarter)., and m (multiplet, for unresolved lines) are the designations for NMR signal multipliers. Each experiment was monitored using analytical thin-layer chromatography (TLC) on pre-coated GF254 silica gel plates. Following elution, the plate was examined for UV active compounds at 254 nm under UV light. PMA staining and charring on a hot plate allowed for much more visibility. After being extracted in a vacuum, the solvents were heated to 35 °C in a water bath. Column chromatography was performed using silica gel that was finer than 200 mesh. Before being used, the columns were equilibrated with the proper solvent or solvent mixture and packed as a silica gel slurry in hexane. Using the proper solvent system, the chemicals were loaded either plain or as a concentrated solution. Using an air pump to provide pressure helped in the elution. Unless otherwise indicated, yields relate to materials that are homogenous in terms of chromatography and spectroscopy. All of the novel compounds were given the proper names with the aid of Chem Bio Office 12.0; 2010.

Synthesis of 9-(2-propynyl)-9H-carbazole (1a) 

Metallic sodium (0.01 mol) was mixed with a solution of carbazole (0.01 mol) in anhydrous dioxane (5 mL) and refluxed for 30 minutes. While stirring, propargyl bromide (0.015 mol) was added to the boiling liquid. For two more hours, the reaction mixture was refluxed. The solvent was removed using a rotary evaporator once the reaction was finished. Using petroleum ether as an eluent, the crude reaction mixture was purified via silica gel column chromatography to obtain compound 2 in a 73% yield as a white solid. m.p:106–108 C; 1H NMR (300 MHz, CDCl3): d 8.09 (d, J = 7.8 Hz, 2H), 7.54–7.41 (m, 4H), 7.26–7.21 (m, 2H), 4.97 (d, J = 2.4 Hz, 2H, carbazole N-CH2), 2.23 (t, J = 2.4 Hz, 1H, acetylenic C1–H); 13CNMR (75 MHz, CDCl3): d 139.74, 125.78, 123.32, 120.12, 119.14, 108.24, 77.45 (acetylenic C2), 72.24(acetylenic C1), 32.68 (N CH2).

Synthesis derivatives of 1,2,3-triazolylmethyl carbazole (2a-2g) 

CuSO₄.5H₂O (20 mole %) and Na-ascorbate (20 mol%) were Inserted to a solution of alkyne 2 (0.7 mmol) and Azido-pyridine derivatives (2a-2g) (0.7 mmole) in tert-butanol: water (1:1, v/v, 4 mL). At RT, the mixture was agitated for nine to twelve hours. The organic solvent layer was separated, cleaned with brine, dried with anhydrous sodium sulfate, and the final product was concentrated under reduced pressure once the reaction was complete (as shown by thin layer chromatography plates). The mixture of reactions was then diluted with ethyl acetate (20 mL) and water (5 mL). Using silica gel column chromatography, the crude residue was refined to get the appropriate 1,2,3-triazoles (2a-2g).

9-((1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole (2a) Solid with a brown hue; m.p:189–191 °C; Infrared spectroscopy data ( in cm-¹): 3,135(aromatic, carbon-H), 1591, 1481 (alkene, C=C), 1451, 1321 (triazole ring, carbon–N), 1051, 747 (carbazole ring, C-N), 724; ¹H NMR (300 MHz, CDCl3) δ 8.51 – 8.48 (m, 2H, protons of pyridine ring in position 2), 8.21 (s, 1H, C-H triazole ring), 7.81 – 7.27 (m, 11 H, Aromatic protons), 5.61 (s, 2H of N–CH2); ¹³C NMR (75 MHz, CDCl3) δ 150.49, 141.92, 139.24, 128.24, 122.83, 120.57, 119.97, 112.59, 109.82 (9C, carbons of aromatic rings), 143.14, 120.24 (Positions C4 and C5 on the triazole ring),  40.68 (N–CH2).

9-((1-(2-methylpyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole (2b) Solid with a red hue; m.p:174–176 °C; Infrared spectroscopy data (cm-1): 3,121(aromatic, carbon-H), 1588, 1489 (alkene, C=C), 1448, 1329 (triazole ring, carbon –N), 1044, 740 (carbazole ring, C-N), 726; ¹H NMR (300 MHz, CDCl3) δ 8.35 (d, J = 5.6 Hz, 1H, protons of pyridine ring in position 2), 8.21 (s, 1H, C-H triazole ring), 7.95–7.24 (m, 11H, Aromatic protons),5.71(s,2H  of N-CH2),2.45 (s,3H, of Pyridine–CH₃); ¹³C NMR (75 MHz, CDCl3) δ 153.25, 148.30, 142.22, 139.24, 128.14, 122.83, 120.65, 120.00, 113.39, 110.02, 109.96(11C, carbons of aromatic rings),143.55, 120.52 (Positions C4 and C5 on the triazole ring), 40.68(N–CH2), 24.47(Pyridine–CH3).

9-((1-(2-bromopyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole (2c) Solid with a red hue; m.p:166–168 °C; Infrared spectroscopy data (cm-1): 3,108(aromatic, carbon -H), 1578, 1490 (alkene, C=C), 1439, 1325 (triazole ring, carbon –N), 1051, 731 (carbazole ring, C-N), 728; 1H NMR (300 MHz, CDCl3): δ 8.38 ((d, J = 5.6 Hz, 1H protons of pyridine ring in position 2), 8.19 (s, 1H, C-H triazole ring), 7.92 – 7.21 (m, 11 H, Aromatic protons), 5.60 (s, 2H of N–CH2); ¹³C NMR (75 MHz, CDCl3) δ 148.38, 144.08, 142.70, 139.24, 127.76, 122.82, 120.50, 120.14, 117.39, 110.04, (11C, carbons of aromatic rings), 143.65, 121.24(Positions C4 and C5 on the triazole ring), 40.61 (N–CH2).

9-((1-(2-methoxypyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole (2d) Solid with a brown hue; m.p:125–127 °C; Infrared spectroscopy data (cm-1): 3,188(aromatic, C-H), 1587, 1479 (alkene, C=C), 1444, 1321 (triazole ring, carbon –N), 1048, 738 (carbazole ring, C-N), 723; 1H NMR (300 MHz, CDCl3): δ 8.45 (d, J = 5.7 Hz, 1H protons of pyridine ring in position 2), 8.18 (s, 1H, C-H triazole ring), 7.85 – 7.23 (m, 11 H, Aromatic protons), 5.61 (s, 2H of N–CH2); ¹³C NMR (75 MHz, CDCl3): δ 166.59, 147.67, 143.28, 139.24, 127.93, 122.83, 120.85, 120.09, 110.01, 106.69, 99.49, 143.84, 120.25(Positions C4 and C5 on the triazole ring), 54.54 (O-CH3), 39.89 (N–CH2).

9-((1-(2-chloropyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole (2e) Solid with a white appearance; m.p:184–186°C; Infrared spectroscopy data (cm-1): 3,125(aromatic, C-H), 1584, 1493 (alkene, C=C), 1435, 1318 (triazole ring, carbon –N), 1047, 739 (carbazole ring, C-N), 721; 1H NMR (300 MHz, CDCl3): δ 8.36 ((d, J = 5.6 Hz, 1H protons of pyridine ring in position 2), 8.21 (s, 1H, C-H triazole ring), 7.94– 7.28 (m, 11 H, Aromatic protons), 5.62 (s, 2H of N–CH2); ¹³C NMR (75 MHz, CDCl3) δ 149.31, 145.18, 140.99, 139.25, 127.85, 122.14, 121.87, 120.04, 116.39, 111.14, (11C, carbons of aromatic rings), 143.25, 121.22(Positions C4 and C5 on the triazole ring), 40.58 (N–CH2).

 9-((1-(2-floropyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole (2f) Solid with a brown color; m.p:202–204°C; Infrared spectroscopy data (cm-1): 3,135(aromatic, carbon -H), 1580, 1487 (alkene, C=C), 1431, 1328 (triazole ring, C–N), 1045, 742 (carbazole ring, C-N), 724;  1H NMR (300 MHz, CDCl3): δ 8.39 ((d, J = 5.7 Hz, 1H protons of pyridine ring in position 2), 8.23 (s, 1H, C-H triazole ring), 7.98– 7.26(m, 11 H, Aromatic protons), 5.61 (s, 2H of N–CH2); ¹³C NMR (75 MHz, CDCl3) δ 151.39, 145.28, 140.25, 139.58, 127.47, 122.98, 121.95, 120.01, 116.98, 111.14, (11C, carbons of aromatic rings), 143.58, 121.47(Positions C4 and C5 on the triazole ring), 40.38 (N–CH2).

9-((1-(2-Nitropyridin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole (2g) Solid with a red color; m.p:157–159°C; Infrared spectroscopy data (cm-1): 3,122(aromatic, carbon-H), 1588, 1498 (alkene, C=C), 1428, 1331 (triazole ring, C–N), 1065,857, 731 (carbazole ring, C-N), 735; 1H NMR (300 MHz, CDCl3): δ 8.35 ((d, J = 5.7 Hz, 1H protons of pyridine ring in position 2), 8.18 (s, 1H, C-H triazole ring), 8.02– 7.25(m, 11 H, Aromatic protons), 5.58 (s, 2H of N–CH2); ¹³C NMR (75 MHz, CDCl3) δ 155.12, 145.24, 140.17, 139.57, 127.87, 124.14, 123.14, 120.00, 118.14, 112.54, (11C, carbons of aromatic rings), 143.52, 121.57(Positions C4 and C5 on the triazole ring), 40.35 (N–CH2).

Antimicrobial activity 

Using the well diffusion method, the antibacterial activity of all the synthesized compounds (2a-2g) was assessed against two Gram-(+) strains, Hay bacillus (MTCC 121) and Staphylococcus aureus (MTCC96), as well as two Gram-(-) strains, Escherichia coli (MTCC43) and Klebsiella pneumonia (MTCC530), at concentrations of 10 µM and 20 µM. [28]. Table 1 shows the results of measuring the zone of inhibition surrounding the well in millimeters using ampicillin as the reference antibiotic. The attachment of electron-withdrawing groups on the triazole ring made compounds 2c, 2e, 2f, and 2g the most potent of the produced compounds. When compared to the usual medication, compounds 2a and 2d demonstrated good antibacterial efficacy against a selection of all bacterial strains. Conclusions 2g, 2f, and 2c had outstanding antibacterial efficacy against the types of bacteria that were examined.

The structure of an antitubercular drug served as the inspiration for the scaffold design (Fig. 1). There are three sections to the new scaffold: The carbazole unit serves as the pharmacophore, N-functionalized 1,2,3-triazole serves as the core backbone, and substituted pyridine is added to the other side of the N-substituted 1,2,3-triazole moiety to improve its Pharmacophore features and induce lipophilicity. 

 Fig. 1 Design and synthesis approach for new pyridyl-1,2,3-triazole based on carbazole derivatives

The selection of aromatic pyridyl azide derivatives allows for variations in the suggested scaffold. The strategy of 1,3-Dipolar cycloaddition reaction (click reaction) served as the foundation for the synthesis of substituted 1,2,3-tria zolylmethyl carbazole derivatives (2a-2g). First, in order to prepare the necessary triazoles, we need 9-(2-propynyl)-9H-carbazole (1a). By altering the literature methodology, early attempts were made to convert carbazole to alkyne (1a) utilizing propargyl bromide in the presence of sodium metal to a solution of carbazole (1) in 1,4 dioxane [30]. (Scheme 1) was effectively accomplished with excellent yields by adding Propargyl bromide was added after 30 minutes of refluxing, and the reaction lasted for an additional two hours. 

 Scheme1 Synthesis and design of new substituted pyridine 1,2,3-triazolylmethyl carbazoles 2a-2g

The resulting alkyne (1a) was thoroughly described using 1H and 13C NMR spectra. The compound (1a)'s 1H NMR spectra showed the distinctive proton of acetylenic at d 2.23 ppm appears as triplet (J = 2.4 Hz) (1H) and the protons of N-methylene at d 4.98 ppm as doublet (J = 2.4 Hz) (2H). Acetylene protons' splitting pattern is not novel and is consistent with findings of closely comparable chemical entities in the literature [31]. The acetylenic carbons were represented by peaks in the 13C NMR spectra at d 77.7 and 72.4 ppm, while the N methylene carbon was represented by a peak at d 32.5 ppm. After obtaining the derivatives of alkyne (1a) and azide, we used Huisgen's (3+2) cycloaddition procedure with a CuSO4 catalyst. For instance, in the presence of sodium ascorbate and 20 mol% CuSO4 catalyst, alkyne building block (1a) reacted with pyridine azide derivatives in tert-butanol and water (1:1, v/v) to produce 9-((substituted pyridine-1H-1,2,3-triazol-5-yl)methyl)-9H-carbazole compounds In substantial yield (Scheme 1). 1H, 13C NMR, and IR data provided a complete characterization of all the products (2a–2g). All produced compounds had carbazole N-methylene bridge protons, which were responsible for the singlet resonances from d 5.58 to 5.63 ppm in the 1H NMR. The methylene group's aliphatic C-H stretching in compounds (2a-2g) was detected in the IR spectra between 2,935 and 2,986 cm-1, whereas the aromatic carbon-H stretching frequencies were observed between 3108 and 3195 cm^-1. The experimental portion included complete spectrum data for each of the novel compounds.

Antimicrobial Activity 

Four distinct bacteria species—B. subtilis, S. aureus, E. coli, and K. pneumonia—were used to assess the antimicrobial qualities of the new 1,2,3-triazolepyridyl derivatives (2a–2g). Table 1 displays the studied drugs' inhibition zone sizes. According to the data, B. subtilis and S. aureus were the most susceptible organisms, exhibiting sensitivity to the majority of the chemicals examined.

Table 1. The widths of the drugs' inhibitory zones surrounding the pathogenic microorganisms under test.

Among the series of newly synthesized compounds, compound (2g) exhibited unique antibacterial activity and was generally the most potent. Since the disc assay revealed that the inhibitory zone sizes for B. subtilis and S. aureus were 31 and 30 mm for B. subtilis and 29 and 31 mm for S. aureus, respectively, compound (2g and 2f) had the largest size. Conversely, the findings showed that compound (2c) had the least amount of antibacterial action. Despite having the lowest inhibition zones, the single Gram-negative species seemed to be both moderately and extremely sensitive to two of the chemicals that were examined (Table 1). Using the disc assay, compounds (2g, 2f, and 2c) exhibit a considerable zone of inhibition against E. coli and K. pneumonia (24, 22, and 24 mm) and (26, 24, and 21 mm), respectively. Based on the results, it can be said that compound (2g and 2f) against B. subtilis and S. aureus has stronger antibacterial activity than the reference medication. 

To sum up, we have discussed the synthesis and antibacterial assessment of a number of pyridyl-1,2,3-triazolyl methyl carbazoles (2a-2g). Carbazole was converted to the necessary alkyne building block (1a) by reacting with propargyl bromide in 1,4 dioxane while sodium metal was present. 1,3-Dipolar cycloaddition reaction (click reaction) process between alkyne (1a) and pyridine azide derivatives in the presence of sodium ascorbate and copper sulphate was used to create new analogues (2a-2g). All of the novel analogues (2a–2g) were tested against K. pneumonia, S. aureus, E. coli, and B. subtilis. The antibacterial activity of compounds (2g and 2f) against specific microorganisms in this investigation are superior to those of the reference medication, according to the data obtained. The findings presented here show how the scaffold hopping technique may be used to create powerful antibacterial medicines for additional optimization by creating novel carbazole analogues with an attached 1,2,3 triazole fragment.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the Jabir Ibn Hayyan University for Medical and Pharmaceutical Sciences.

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