Introduction

Five-membered heterocyclic compounds containing nitrogen, oxygen, and sulfur atoms have possessed a great biological (Kumar et al., 2013a; Kaur et al., 2014; Lu et al., 2012; Bondock et al., 2013) and medicinal significance (Hassan et al., 2012). Among them, substituted pyrazoles are an important class of azoles family that has been used extensively as an important class of synthons in the field of heterocyclic chemistry and drug designing approach. They are also known to possess a broad spectrum of pharmacological properties such as antibacterial (Kumar et al., 2005; Aggarwal et al., 2006), antitumor (Mohareb et al., 2012), anti-tubercular (Ravala et al., 2011), antioxidant (Al-Ayed, 2011), anti-obesity (Gupta et al., 2011), anti-inflammatory (Kumar et al., 2013b; Mariappan et al., 2010), and antidepressant (Aziz et al., 2009) activities.

Similarly, 1,2,4-triazole derivatives belong to an another important class of azoles possessing versatile utility in synthetic approaches for precursors used in synthesis of heterocycles that possess antimicrobial (Bektas et al., 2010; Kumar et al., 2009), anti-tubercular (Shiradkar et al., 2007), and anticancer (Sztanke et al., 2008) activities. The active pharmaceutical ingredients such as Conazoles, Itraconazole, Fluconazole, and Ravuconazole (Yu et al., 2007; Gupta et al., 2007; Ashok et al., 2007) containing triazole moiety have already been reported to exhibit interesting medicinal properties and therapeutic index.

The basic approach in drug discovery with an improved medicinal value is the structural modification of bioactive components. Quinoline nucleus is a well-known basic bioactive component found in various drugs such as Levofloxacin, Norfloxacin, and Ciprofloxacin. Many quinoline-based pyrazoles and pyrazoline derivatives showed potent pharmacological activities (Mistry et al., 2012; Dubey et al., 1998; Tiwari et al., 2000; Zhan et al., 2008; Lamani et al., 2010; Chandrakanthaa et al., 2012; Parekh and Maharia, 2012; Eswarn et al., 2010; EI-Agrody et al., 2013; Savini et al., 2002). Nowadays, emergence of resistance against antibacterial drugs which are currently being used has become a world-wide challenging problem before chemists and microbiologists. Therefore, development of novel and effective chemotherapeutics is still in demand to overcome these problems. Keeping in view of a wide range of pharmaceutical activities of quinoline-linked pyrazoles and pyrazolines, in this report, we disclosed the synthesis of some novel aryl/heteroaryl substituted quinoline-based triazoles under milder reaction conditions with an aim to find more effective antibacterial agents.

Materials and methods

Chemistry

Melting points of all synthesized compounds were determined in an open capillary using digital melting point apparatus and are uncorrected. IR spectra were recorded as KBr disks on a Perkin-Elmer spectrophotometer in the 4,000–450 cm−1 range. Both 1H and 13C NMR spectra of the compounds were recorded on the Bruker Advance NMR Spectrophotometer at 300/400 MHz and 75/100 MHz, respectively. Chemical shifts were measured relative to internal reference standard, tetramethylsilane (TMS) (δ = 0) in CDCl3 or DMSO-d 6, and were reported on δ scale (ppm). Coupling constants (J) were given in Hz. Mass spectra were recorded on Agilent Mass Spectrometer. Carbon, nitrogen, and hydrogen contents were analyzed using LECO 9320 analyzer.

Initially, we prepared the key substrate, 2-hydrazino-4-methylquinoline 1 which was used in the synthesis of 3-aryl/heteroaryl-9-methyl-1,2,4-triazolo[4,3-a]quinolines. The reactant 1 was synthesized by the reaction of aniline with ethylacetoacetate (Hauser and Reynolds, 1948; March et al., 1973) followed by the successive reactions with different reagents such as sulfuric acid, phosphorous oxychloride, and hydrazine hydrate (Potts et al., 1972). Another starting material, 4-formylpyrazole was prepared according to Rajput et al. (Rajput and Rajput, 2011). The quinolinyl hydrazones (3a–l) were obtained by the condensation of 1 with substituted 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehydes (2a–f) or aryl aldehydes (2g–l) in ethanol under reflux in the presence of a catalytic amount of concentrated sulfuric acid. The oxidative cyclization of 3a-l has been carried out using 1.1 equivalent of iodobenzene diacetate in dichloromethane at room temperature where desired products were successfully obtained with 80–90 % yields.

Synthesis of substituted Quinolinyl hydrazones (3a–l)

General procedure

4-Formylpyrazole (2a–f, 0.01 mol) or substituted benzaldehyde (2g–l, 0.01 mol) and one drop of conc. sulfuric acid (~0.2 mL) were added to an ethanolic solution of 2-hydrazino-4-methylquinoline (1, 0.01 mol). The reaction mass was refluxed for 20–25 min till completion of the reaction. The reaction was monitored by TLC, and excess of solvent was evaporated. The reaction mass was allowed to cool to room temperature. The obtained solid was filtered, washed with alcohol and recrystallised from ethanol. Noted m.p. and submitted to analysis.

2-[2-(1′,3′-Diphenylpyrazol-4′-yl)methylidene]hydrazinyl-4-methylquinoline (3a)

Yield 90 %; Mp (°C) 113–115; TLC R f = 0.56 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,396 (N–H str.), 1,595 (C=N str.) cm−1; 1H NMR (DMSO-d 6, 300 MHz): δ = 2.55 (s, 3H, 4-CH3), 7.26–7.58 (m, 10H, 3, 5, 6, 7, Ph‚‴-H & 4″-H), 7.80 (d, 2H, J = 7.8 Hz, 3″, 5″-H), 7.86 (d, 1H, J = 8.0 Hz, 8-H), 8.01 (d, 2H, J = 8.0 Hz, 2″, 6″-H), 8.23 (s, 1H, 6′-H), 9.00 (s, 1H, 5′-H), 11.1 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.5 (CH3), 110.0 (C-4′), 117.8 (C-3), 118.8 (C-2‴, 6‴), 122.1 (C-4a), 124.1 (C-3‴, 5‴), 124.3 (C-5), 124.4 (C-6), 124.7 (C-1″), 125.2 (C-2″, 6″), 126.8 (C-3″, 5″), 127.3 (C-4‴), 128.2 (C-4″), 129.3 (C-8a), 129.8 (C-7), 129.9 (C-8), 131.0 (C-5′), 131.4 (C-1‴), 139.6 (C-4), 142.1 (C-3′), 150.2 (C-2), 156.2 (C-6′); MS (ESI) m/z: 403.18 (M+); Anal. calcd. for C26H21N5: C, 77.40; H, 5.25; N, 17.36. Found: C, 77.35; H, 5.21; N, 17.31.

2-[2-(3′-(4″-Nitrophenyl-1′-phenylpyrazol-4′-yl)methylidene]hydrazinyl-4-methylquinoline (3b)

Yield 85 %; Mp (°C) 198–200; TLC R f = 0.41 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,404 (N–H str.), 1,593 (C=N str.), 1,540 (NO2− asymmetric str.), 1,351 (NO2 symmetric str.) cm−1; 1H NMR (DMSO-d 6, 400 MHz): δ = 2.52 (s, 3H, 4-CH3), 7.1 (s, 1H, 3-H), 7.30–7.50 (m, 11H, 5, 6, 7, 8, Ph‴-H & 2″, 6″-H), 8.20 (s, 1H, 6′-H), 8.45 (d, 2H, J = 8.3 Hz, 3″, 5″-H), 9.58 (s, 1H, 5′-H), 12.9 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.7 (CH3), 108.7 (C-4′), 118.2 (C-3), 119.2 (C-2‴, 6″′), 122.2 (C-4a), 123.9 (C-3″, 5″), 124.4 (C-3‴, 5‴), 124.6 (C-5), 124.8 (C-6), 126.4 (C-2″, 6″), 127.9 (C-4‴), 129.5 (C-8a), 130.1 (C-7), 130.3 (C-8), 130.7 (C-5′), 132.6 (C-1‴), 137.3 (C-1″), 141.8 (C-4), 145.4 (C-3′), 146.2 (C-4″), 150.4 (C-2), 155.8 (C-6′); MS (ESI) m/z: 448.16 (M+); Anal. calcd. for C26H20N6O2: C, 69.63; H, 4.49; N, 18.74. Found: C, 69.66; H, 4.50; N, 18.71.

2-[2-(3′-(4″-Methoxyphenyl-1′-phenylpyrazol-4′-yl)methylidene]hydrazinyl-4-methylquinoline (3c)

Yield 86 %; Mp (°C) 146–148; TLC R f = 0.52 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,400 (N–H str.), 1,597 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.50 (s, 3H, 4-CH3), 3.80 (s, 3H, 4″-OCH3), 6.88 (d, 2H, J = 8.5 Hz, 3″, 5″-H), 7.20–7.44 (m, 6H, 3, 6, 7-H & 3‴, 4‴, 5‴-H), 7.48 (d, 2H, J = 7.8 Hz, 2‴, 6‴-H), 7.71 (d, 1H, J = 8.0 Hz, 5-H), 7.74–7.78 (m, 3H, 8-H & 2″, 6″-H), 8.20 (s, 1H, 6′-H), 8.43 (s, 1H, 5′-H), 10.1 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.6 (CH3), 109.5 (C-4′), 114.3 (C-3″, 5″), 118.1 (C-3), 118.6 (C-2‴, 6‴), 120.3 (C-1″), 121.7 (C-4a), 123.0 (C-5), 123.6 (C-6), 123.9 (C-3‴, 5‴), 127.1 (C-4‴), 127.4 (C-2″, 6″), 129.9 (C-8a), 130.1 (C-7), 130.2 (C-8), 130.9 (C-1″′), 131.4 (C-5′), 139.5 (C-4), 142.2 (C-3′), 150.1 (C-2), 156.0 (C-6′), 159.4 (C-4″); MS (ESI) m/z: 433.19 (M+); Anal. calcd. for C27H23N5O: C, 74.81; H, 5.35; N, 16.16. Found: C, 74.79; H, 5.37; N, 16.19.

2-[2-(3′-(4″-Fluorophenyl-1′-phenylpyrazol-4′-yl)methylidene]hydrazinyl-4-methylquinoline (3d)

Yield 80 %; Mp (°C) 166–167; TLC R f = 0.55 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,408 (N–H str.), 1,599 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.4 (s, 3H, 4-CH3), 7.00 (appeared as t, 2H, J = 8.4 Hz, 3″, 5″-H), 7.20–7.80 (m, 12H, 3, 5, 6, 7, 8, Ph‴-H & 2″, 6″-H), 8.28 (s, 1H, 6′-H), 8.55 (s, 1H, 5′-H), 10.15 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.7 (CH3), 109.7 (C-4′), 115.6 (d, 2 J C–F = 20 Hz, C-3″, 5″), 117.6 (C-3), 118.3 (C-2‴, 6‴), 122.3 (C-4a), 123.8 (C-3‴, 5‴), 124.2 (C-5), 124.4 (C-6), 127.4 (C-4‴), 128.9 (C-1″), 129.2 (C-5′), 129.4 (d, 3 J C–F = 8.2 Hz, C-2″, 6″), 129.6 (C-8a), 129.8 (C-7), 130.0 (C-8), 131.2 (C-1‴), 138.8 (C-4), 143.9 (C-3′), 150.4 (C-2), 155.1 (C-6′), 161.4 (d, 1 J C–F = 239 Hz, C-4″); MS (ESI) m/z: 421.17 (M+); Anal. calcd. for C26H20FN5: C, 74.09; H, 4.78; N, 16.62. Found: C, 74.08; H, 4.73; N, 16.65.

2-[2-(3′-(4″-Chlorophenyl-1′-phenylpyrazol-4′-yl)methylidene]hydrazinyl-4-methylquinoline (3e)

Yield 86 %; Mp (°C) 158–160; TLC R f = 0.49 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,412 (N–H str.), 1,603 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.40 (s, 3H, 4-CH3), 7.47–7.79 (m, 14H, 3″, 5″, 3, 5, 6, 7, 8-H, Ph‴-H & 2″, 6″-H), 8.28 (s, 1H, 6′-H), 8.41 (s, 1H, 5′-H), 10.01 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6, 100 MHz): δ = 18.6 (CH3), 109.9 (C-4′), 117.9 (C-3), 118.4 (C-2‴, 6‴), 121.9 (C-4a), 123.6 (C-3‴, 5‴), 123.9 (C-5), 124.8 (C-6), 126.4 (C-1″), 126.8 (C-4‴), 128.2 (C-3″, 5″), 128.9 (C-8a), 129.0 (C-7), 129.1 (C-8), 129.2 (C-5′), 129.9 (C-2″, 6″), 131.5 (C-1‴), 133.2 (C-4″), 139.0 (C-4), 144.9 (C-3′), 149.3 (C-2), 155.1 (C-6′); MS (ESI) m/z: 437 (M+) and 439 (M++2) in the ratio showing typical chlorine isotope profile (3:1); Anal. calcd. for C26H20ClN5: C, 71.31; H, 4.60; N, 15.99. Found: C, 71.33; H, 4.59; N, 15.97.

2-[2-(3′-(4″-Bromophenyl-1′-phenylpyrazol-4′-yl)methylidene]hydrazinyl-4-methylquinoline (3f)

Yield 87 %; Mp (°C) 135–136; TLC R f = 0.48 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,416 (N–H str.), 1,608 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.58 (s, 3H, 4-CH3), 7.28–7.65 (m, 14H, 3″, 5″, 3, 5, 6, 7, 8-H, Ph‴-H & 2″, 6″-H), 8.23 (s, 1H, 6′-H), 9.38 (s, 1H, 5′-H), 10.06 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.6 (CH3), 110.3 (C-4′), 118.1 (C-3), 118.5 (C-2‴, 6‴), 121.7 (C-4a), 123.5 (C-3‴, 5‴), 123.8 (C-5), 124.0 (C-4″), 124.6 (C-6), 125.8 (C-4‴), 127.6 (C-2″, 6″), 128.7 (C-8a), 128.9 (C-7), 129.1 (C-8), 129.4 (C-5′), 130.1 (C-1″), 131.7 (C-1″′), 132.5 (C-3″, 5″), 139.0 (C-4), 143.7 (C-3′), 148.9 (C-2), 154.9 (C-6′); MS (ESI) m/z: 481 (M+) and 483.1 (M++2) in the ratio showing typical bromine isotope profile (1:1); Anal. calcd. for C26H20BrN5: C, 64.74; H, 4.18; N, 14.52. Found: C, 64.72; H, 4.18; N, 14.51.

4-Methyl-2-[2-(thiophen-2′-yl)methylidene]hydrazinylquinoline (3g)

Yield 85.5 %; Mp (°C) (Obs.) 172–173, Mp (°C) (Lit.) 171–172; TLC R f = 0.53 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,428 (N–H str.), 1,596 (C=N str.) cm−1; 1H NMR (DMSO-d 6, 400 MHz): δ = 2.7 (s, 3H, 4-CH3), 6.67–7.84 (m, 8H, 3, 5, 6, 7, 8-H & 2′, 3′, 4′-H), 7.85 (s, 1H, 6′-H), 9.30 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6 , 100 MHz): δ = 19.6 (CH3), 117.9 (C-3), 122.4 (C-4a), 122.9 (C-5), 123.1 (C-6), 125.9 (C-2′), 128.7 (C-3′), 129.2 (C-8a), 129.7 (C-7), 129.9 (C-8), 130.2 (C-1′), 132.1 (C-4′), 138.7 (C-4), 150.0 (C-2), 155.3 (C-6′); MS (ESI) m/z: 267.1 (M+); Anal. calcd. for C15H13N3S: C, 67.39; H, 4.90; N, 15.72. Found: C, 67.41; H, 4.89; N, 15.72.

2-[2-(4′-Fluorobenzylidene)hydrazinyl]-4-methylquinoline (3h)

Yield 87 %; Mp (°C) 214–216; TLC R f = 0.64 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,416 (N–H str.), 1,597 (C=N str.) cm−1; 1H NMR (DMSO-d 6, 400 MHz): δ = 2.66 (s, 3H, 4-CH3), 7.10–7.72 (m, 6H, 3′, 5′-H & 3, 5, 6, 7-H), 7.86–7.97 (m, 3H, 2′, 6′-H & 8-H), 8.14 (s, 1H, NH, D2O exchangeable), 8.64 (s, 1H, 7′-H); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.7 (CH3), 115.7 (d, 2 J C–F = 20.5 Hz, C-3′, 5′), 115.9 (C-3), 125.6 (C-1′), 125.8 (C-4a), 126.4 (C-5), 126.7 (C-6), 127.9 (C-2′, 6′), 130.2 (C-8a), 131.6 (C-7), 131.9 (C-8), 138.6 (C-4), 147.9 (C-2), 151.9 (C-7′), 161.3 (d, 1 J C–F = 237 Hz, C-4′); MS (ESI) m/z: 279 (M+); Anal. calcd. for C17H14FN3: C, 73.10; H, 5.05; N, 15.04. Found: C, 73.08; H, 5.04; N, 15.06.

2-[2-(4′-Bromobenzylidene)hydrazinyl]-4-methylquinoline (3i)

Yield 89 %; Mp (°C) 188–190; TLC R f = 0.67 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,419 (N–H str.), 1,594 (C=N str.) cm−1; 1H NMR(DMSO-d 6, 400 MHz): δ = 2.74 (s, 3H, 4-CH3), 7.55–7.90 (m, 6H, 3′, 5′-H & 3, 5, 6, 7-H), 7.91 (d, 2H, J = 7.8 Hz, 2′, 6′-H), 8.00 (d, 1H, J = 7.6 Hz, 8-H), 8.13 (s, 1H, NH, D2O exchangeable), 8.40 (s, 1H, 7′-H); 13C NMR (CDCl3, 400 MHz): δ = 19.6 (CH3), 116.8 (C-3), 125.0 (C-4′), 125.2 (C-4a), 126.1 (C-5), 126.2 (C-6), 128.6 (C-1′), 128.8 (C-2′, 6′), 129.3 (C-8a), 131.4 (C-7), 131.5 (C-8), 132.4 (C-3′, 5′), 136.9 (C-4), 147.7 (C-2), 149.9 (C-7′); MS (ESI) m/z: 339.9 (M+) and 342 (M++2) in the ratio showing typical bromine isotope profile (1:1); Anal. calcd. for C17H14BrN3: C, 60.02; H, 4.15; N, 12.35. Found: C, 60.01; H, 4.17; N, 12.35.

2-[2-(4′-Nitrobenzylidene)hydrazinyl]-4-methylquinoline (3j)

Yield 90 %; Mp (°C) 220–221; TLC R f = 0.48 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,410 (N–H str.), 1,597 (C=N str.) 1,565 (NO2− asymmetric str.), 1,345 (NO2− symmetric str.) cm−1; 1H-NMR (DMSO-d 6, 400 MHz): δ = 2.67 (s, 3H, 4-CH3), 7.33–7.37 (m, 1H, 7-H), 7.42 (s, 1H, 3-H), 7.56–7.86 (m, 4H, 5, 6-H & 2′, 6′-H), 7.94 (d, 2H, J = 7.8 Hz, 3′, 5′-H), 8.18–8.24 (m, 2H, 8-H & 7′-H), 8.24 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d 6 , 100 MHz): δ = 19.7 (CH3), 117.1 (C-3), 124.1 (C-3′, 5′), 126.1 (C-4a), 126.7 (C-5), 127.0 (C-6), 130.1 (C-8a), 130.7 (C-2′, 6′), 132.3 (C-7), 132.5 (C-8), 135.2 (C-1′), 138.9 (C-4), 145.6 (C-4′), 148.9 (C-2), 152.3 (C-7′); MS (ESI) m/z: 306 (M+); Anal. calcd. for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29. Found: C, 66.69; H, 4.58; N, 18.27.

2-[2-(2′, 4′-Dichlorobenzylidene)hydrazinyl]-4-methylquinoline (3k)

Yield 82.30 %; Mp (°C) 215–217; TLC R f = 0.87 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,425 (N–H str.), 1,595 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.10 (s, 3H, 4-CH3), 6.98–7.65 (m, 6H, 3, 5, 6, 7-H & 5′, 6′-H), 7.73 (s, 1H, 3′-H), 7.87 (d, 1H, J = 8.0 Hz, 8-H), 8.15 (s, 1H, NH, D2O exchangeable), 8.44 (s, 1H, 7′-H); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.7 (CH3), 114.1 (C-3′), 115.5 (C-3), 125.2 (C-4a), 126.0 (C-5), 126.2 (C-6), 127.7 (C-5′), 129.8 (C-8a), 130.2 (C-1′), 130.7 (C-7), 131.1 (C-8), 132.4 (C-6′), 137.3 (C-4′), 137.6 (C-2′), 139.1 (C-4), 147.5 (C-2), 150.2 (C-7′); MS (ESI) m/z: 329 (M+); Anal. calcd. for C17H13Cl2N3: C, 61.85; H, 3.97; N, 12.73. Found: C, 61.85; H, 3.96; N, 12.71.

2-[2-(4′-Hydroxybenzylidene)hydrazinyl]-4-methylquinoline (3l)

Yield 80 %; Mp (°C) 182–184; TLC R f = 0.31 [ethylacetate: petroleum ether (3:7)]; FT-IR (KBr) υ max: 3,402 (N–H str.), 1,594 (C=N str.) cm−1; 1H NMR (DMSO-d 6 , 400 MHz): δ = 2.62 (s, 3H, 4-CH3), 6.81 (d, 2H, J = 8.0 Hz, 3′, 5′-H), 7.28–7.66 (m, 6H, 3, 5, 6, 7, 8-H & 4′-OH), 7.80 (d, 2H, J = 8.1 Hz, 2′, 6′-H), 8.17 (s, 1H, NH, D2O exchangeable), 9.72 (s, 1H, 7′-H); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.5 (CH3), 116.1 (C-3′, 5′), 116.5 (C-3), 119.9 (C-1′), 125.3 (C-4a), 126.2 (C-5), 126.9 (C-6), 127.9 (C-2′, 6′), 129.9 (C-8a), 130.8 (C-7), 131.3 (C-8), 138.2 (C-4), 148.2 (C-2), 148.9 (C-7′), 154.9 (C-4′); MS (ESI) m/z: 277.15 (M+); Anal. calcd. for C17H15N3O: C, 73.66; H, 5.45; N, 15.15. Found: C, 73.67; H, 5.44; N, 15.14.

Synthesis of 3-aryl/heteroaryl-9-methyl-1,2,4-triazolo[4,3-a]quinolines (4a–l)

General procedure

IBD (0.011 mol) was added in a lot wise manner to the suspension or solution of 3a–l (0.01 mol) in dichloromethane under stirring. The reaction mass was further stirred for 1.0 h, and the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated and residues were triturated with petroleum ether twice to obtain crude product which was recrystallised from ethanol (Prakash et al., 2004).

3-(1′,3′-Diphenylpyrazol-4′-yl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4a)

Yield 89 %; Mp (°C) 222–223; TLC R f = 0.18 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,572 (C=N str.) cm−1; 1H NMR (DMSO-d 6, 300 MHz): δ = 2.6 (s, 3H, 9-CH3), 7.22–7.55 (m, 8H, 6, 7, Ph‴-H & 4″-H), 7.60 (d, 2H, J = 8.1 Hz, 3″, 5″-H), 7.70 (s, 1H, 10-H), 7.76 (d, 1H, J = 8.0 Hz, 8-H), 8.00 (d, 1H, J = 8.4 Hz, 5-H), 8.05 (d, 2H, J = 7.8 Hz, 2″, 6″-H), 9.16 (s, 1H, 5′-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 110.0 (C-4′), 113.9 (C-2″, 6″), 116.3 (C-10), 119.3 (C-2‴, 6‴), 124.9 (C-8a), 125.7 (C-8), 126.0 (C-7), 126.7 (C-3″, 5″), 127.3 (C-4‴), 128.5 (C-1″), 128.6 (C-5, 6), 129.0 (C-4″), 129.7 (C-3‴, 5‴), 130.1 (C-4a), 131.6 (C-5′), 131.9 (C-1‴), 137.0 (C-9), 139.5 (C-3′), 150.0 (C-3), 151.8 (C-10a); MS (ESI) m/z: 401 (M+); Anal. calcd. for C26H19N5: C, 77.80; H, 4.77; N, 17.44. Found: C, 77.82; H, 4.75; N, 17.43.

9-Methyl-3-(3′-(4″-nitrophenyl)-1′-phenylpyrazol-4′-yl)-[1,2,4]triazolo[4,3-a]quinoline (4b)

Yield 87.5 %; Mp (°C) 210–211; TLC R f = 0.11 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,573 (C=N str.), 1,543 (NO2− asymmetric str.), 1,349 (NO2 symmetric str.) cm−1; 1HNMR (CDCl3, 400 MHz): δ = 2.72 (s, 3H, 9-CH3), 7.38–7.61 (m, 5H, 6, 7-H & 3‴, 4‴, 5‴-H), 7.63–7.83 (m, 4H, 2‴, 6‴-H & 8, 10-H), 7.90 (d, 2H, J = 8.0 Hz, 2″, 6″-H), 7.95 (d, 1H, J = 7.8 Hz, 5-H), 8.02 (d, 2H, J = 8.2 Hz, 3″, 5″-H), 8.40 (s, 1H, 5′-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 108.9 (C-4′), 116.8 (C-10), 119.4 (C-2‴, 6‴), 124.8 (C-8a), 126.5 (C-8), 126.7 (C-7), 126.9 (C-3″, 5″), 128.0 (C-4‴), 129.0 (C-2″, 6″), 129.2 (C-6), 129.3 (C-5), 130.0 (C-3‴, 5‴), 130.2 (C-4a), 130.7 (C-5′), 132.3 (C-1‴), 137.2 (C-1″), 138.8 (C-9), 142.4 (C-3′), 146.2 (C-4″), 150.8 (C-3), 150.9 (C-10a); MS (ESI) m/z: 446.18 (M+); Anal. calcd. for C26H18N6O2: C, 69.95; H, 4.06; N, 18.82. Found: C, 69.96; H, 4.06; N, 18.80.

3-(3′-(4″-Methoxyphenyl)-1′-phenylpyrazol-4′-yl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4c)

Yield 90 %; Mp (°C) 256–258; TLC R f = 0.075 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,575 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.76 (s, 3H, 9-CH3), 3.60 (s, 3H, 4″-OCH3), 6.64 (d, 2H, J = 8.0 Hz, 3″, 5″-H), 6.87–7.39 (m, 5H, 6, 7-H & 3‴, 4‴, 5‴-H), 7.42–7.73 (m, 4H, 8, 10-H & 2‴, 6‴-H), 7.78–8.02 (m, 4H, 5, 2″, 6″-H & 5′-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 55.1 (OCH3), 109.5 (C-4′), 114.0 (C-3″, 5″), 116.3 (C-10), 119.2 (C-2‴, 6‴), 124.6 (C-1″), 124.8 (C-8a), 125.6 (C-8), 126.0 (C-7), 127.1 (C-4‴), 128.0 (C-2″, 6″), 129.1 (C-5, 6), 129.7 (C-3‴, 5‴), 129.9 (C-1‴), 131.00 (C-4a), 131.6 (C-5′), 136.9 (C-9), 139.6 (C-3′), 150.0 (C-3), 151.7 (C-10a), 159.8 (C-4″); MS (ESI) m/z: 431.2 (M+); Anal. calcd. for C27H21N5O: C, 75.16; H, 4.91; N, 16.23. Found: C, 75.14; H, 4.92; N, 16.24.

3-(3′-(4″-Fluorophenyl)-1′-phenyl-pyrazol-4′-yl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4d)

Yield 85 %; Mp (°C) 262–264; TLC R f = 0.08 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,578 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.73(s, 3H, 9-CH3), 6.79–7.57 (m, 9H, 3″, 5″, 6, 7-H & Ph‴-H), 7.83 (d, 2H, J = 8.0 Hz, 2″, 6″-H), 7.86 (s, 1H, 10-H), 7.98 (d, 1H, J = 7.8 Hz, 8-H), 8.12 (d, 1H, J = 8.0 Hz, 5-H), 8.52 (s, 1H, 5′-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 110.2 (C-4′), 115.8 (d, 2 J C–F = 21.5 Hz, C-3″, 5″), 116.3 (C-10), 119.2 (C-2‴, 6‴), 125.0 (C-8a), 125.6 (C-8), 126.1 (C-7), 127.8 (C-4‴), 129.4 (C-6), 129.5 (C-5), 129.8 (C-1″), 129.9 (C-3‴, 5‴), 130.4 (d, 3 J C-F  = 8.5 Hz, C-2″, 6″), 130.7 (C-4a), 131.1 (C-1‴), 131.6 (C-5′), 136.8 (C-9), 139.6 (C-3′), 150.1 (C-3), 151.6 (C-10a), 162.3 (d, 1 J C–F = 246.0 Hz, C-4″); MS (ESI) m/z: 419.20 (M+); Anal. calcd. for C26H18FN5: C, 74.45; H, 4.33; N, 16.70. Found: C, 74.40; H, 4.34; N, 16.72.

3-(3′-(4″-Chlorophenyl)-1′-phenyl-pyrazol-4′-yl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4e)

Yield 86 %; Mp (°C) 257–258; TLC R f = 0.09 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,576 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.76 (s, 3H, 9-CH3), 7.14 (d, 2H, J = 8.0 Hz, 3″, 5″-H), 7.36–7.62 (m, 7H, 6, 7-H & Ph‴-H), 7.88–7.91 (m, 3H, 10-H & 2″, 6″-H), 8.00–8.06 (m, 2H, 8, 5-H), 8.53 (s, 1H, 5′-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 110.2 (C-4′), 116.4 (C-10), 119.2 (C-2‴, 6‴), 125.1 (C-8a), 126.2 (C-8), 126.6 (C-7), 127.4 (C-4‴), 128.5 (C-6), 128.6 (C-5), 129.6 (C-3‴, 5‴), 129.9 (C-4a), 130.4 (C-3″, 5″), 131.0 (C-1″), 131.2 (C-2″, 6″), 131.6 (C-5′), 132.3 (C-1‴), 135.1 (C-4″), 136.9 (C-9), 139.2 (C-3′), 150.2 (C-3), 151.4 (C-10a); MS (ESI) m/z: 435.3 (M+) and 437.1 (M++2) in the ratio showing typical chlorine isotope profile (3:1); Anal. calcd. for C26H18ClN5; C, 71.64; H, 4.16; N, 16.07. Found: C, 71.63; H, 4.18; N, 16.04.

3-(3′-(4″-Bromophenyl)-1′-phenyl-pyrazol-4′-yl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4f)

Yield 89 %; Mp (°C) 268-269; TLC R f = 0.12 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,577 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.77 (s, 3H, 9-CH3), 7.31–7.67 (m, 9H, 3″, 5″, 6, 7-H & Ph‴-H), 7.74–7.90 (m, 3H, 10-H & 2″, 6″-H), 8.02 (d, 1H, J = 7.8 Hz, 8-H), 8.11 (d, 1H, J = 8.0 Hz, 5-H), 8.49 (s, 1H, 5′-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 110.4 (C-4′), 116.5 (C-10), 119.3 (C-2‴, 6‴), 124.6 (C-4″), 124.9 (C-8a), 126.0 (C-8), 126.3 (C-7), 127.0 (C-4‴), 128.3 (C-5, 6), 129.1 (C-3‴, 5‴), 129.8 (C-4a), 130.6 (C-2″, 6″), 131.2 (C-5′), 131.5 (C-1″), 132.1 (C-1″′), 133.5 (C-3″, 5″), 136.8 (C-9), 139.0 (C-3′), 150.1 (C-3), 151.2 (C-10a); MS (ESI) m/z: 479.2 (M+) and 481.1 (M++2) in the ratio showing typical bromine isotope profile (1:1); Anal. calcd. for C26H18BrN5: C, 65.01; H, 3.78; N, 14.59. Found: C, 64.99; H, 3.79; N, 14.58.

9-Methyl-3-(thiophen-2′-yl)-[1,2,4]triazolo[4,3-a]quinoline (4g)

Yield 81.5 %; Mp (°C) (Obs.) 163–164, Mp (°C) (Lit.) 164–165; TLC R f = 0.14 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,574 (C=N str.) cm−1; 1H NMR (DMSO-d 6, 400 MHz): δ = 2.6 (s, 3H, 9-CH3), 7.27–7.93 (m, 8H, 5, 6, 7, 8, 10-H & 2′, 3′, 4′-H); 13C NMR (DMSO-d 6, 100 MHz): δ = 19.7 (CH3), 116.4 (C-10), 125.1 (C-8a), 125.6 (C-8), 126.1 (C-7), 126.7 (C-2′), 128.8 (C-6), 128.9 (C-5), 129.1 (C-3′), 130.2 (C-1′), 130.6 (C-4a), 132.9 (C-4′), 136.7 (C-9), 150.4 (C-3), 151.3 (C-10a); MS (ESI) m/z: 265.07 (M+); Anal. calcd. for C15H13N3S: C, 67.90; H, 4.18; N, 15.84. Found: C, 67.88; H, 4.09; N, 15.83.

3-(4′-Fluorophenyl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4h)

Yield 82.3 %; Mp (°C) 182–183; TLC R f = 0.1 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,568 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.66 (s, 3H, 9-CH3), 7.25–7.56 (m, 5H, 3′, 5′-H & 6, 7, 8-H), 7.64 (d, 2H, J = 7.9 Hz, 2′, 6′-H), 7.77 (s, 1H, 10-H), 7.95 (d, 1H, J = 8.0 Hz, 5-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 116.4 (d, 2 J C–F = 21.0 Hz, C-3′, 5′), 116.7 (C-10), 125.2 (C-8a), 125.9 (C-1′), 126.0 (C-8), 126.1 (C-7), 128.7 (C-2′, 6′), 131.6 (C-4a), 132.0 (C-6), 132.1 (C-5), 136.8 (C-9), 147.8 (C-3), 149.8 (C-10a), 164.0 (d, 1 J C–F = 250 Hz, C-4′); MS (ESI) m/z: 277 (M+); Anal. calcd. for C17H12FN3: C, 73.64; H, 4.36; N, 15.15. Found: C, 73.65; H, 4.37; N, 15.15.

3-(4′-Bromophenyl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4i)

Yield 90 %; Mp (°C) 140–142; TLC R f = 0.13 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,564 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.62 (s, 3H, 9-CH3), 7.36–7.60 (m, 6H, 3′, 5′-H & 6, 7, 8, 10-H), 7.68 (d, 2H, J = 8.0 Hz, 2′, 6′-H), 7.90 (d, 1H, J = 8.0 Hz, 5-H); 13C NMR (CDCl3, 100 MHz): δ = 19.2 (CH3), 116.2 (C-10), 122.9 (C-4′), 123.0 (C-8a), 124.1 (C-8), 125.0 (C-7), 128.0 (C-2′, 6′), 129.1 (C-6), 129.2 (C-5), 129.9 (C-1′), 131.7 (C-4a), 131.8 (C-3′, 5′), 133.9 (C-9), 148.7 (C-3), 154.9 (C-10a); MS (ESI) m/z: 337.15 (M+) and 339.2 (M++2) in the ratio showing typical bromine isotope profile (1:1); Anal. calcd. for C17H12BrN3: C, 60.37; H, 3.58; N, 12.42. Found: C, 60.38; H, 3.59; N, 12.43.

9-Methyl-3-(4′-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinoline (4j)

Yield 90 %; Mp (°C) 206–207; TLC R f = 0.09 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,562 (C=N str.), 1,566 (NO2 asymmetric str.), 1,342 (NO2 symmetric str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.74 (s, 3H, 9-CH3), 7.48–7.51 (m, 3H, 6, 7, 8-H), 7.79 (s, 1H, 10-H), 7.97 (d, 2H, J = 6.8 Hz, 2′, 6′-H), 8.04 (d, 1H, J = 8.0 Hz, 5-H), 8.49 (d, 2H, J = 6.6 Hz, 3′, 5′-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 116.8 (C-10), 124.2 (C-3′, 5′), 125.3 (C-8a), 126.4 (C-8), 126.6 (C-7), 129.0 (C-5, 6), 130.9 (C-2′, 6′), 131.2 (C-4a), 136.0 (C-1′), 137.6 (C-9), 146.7 (C-4′), 148.9 (C-3), 150.3 (C-10a); MS (ESI) m/z: 304.1 (M+); Anal. calcd. for C17H12N4O2: C, 67.10; H, 3.97; N, 18.41. Found: C, 67.11; H, 3.95; N, 18.39.

3-(2′,4′-Dichlorophenyl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4k)

Yield 88 %; Mp (°C) 202–203; TLC R f = 0.15 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,569 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.70 (s, 3H, 9-CH3), 7.37–7.60 (m, 4H, 6, 7, 8-H & 5′-H), 7.64 (s, 1H, 3′-H), 7.66 (d, 1H, J = 8.0 Hz, 6′-H), 7.72 (s, 1H, 10-H), 7.98 (d, 1H, J = 7.8 Hz, 5-H); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 114.0 (C-3′), 116.0 (C-10), 125.0 (C-8a), 125.9 (C-8), 126.3 (C-7), 128.1 (C-5′), 128.2 (C-6), 129.3 (C-5), 130.1 (C-1′), 131.6 (C-4a), 133.4 (C-6′), 136.2 (C-9), 137.2 (C-4′), 137.8 (C-2′), 145.0 (C-3), 149.8 (C-10a); MS (ESI) m/z: 327 (M+); Anal. calcd. for C17H11Cl2N3: C, 62.22; H, 3.38; N, 12.80. Found: C, 62.23; H, 3.37; N, 12.79.

3-(4′-Hydroxyphenyl)-9-methyl-[1,2,4]triazolo[4,3-a]quinoline (4l)

Yield 82 %; Mp (°C) 150–151; TLC R f = 0.03 [ethylacetate: petroleum ether (4:6)]; FT-IR (KBr) υ max: 1,564 (C=N str.) cm−1; 1H NMR (CDCl3, 400 MHz): δ = 2.70 (s, 3H, 9-CH3), 7.15–7.55 (m, 5H, 3′, 5′-H & 6, 7, 8-H), 7.65–7.80 (m, 3H, 10-H & 2′, 6′-H), 7.95–7.99 (m, 2H, 5-H, 4′-OH); 13C NMR (CDCl3, 100 MHz): δ = 19.7 (CH3), 115.9 (C-3′, 5′), 116.3 (C-10), 119.5 (C-1′), 125.8 (C-8a), 126.0 (C-8), 127.3 (C-7), 128.5 (C-6), 128.9 (C-5), 129.0 (C-2′, 6′), 130.9 (C-4a), 135.9 (C-9), 148.8 (C-3), 150.7 (C-10a), 154.9 (C-4′); MS (ESI) m/z: 275.5 (M+); Anal. calcd. for C17H13N3O: C, 74.17; H, 4.76; N, 15.26. Found: C, 74.15; H, 4.77; N, 15.25.

Biology

Antibacterial evaluation

Antibacterial activity of all synthesized compounds has been evaluated by the agar well-diffusion method in dimethyl formamide (DMF) against various pathogenic strains of bacteria (Psuedomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterococcus, Bacillus subtilis, and Staphylococcus aureus). All bacterial strains were isolated from the patients in Maharishi Markandeshwar Medical College, Maharishi Markandeshwar University, Mullana-Ambala, Haryana (Sadashiva et al., 2004). The nutrient agar medium 25 mL was poured into each petri plate, and the agar plates were swabbed with 100 μL inocula of each test bacterium and kept for 15 min for adsorption. Using sterile cork borer of 8 mm diameter, wells were bored into the seeded agar plates and loaded with a 50 μL volume. Solutions of the test compounds and standard were prepared in DMF at concentration of 2,000 µg/mL. From this stock solution, two-fold dilutions (2, 4, 8, …… 1,024 µg/mL) of the compounds were inoculated to the corresponding wells. All the plates were incubated at 37°C for 24 h, and antibacterial activity of each synthesized compound was evaluated by measuring the zone of growth inhibition with zone reader (Hi Antibiotic zone scale), and further MIC was determined at lowest concentration of each compound which was able to inhibit the visible growth of bacteria. DMF was used as a negative control whereas Cefixime was used as a reference drug.

Computational study: structural similarity assessment

Success of SAR studies depends on the selection of appropriate molecular descriptors to explain the biological activity. It has already been found that the topological index signifies the degree of branching, connectivity of atoms, and unsaturation in the molecule that accounts for variation in activity. Topological parameter, balaban topological index coupled with electronic parameter, and electronic energy resulted in a significant improvement to assess the structural similarity. In this study, we considered a number of molecular parameters such as Molar refractivity (MR), Molecular weight (MW), Total energy (TotE), Electronic energy (ElcE), HOMO energy (Homo), LUMO energy (Lumo), Balaban index (BIndx), Molecular topological index (TIndx), Wiener index (WIndx) of compounds, and standard drug, Cefixime using Chem3D (Nikolova and Jaworska, 2004; Sigroha et al., 2012). The values of theses parameters for synthesized compounds were compared with Cefixime to assess the structural similarity (Table 1).

Table 1 Calculation of various steric and physico-chemical parameters of the compounds 3a–l and 4a–l and the standard drug, Cefixime
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Result and Discussion

Chemistry

Synthetic procedures for 1,2,4-triazoles by the oxidative transformation of hydrazide or hydrazone derivatives with copper (II) chloride (Aggarwal et al., 2011), bromine (Gibson, 1963; Pollak and Tisler, 1966), etc., have been reported which provide lesser yields besides their non eco-friendly nature. There are several reports that disclosed the use of hypervalent iodine (III) compounds as environmentally benign reagents due to lesser toxic effects to the environment. Iodine reagents have been used in many oxidative rearrangements (Vorvoglis, 1997; Zhdankin, 2009) to yield selective product formation. In literature, preparations of various 1,2,4-triazoles derivatives were reported via oxidation of substituted hydrazones such as pyrimidinyl hydrazones (Prakash et al., 2004; Prakash et al., 2011; Sadana et al., 2003), 2-pyridyl hydrazones and 4-methyl-2-quinolinyl hydrazones (Kumar, 2012) with 1.1 equivalent of iodobenzene diacetate in dichloromethane (DCM) at room temperature. In this study, a series of twelve novel triazoloquinolines (4) has been synthesized by oxidative cyclization of their corresponding new quinolinyl hydrazones using IBD in dichloromethane under mild reaction conditions with high purity and excellent yields as outlined in Scheme 1. All the synthesized compounds were characterized on the basis of their FT-IR, 1H,13C NMR, and mass spectral data. To achieve the target, first we prepared a key substrate, 2-hydrazino-4-methylquinoline by the reaction of aniline with ethylacetoacetate (Hauser and Reynolds, 1948; March et al., 1973) followed by the successive reactions with sulfuric acid, phosphorous oxychloride, and hydrazine hydrate (Potts et al., 1972). Another starting material, 4-formylpyrazole (2) was also prepared according to the literature method (Rajput et al., 2011). The quinolinyl hydrazones (3a–l) were obtained by the condensation of 1 with an appropriate substituted 3-aryl-1-phenyl-1H-pyrazole-4-carbaldehyde (2a–f) or aryl aldehyde (2g–l) in ethanol under reflux in the presence of a catalytic amount of concentrated sulfuric acid. Further, the oxidative cyclization of quinolinyl hydrazones has been achieved using 1.1 equivalent of IBD (Prakash et al., 2011; Sadana et al., 2003) in dichloromethane at room temperature, and desired products were successfully obtained with 80–90 % yields.

Scheme 1
scheme 1

Synthesis of 3-aryl/hetroaryl-9-methyl-1,2,4-triazolo[4,3-a]quinolines

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The IR spectra of the compounds 3a–l showed an absorption band in a range 3,396–3,428 cm−1 due to –NH stretch and therefore, indicated the formation of hydrazones. The two singlets due to 5-H of pyrazole ring and N=CH in the range 8.40–9.58 and 8.20–8.79 ppm were appeared in 1H NMR spectrum of quinolinyl hydrazones (3a–l), respectively. In 1H NMR spectra of hydrazones 3a–l, the characteristic downfield signal at δ 11.1 was attributed to NH proton and rest of the protons exhibited multiplets in the aromatic region. The chemical shifts in 13C NMR spectra at δ 155.07 and 144.95 correspond to CH=N and pyrazole carbon-3, respectively.

The structures of final products (4) were established by comparing their FT-IR, 1H, and 13C NMR spectra with hydrazones (3a–l). The FT-IR spectra of 4a–l were transparent in the region of NH stretching which confirmed the successful oxidation of 3 into 4. Disappearance of chemical shifts at δ 8.20–8.79 (N=CH) and 11.1 (NH) in 1H NMR spectrum of the product (4a–l) confirmed the oxidative transformation of quinolinylhydrazones into 3-aryl/heteroaryl-9-methyl-1,2,4-triazolo[4,3-a]quinolines. The 13C NMR spectra displayed signals at around 150.03 and 151.81 ppm for triazole carbons, and other signals at 110.04 and 131.95 ppm correspond to carbon-4 and -5 of the pyrazole ring. In 13C NMR spectrum, disappearance of a signal at 155.07 ppm further confirmed the formation of titled compounds. The signal at 110.04 ppm was appeared due to pyrazole carbon attached to triazole ring. (Figs. 1, 2)

Fig. 1
figure 1

Chemical structures of compounds 3a–l

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Fig. 2
figure 2

Chemical structures of compounds 4a–l

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Biology

Antibacterial activity

All twenty four compounds were evaluated for their in vitro antibacterial activity against three Gram-positive bacteria, namely Enterococcus, B. subtilis, and S.aureus, and three Gram-negative bacterial strains, namely P. aeruginosa, Escherichia coli, and K. pneumoniae. The potential of synthesized compounds was compared with a well-known antibiotic, Cefixime. The results of antibacterial activity against both Gram-positive and Gram-negative bacteria were summarized in Table 2; Fig. 3. The antibacterial evaluation data revealed that compounds containing pyrazole moiety in general were possessing admirable activity in comparision with other compounds. In case of quinolin-2-yl hydrazones, 3a, 3c, and 3d were found as the most effective antibacterial agents against two Gram-positive bacteria, S. aureus and B. subtilis. On ther other hand, triazole derivatives, 4a and 4b were also found to possess excellent antibacterial activity against the same bacterial strains. It has been observed that conversion of hydrazone (3a) into corresponding traizole (4b) does not affect the antibacterial potential significantly. However, in certain cases activity was found to be decreased. It is also important to mention that compounds (3a, 3h, 4d, and 4h) bearing fluorophenyl group attached either to pyrazole ring or to imine carbon directly were exhibiting good activity in comparison with other halogen or non-halogen substituted compounds of the mentioned series. Pyrazole containing compounds having electron-releasing group (OCH3 and F) attached to phenyl ring at para position were possessing potent antibacterial activity and rest of the compounds have shown moderate activity only. Furthermore, triazoloquinoline 4b containing electron-withdrawing substitutation (NO2) at para position on phenyl ring attached to pyrazole moiety was found to be more active than other substituted triazoles. Among triazoles 4a was also found effective against Gram-negative bacteria, E.coli.

Table 2 Zone of inhibition (mm) and minimum inhibitory concentration (MIC) (in μg/mL) of compounds 3a–l and 4a–l
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Fig. 3
figure 3

Comparison of diameter of growth of inhibition of the compounds with standard drug

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Further, in vitro antibacterial activity results were supported by considering the three molecular descriptors namely BIndxg, TIndgh, and WIndxi for assessing biological potential of the synthesized compounds with the standard drug, Cefixime. Interestingly, it has been observed that the calculated values of these three molecular parameters for the most effective compounds against Gram-positive bacteria were comparable to the standard antibiotic and these compounds also showed good structural similarity as presented in Table 3. Whereas, compounds 3g and 4g have least value of theses molecular parameters as compared to other synthesized compounds as a result structural similarity was also found to be less. This observation also supports the MIC data expressed by 3g and 4g, and thus indicated the least active nature of these compounds. Therefore, results of in vitro biological study were fully supported by theoretical study of entitled compounds.

Table 3 Assessment of structural similarities of the titled compounds 3a–l and 4a–l with the standard drug, Cefixime
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Structural similarity assessment

The biological activity assessment of all compounds was also predicted on the basis of computational study using Chem 3D software. In this part of investigation, the compounds were assessed for their percentage similarity with the standard drug on the basis of some important molecular parameters. The sets of parameters used in an equation to calculate the distance d i of titled compounds are given in Table 1. The equation can be expressed as:

$$ d_{i}^{2} = \, \sum \, \left( {1 - X_{i,j} /X_{{i,{\text{standard}}}} } \right)^{2} /n $$

In X i,j , the i denotes the value of physico-chemical parameter for synthesized compound j, and X i ,standard is the value of same parameters calculated against standard. n is the total number of considered molecular parameter for standard compound.

The similarity of the compounds can be calculated as (Table 3):

$$ \% {\text{ similarity }} = \, \left( { 1- R} \right) \, \times { 1}00, $$

where, R is quadratic mean also known as the root mean square and can be calculated as:

$$ R \, = \, \surd d_{i}^{2} $$

Conclusion

In this study, synthesis of a series of novel triazoles via oxidative cyclization of quinolinyl hydrazones using IBD; a hypervalent iodine(III) reagent has been achieved under milder reaction conditions. The inhibitory and MIC data have shown that compounds 3a, 3c, 3d, 4a, and 4b were displayed excellent antibacterial activity. It is concluded that in quinolinyl hydrazones, para substitution with electron-releasing group on phenyl ring attached to position-3 of pyrazole moiety increases whereas electron-withdrawing group decreases the antibacterial activity. However, in triazoloquinolines, an electron-withdrawing group substituted at para position on the phenyl ring attached to position-3 of pyrazole nucleus increases the antibacterial potential. Among triazoloquinolines, 4b was found to be most active antibacterial agent particularly against Gram-positive bacteria than other substituted triazoles. Variation in para substitution on phenyl ring attached to pyrazole-3 position has clearly shown the variation in antibacterial activity of synthesized compounds. Quinolinyl hydrazones and triazole derivatives having pyrazole as well as quinoline moieties were found to be more active antibacterial agents. The in vitro antibacterial activity results were also supported by computational study of entitled compounds particularly by considering the three important molecular parameters namely BIndxg, TIndgh, and WIndxi. It was observed that for the most effective compounds the values of theses parameters were comparable to the standard antibiotic along with good structural similarity. Some structural modifications in these compounds may further lead to the developments of newer and effective antibacterial agents in the future.