Synthesis and Biological activities of New Pyrazoline Incorporated Pyridine-Triazole Derivatives

Introduction

The emergence of bacterial resistance to conventional antibiotics has grown to be a worldwide issue, necessitating the continuous seeking out novel antimicrobial agents. In this regard, heterocycle’s diverse biological activities and structural versatility have drawn significant interest.^1–3 Among various heterocyclic scaffolds, pyridine, 1,2,4-triazole, and 4,5-dihydro-pyrazole have demonstrated remarkable potential in medicinal chemistry,^4,5 particularly in the development of antimicrobial agents.⁶

Pyridine is a fundamental nitrogen-containing heterocycle widely found in bioactive molecules. Its unique electronic properties and ability to participate in hydrogen bonding make it a crucial pharmacophore in drug design. Pyridine derivatives possess antibacterial activity,^7–9 making them promising candidates for the development of new antimicrobial agents.

Similarly, 1,2,4-triazole is an important five-membered heterocyclic ring known for its therapeutic potential.^10–12 The presence of nitrogen atoms in the triazole ring enhances its binding interactions with biological targets, improving its pharmacokinetic and pharmacodynamic properties.^13–15 Triazole derivatives have been extensively studied for their role in inhibiting bacterial growth and overcoming resistance mechanisms.

Furthermore, the 4,5-dihydro-pyrazole moiety has been widely explored in medicinal chemistry due to its significant biological activities. Dihydro-pyrazole derivatives are known for their antimicrobial, anti-inflammatory, and anticancer properties.^16–18 Their ability to interact with bacterial enzymes and disrupt essential metabolic pathways makes them promising leads in the development of antibacterial agents.

Currently, our team have designed and prepared novel compounds incorporating pyridine, 1,2,4-triazole, and 4,5-dihydro-pyrazole scaffolds to evaluate their antibacterial potential. The efficacy of the newly developed derivatives was assessed by antimicrobial screening. Our findings contribute to the ongoing efforts in developing new antimicrobial agents to combat resistant bacterial strains.

Materials and Methods

Sigma Aldrich is the source of all Initial materials. The Perkin-Elmer RX₁ spectrophotometer was used to record the infrared spectra. Using a Brucker 500 MHz spectrometer, the ¹HNMR and ¹³CNMR spectra were captured in CDCl₃ solutions. The ElementarVario EL III elemental analyzer was used to perform the elemental analysis. Progress of reaction was recorded by TLC.

General procedure

Synthesis of 1,2,4-triazol-3-thiol derivative(3)

1,2,4-triazol-3-thiol was prepared as per reported method.¹⁹ Isoniazid (20 mmol) and ethyl isothiocyanate (20 mmol) in methanol were reflux for 2 hours. The resultant reaction mixture was poured into cold water to isolate compound 2. Compound 2 was solubilized in 20% NaOH and cyclized through reflux for 3 hours. The reaction mixture was acidified by dil HCl to yield 4-ethyl-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol (3). Solids were filtered, dried and recrystallized using ethanol. Yield – 72%

Synthesis of Chalcones derivatives( 4a-o)

Pyrazolines were prepared as per reported method.^20,21 acetophenone (50 mmol), various aldehydes (50 mmol), and NaOH (50 mmol) were triturated in a mortar at 30⁰C for 30 minutes. The solid was rinsed with water to remove excess NaOH. The resultant chalcones (4a-4o) were filtered and recrystallized using ethanol. Yield between 80% – 86%

Synthesis of chloro acetyl pyrazoline derivatives( 5a-o)

Compounds (4a-4o) (15 mmol) and hydrazine hydrate (20 mmol) were solubilized in ethanol in FBF. The reaction mixture was subjected to reflux for 11 hours. The solvent was eliminated via distillation to obtain pyrazole. Pyrazoles were subsequently dissolved in dichloromethane. 15 millimoles of chloroacetyl chloride were introduced at 5°C and agitated for seven to eight hours at ambient temperature. Compounds (5a-5o) were obtained via distillation and recrystallized using ethanol.

Synthesis of pyrazoline incorporated pyridine-triazole (6a-o)

4-ethyl-5-(4-pyridinyl)-4H-1,2,4-triazole-3-thiol (0.005 mol) 2-chloro-(5-aryl-3-arylpyrazol-1-yl)ethane-one (0.005 mol) and anhydrous K₂CO₃ were dissolved in 100 ml DMF.  Reaction mass was stirred for 8-9 hours at ambient temperature. The resultant content was then added in the cold water. Solids were filtered off as well as recrystallized with ethyl alcohol. Yield between 62%-71%

Scheme 1: Preparation route of derivatives 6a-o. Click here to View Scheme

Results and Discussion

Biological Screening

Compounds 6a–6o  have been screened against S. aureus, B. subtilis, E. coli,  E.aerogenes , C.albicans  and A.niger  using disc diffusion method (figure 1).²² All new compound exhibit moderate to good potential towards bacterial and fungal strains(table 1). When compared to conventional antibiotics, several of these substances exhibit superior inhibitory zones, including compound 6l is quite efficient against B. subtilis and E. coli and it has the maximum activity against S. aureus (36 mm).

Another potent chemical is compound 6e, which exhibits excellent suppression against a variety of pathogens, including a 32 mm zone for S. aureus. Compound 6h has displayed antifungal potential with 22 and 20 mm inhibition against C.albicans and A.niger respectively.

The type of substitution at positions R and R′ markedly changed the studied compounds’ antimicrobial properties. Substitution at R′ with electron-withdrawing groups like 4-nitro (6e) was greatly increased activity, particularly against S. aureus and E. coli, as compared to the unsubstituted comp. 6a. While to a lesser degree, activity was also enhanced by electron-donating groups such as 4-methoxy (6d). In general, adding a methyl group at R (6f–6j) increased potency overall, especially when paired with substituents like 3-nitro or 4-chloro at R′, as compounds 6g and 6j demonstrated, which showed broad-spectrum action. Strong antibacterial effects were produced by methyl substitution at R (6k–6l), with 6l (R = 4-OCH₃, R′ = 4-NO₂) showing the greatest activity among all tested bacteria and even coming close to conventional medicines like amoxicillin. Likewise, chloro substitution at R (6m–6o) in conjunction with groups like 3,4-dimethoxy or 4-dimethylamino improved the antifungal and antibacterial properties even further. The antimicrobial profile was often enhanced by the combination of electron-donating and withdrawing groups, with compounds such as 6j, 6l, and 6o exhibiting particularly strong and wide-ranging action.

Table 1: Antimicrobial activity of 6a-6o

Figure 1: Antimicrobial activity of 6a-6o Click here to View Figure

Antioxidant activities

Radical scavenging activities of compound 6a-6o have been performed at 50,100, 150 µg/ml concentration using ascorbic acid by DPPH method.²³ Compound 6l bearing methoxy and nitro substitution has shown highest inhibition with 53 % at 150 µg/ml. while comp 6k with methoxy substitution has shown inhibition with 52.46 % at 150 µg/ml. all other compound have displayed moderate radical scavenging activities.

Table 2: Antioxidant activities

Chemistry

The synthesis route of pyrazoline incorporated pyridine-triazole molecules is shown in Scheme 1. Pyrazolines (5a-o) were obtained through claisen condensation reaction followed by condensation with hydrazine hydrated and chloroacetyl chloride. Pyridyl-1,2,4-triazole (3) was synthesized through the coupling of isoniazide (1) with ethyl isothyocynate followed by cyclization in the presence of NaOH. 1-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-((4-ethyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)thio)ethan-1-one (6a-o) derivatives were synthesized by coupling of pyrazoline (5a-o) and Pyridyl-1,2,4-triazole(3) in the presence of anhydrous K₂CO₃ (Scheme 1).

Spectroscopic methods were used to characterize newly synthesized derivatives (6a-e). Mass spectrum of compound 6a revealed the molecular weight M+H at m/z = 469(Figure 2). The >C=O group’s existence has been shown by the absorption band at 1674 cm⁻¹ in the IR spectra of comp. 6a. The C-H- stretching bands has been located at 3055 and 2974 cm⁻¹. Vibrations at 1427 cm⁻¹, caused by –C-N< stretching, indicated the existence of a pyrazoline ring(Figure 3).

The presence of 14 and 10 protons of compound 6a in the aromatic and aliphatic regions were confirmed by ¹H NMR spectra (Figure 4). Three double doublets at 3.1, 3.7, & 5.5 δ ppm in ¹H-NMR spectrum indicate an AMX pattern rising due to the vicinal interaction of two diastereomeric and one methine protons of pyrazoline. The existence of an ethyl chain of triazole has been shown by the ¹H NMR spectrum, which displays a triplet at 1.3 ppm and a quartet peak at 4.0 δ ppm. A singlet at 8.7 ppm of ¹H-NMR spectrum indicates the existence of pyridine ring.

The ¹³CNMR spectra displayed a distinctive peak at δ=164 ppm, which resulted from carbonyl group. The ethyl chain has shown peak at δ = 15.62 ppm, whereas the pyrazoline ring showed signals at 60.51 & 42.2 δ ppm (Figure 5).

Figure 2: Mass spectrum of comp. 6a Click here to View Figure

Figure 3: FT-IR of comp. 6a Click here to View Figure

Figure 4: 1H NMR of comp. 6a Click here to View Figure

Figure 5: 13C NMR of comp. 6a Click here to View Figure

Characterization

Compound 6a

Scheme 2 Click here to View Scheme

Yellow solid, Molecular Formula: C₂₆H₂₄N₆OS; FT-IR (cm-1, KBr): 3028, 2935, 2974.33, (C-H), 1674 (C=O), 1600 (C=C -Ar), 1427 (C=N – triazole), 702 (str of S-C); ¹H NMR: 1.33 (H, CH₃), 3.20, 3.81 (dd, H, Pyrazoline), 4.05, 4.75 (2H,CH₂), 5.58 (dd,H,CH), 7.23-8.76 (14H, Ar-H) ; ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.61, 37.31, 40.16, 42.44, 60.60, 122.28, 125.72, 126.89, 127.89, 128.82, 128.99, 130.80, 130.82, 135.04, 141.05, 150.56, 152.14, 153.03, 155.42 164.86; Mass: M+H  469 

Compound 6b

Scheme 3 Click here to View Scheme

Yellow solid, Molecular Formula:C₂₆H₂₃ClN₆OS; FT-IR (cm^-1, KBr): 3042, 2972, 2929 (C-H), 1677 (C=O), 1599 (C=C -Ar), 1431 (C=N – triazole), 710 (S-C); ¹H NMR : 1.31 (H, CH₃), 3.21, 3.77 (dd, H, Pyrazoline), 4.04, 4.76 (2H,CH₂), 5.56 (dd,H,CH), 7.26 – 8.80 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.63, 37.35, 40.19, 42.45, 60.39, 122.29, 125.75, 126.88, 127.89, 128.82, 128.91, 129.51, 135.04, 141.15, 141.30, 150.57, 152.16, 153.04, 155.54, 164.78; Mass: M+H 503 

Compound 6c 

Scheme 4 Click here to View Scheme

Yellow solid, Molecular Formula:C₂₇H₂₆N₆OS; FT-IR (cm^-1, KBr):  3055, 2969, 2926 (C-H) 1671 (C=O), 1602 (C=C -Ar), 1422 (C=N – triazole), 708 (S-C); ¹H NMR :  1.32 (H, CH₃), 2.43 (H, CH₃) 3.24, 3.82 (dd, H, Pyrazoline),  4.05, 4.75 (2H,CH₂), 5.54 (dd,H,CH), 7.21 – 8.77 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.63, 21.55, 37.37, 40.13, 42.47, 60.49, 122.25, 125.71, 126.84, 127.83, 128.02, 128.95, 129.51, 135.04, 141.14, 141.28, 150.55, 152.16, 153.00, 155.52, 164.74; Mass: M+H 483 

Compound 6d

Scheme 5 Click here to View Scheme

Yellow solid, Molecular Formula:C₂₇H₂₆N₆O₂S; FT-IR (cm^-1, KBr): 2941, 2968, 3035 (C-H), 1665 (C=O), 1605 (C=C Ar), 1421 (C=N – triazole), 699 (S-C); ¹H NMR :  1.33 (H, CH₃), 2.89 (H, OCH₃) 3.15, 3.78 (dd, H, Pyrazoline), 4.04, 4.79 (2H,CH₂), 5.58 (dd, H,CH), 7.24 – 8.82 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.63, 37.33, 40.15, 42.39, 55.89, 60.47, 114.66, 122.21, 125.75, 126.87, 128.79, 128.95, 130.81, 135.06, 141.04, 150.54, 152.11, 153.00, 154.21, 155.41, 164.81; Mass: M+H  499

Compound 6e

Scheme 6 Click here to View Scheme

Yellow solid, Molecular Formula:C₂₆H₂₃N₇O₃S; FT-IR (cm^-1, KBr): 2942, 2981, 3033 (C-H), 1669 (C=O), 1606 (C=C Ar), 1419 (C=N – triazole), 699 (str of S-C); ¹H NMR : 1.33 (H, CH₃),  3.11, 3.76 (dd, H, Pyrazoline), 4.06, 4.73 (2H,CH₂), 5.56 (dd,H,CH), 7.24 – 8.76 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.61, 37.31, 40.16, 42.44, 60.48, 122.22, 125.69, 126.87, 127.87, 128.85, 128.97, 130.82, 135.04, 141.01, 144.23, 150.57, 152.11, 153.01, 155.45, 164.81; Mass: M+H 514

Compound 6f

Scheme 7 Click here to View Scheme

White solid, Molecular Formula:C₂₇H₂₆N₆OS; FT-IR (cm^-1, KBr): 3032, 2978, 2931 (C-H), 1666 (C=O), 1597 (C=C Ar), 1435 (C=N – triazole), 709 (str of S-C); ¹H NMR: 1.33 (H, CH₃), 2.39 (H, CH₃) 3.16, 3.78 (dd, H, Pyrazoline),  4.05, 4.70 (2H,CH₂), 5.55 (dd, H,CH), 7.21 – 8.75 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.62, 21.54, 37.38, 40.15, 42.48, 60.50, 122.27, 125.72, 126.86, 127.85, 128.05, 128.96, 129.52, 135.03, 141.13, 141.25, 150.56, 152.17, 153.02, 155.51, 164.75; Mass: M+H  483

Compound 6g

Scheme 8 Click here to View Scheme

White solid, Molecular Formula:C₂₇H₂₅ClN₆OS; FT-IR (cm^-1, KBr): 2953, 2977, 3044 (C-H), 1668 (C=O), 1608 (C=C Ar), 1431 (C=N – triazole), 707 (str of S-C); ¹H NMR : 1.32 (H, CH₃), 2.40 (H, CH₃) 3.14, 3.79 (dd, H, Pyrazoline),  4.06, 4.71 (2H,CH₂), 5.55 (dd,H,CH), 7.23 – 8.78 (12H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.63, 37.32, 40.15, 42.42, 60.56, 122.25, 125.74, 126.84, 127.84, 128.78, 128.93, 135.06, 141.44, 141.43, 150.56, 152.11, 153.08, 155.46 164.70; Mass: M+H 517

Compound 6h

Scheme 9 Click here to View Scheme

White solid, Molecular Formula:C₂₉H₃₀N₆O₃S; FTIR (cm-1, KBr): 2942, 2968, 3024(C-H) 1675 (C=O amide), 1602 (C=C – aromatic), 1421 (C=N str – triazole), 702 (str of S-C); 1.33 (H, CH₃), 2.41 (H, CH₃) 2.96 (H, OCH₃) 3.12, 3.82 (dd, H, Pyrazoline),  4.04, 4.71 (2H,CH₂), 5.56 (dd, H,CH), 7.23 – 8.79 (11H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.62, 21.59, 37.34, 40.17, 42.46, 55.86, 60.35, 122.28, 125.74, 126.82, 127.88, 128.01, 128.95, 129.49, 135.09, 141.14, 141.38, 150.58, 152.14, 153.04, 155.54, 164.73; Mass: M+H 543

Compound 6i

Scheme 10 Click here to View Scheme

Yellow solid, M. Formula :C₂₉H₃₁N₇OS;  FTIR (cm-1, KBr): 2942, 2981, 3043 (C-H), 1666.70 (C=O amide), 1597.60 (C=C- aromatic ring), 1426 (C=N – triazole), 693 (S-C); 1.32,  2.40 (H, CH₃) 2.99 (6H, CH₃) 3.14, 3.81 (dd, H, Pyrazoline), 4.06, 4.75 (2H,CH₂), 5.59 (dd, H,CH), 7.20 – 8.75 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.64, 21.56, 37.39, 40.13, 42.42, 42.55, 60.29, 112.24, 122.27, 125.72, 126.86, 127.85, 128.91, 129.69, 135.09, 141.15, 141.28, 150.53, 152.11, 153.11, 155.58, 164.69; Mass: M+H  526

Compound 6j

Scheme 11 Click here to View Scheme

Yellow solid, M Formula :C₂₇H₂₅N₇O₃S; FTIR (cm-1, KBr): 2935, 2965, 3050, (C-H), 1677.40 (C=O amide), 1610 (C=C -Ar), 1431 (C=N– triazole), 709 (S-C); 1.33 (H, CH₃), 2.42 (H, CH₃), 3.11, 3.79 (dd, H, Pyrazoline),  4.05, 4.72 (2H,CH₂), 5.55 (dd, H,CH), 7.23 – 8.81 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.62, 21.55, 37.32, 40.14, 42.41, 60.46, 122.28, 125.76, 126.84, 127.85, 128.06, 128.89, 129.48, 135.01, 141.09, 141.17, 150.53, 152.15, 153.03, 155.50, 164.72; Mass: M+H 528 

Compound 6k

Scheme 12 Click here to View Scheme

White solid, M. Formula:C₂₇H₂₆N₆O₂S; FTIR (cm^-1, KBr): 2930, 2971, 3022 (C-H), 1667 (C=O amide), 1611 (C=C -aromatic), 1426 (C=N  – triazole), 707 (str of S-C); ¹H NMR : 1.33 (H, CH₃), 2.94 (H, OCH₃) 3.11, 3.85 (dd, H, Pyrazoline), 4.04, 4.81 (2H,CH₂), 5.54 (dd, H,CH), 7.26 – 8.79 (14H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.64, 21.56, 37.30, 40.12, 42.42, 56.12,  59.90, 122.21, 125.68, 126.85, 127.83, 128.01, 128.95, 129.54, 135.01, 141.10, 141.22, 150.52, 152.16, 153.05, 155.56, 164.79; Mass: M+H  499

Compound 6l

Scheme 13 Click here to View Scheme

White solid, Molecular Formula:C₂₇H₂₅N₇O₄S; FTIR (cm^-1, KBr): 2946, 2983, 3042 (C-H ), 1665 (C=O amide), 1598 (C=C- aromatic ring), 1419 (C=N– triazole), 698 (str of S-C); ¹H NMR :  1.32 (H, CH₃), 3.01 (H, OCH₃) 3.15, 3.86 (dd, H, Pyrazoline), 4.07, 4.78 (2H,CH₂), 5.60 (dd, H,CH), 7.21 – 8.78 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.62, 21.56, 37.37, 40.20, 42.49, 55.98, 60.30, 122.21, 125.72, 126.86, 127.81, 128.00, 128.91, 129.46, 135.07, 141.18, 141.34, 150.51, 152.14, 153.08, 155.59, 164.76; Mass: M+H  544

Compound 6m

Scheme 14 Click here to View Scheme

White solid, Molecular Formula:C₂₆H₂₃ClN₆OS; FTIR (cm-1, KBr): 2928, 2971, 3032, 3059 (C-H), 1677.40 (C=O amide), 1606 (C=C Ar), 1421 (C=N – triazole), 709 (S-C); ¹H NMR:  1.32 (H, CH₃), 2.45 (H, CH₃), 3.11, 3.79 (dd, H, Pyrazoline), 4.07, 4.78 (2H,CH₂), 5.55 (dd, H,CH), 7.22 – 8.83 (12H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.62, 21.54, 37.38, 40.15, 42.48, 60.50, 122.27, 125.72, 126.86, 127.85, 128.05, 128.96, 129.52, 135.03, 141.13, 141.25, 150.56, 152.17, 153.02, 155.51, 164.75; Mass: M+H  504

Compound 6n

Scheme 15 Click here to View Scheme

Pale yellow solid, Molecular Formula:C₂₈H₂₇ClN₆O₃S; FTIR (cm^-1, KBr): 2945, 2984, 3039 (C-H), 1675 (C=O amide), 1612 (C=C- aromatic), 1424 (C=N – triazole), 706 (S-C); ¹H NMR:  1.31 (H, CH₃), 2.96 (6H, OCH₃) 3.12, 3.79 (dd, H, Pyrazoline),  4.05, 4.79 (2H,CH₂), 5.56 (dd,H,CH), 7.19 – 8.74 (11H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.63, 21.56, 37.38, 40.12, 42.47, 56.81, 60.29, 122.25, 125.75, 126.85, 127.88, 128.04, 128.92, 129.42, 135.03, 141.16, 141.27, 150.56, 152.17, 153.08, 155.56, 164.71; Mass: M+H 564

Compound 6o

Scheme 16 Click here to View Scheme

Pale yellow solid, Molecular Formula:C₂₈H₂₈ClN₇OS; FTIR (cm-1, KBr): 2940, 2979, 3035, 3061 (C-H), 1678.30 (C=O amide), 1612 (C=C – aromatic ring), 1419 (C=N – triazole), 694 (S-C); ¹H NMR:  1.31 (H, CH₃), 2.88 (6H, CH₃) 3.12, 3.77 (dd, H, Pyrazoline),  4.04, 4.77 (2H,CH₂), 5.58 (dd,H,CH), 7.24 – 8.82 (13H, Ar-H); ¹³C NMR (500 MHz, δ ppm CDCl₃): 15.61, 21.53, 37.31, 40.12, 42.43, 42.55, 60.29, 122.25, 125.70, 126.81, 127.85, 128.03, 128.88, 129.47, 135.01, 141.16, 141.24, 150.55, 152.18, 153.05, 155.57, 164.69; Mass: M+H 547

Elemental analysis (EA)

Table 3: Physical data and elemental analysis

Conclusion

Potent triazole-pyridine fused pyrazoline derivatives 6a-6o were synthesized from pyrazoline and 3-mercapto triazole. Potential as antimicrobial agents was demonstrated by screening against bacterial and fungal strains. Methoxy and nitro functionalized com. 6l has shown highest inhibition towards S. aureus, E. coli,  E.aerogenes. All compounds have demonstrated modest scavenging capabilities where methoxy substitution promotes antioxidant activities.

Acknowledgment

We acknowledge the laboratory resources provided by K.S.K.V. Kachchh University, Bhuj.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The author(s) do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

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