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Design, synthesis, docking and in vitro antifungal study of 1,2,4-triazole hybrids of 2-(aryloxy)quinolines

  • Shilpa M. Somagond , Ravindra R. Kamble EMAIL logo , Pramod P. Kattimani , Shrinivas D. Joshi and Sheshagiri R. Dixit
Published/Copyright: July 19, 2017
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 23 Issue 4

Abstract

Substituted quinolines containing a 1,2,4-triazole moiety were synthesized using reported methods. The molecular docking studies support the experimental results that these compounds are active against A. fumigatus and C. albicans where N-myristoyl transferase (NMT) and dihydrofolate reductase (DHFR), respectively, are the target enzymes. The analogues that contain methoxy and chloro substituents exhibit the best antifungal activity.

Keywords: antifungal; dihydrofolate reductase; N-myristoyl transferase; quinoline

Introduction

The number of immuno-suppressed patients with transplants, cancer or AIDS is growing rapidly due to invasive mycosis. The increasing occurrence of fungal infections, particularly among AIDS patients motivate the search for better antifungal agents [1], [2], [3], [4], [5], [6], [7]. The commonly used antifungal agents are azoles, polyenes and echinocandins. Some organisms have developed resistance to these antifungal agents because of their side effects and/or drug-drug interactions. Oral antifungal agents with a novel mode of action and excellent bioavailability [8] are in demand. In this report, which is aimed at identifying novel antifungal agents, we focused on developing the scaffolds that would selectively inhibit the enzymes N-myristoyl transferase (NMT) and dihydrofolate reductase (DHFR) from fungal species.

N-myristoyl transferase (NMT) is a promising target for antifungal, antiparasitic, and anticancer agents. Many potent NMT inhibitors with antifungal, antiparasitic, and anticancer activities have been reported [9]. Inhibition of DHFR is a well-established mechanism of drug action [10], [11], [12]. The inability to synthesize DNA because of inhibition of DHFR can ultimately lead to cell death. To minimize DHFR related toxicities to the human host, the ideal antifungal agent should selectively inhibit the fungal enzyme. Such species-selective inhibition of DHFR has proven clinically useful in other therapeutic applications [13], [14], [15], [16]. For example, the therapeutic value of the antibacterial agent trimethoprim lies in its ability to selectively inhibit the bacterial enzyme. Certain pyrrolo-2,4-diaminoquinazolines 1 which are potent, but non-selective inhibitors of DHFR, have been reported to exhibit in vitro antifungal activity [17]. Other DHFR inhibitors include 5-methyl-6-alkyl-2,4-diaminoquinazolines 2 [18] and 6-substituted-2,4-diaminoquinazolines 3 [19].

Quinoline moiety is present in many synthetic and naturally occurring biologically active compounds [20], [21]. Quinolines possess antibacterial, anthelmintic, antimalarial, antifungal, cardiotonic, anticonvulsant, analgesic and anti-inflammatory activities [22]. Compounds 4–6, extracted from alkaloid Haplophylham sieversii are examples of antifungal agents [23].

1,2,4-Triazoles are an important class of heterocyclic compounds that possess a broad spectrum of chemotherapeutic properties including antifungal, antiviral, anti-inflammatory, anti-proliferative, anti-asthmatic, hypnotic, pesticidal, antidepressant, and antimicrobial properties [24], [25], [26].

In the present report, we have synthesized 2-(aryloxy)quinolines carrying a 1,2,4-triazole moiety at position 3 spaced through a methylene group. The molecular docking study has been undertaken for the detailed study of the interaction of molecules for the inhibition of enzymes NMT and DHFR to aid in analysis of the antifungal activity. The in vitro antifungal activity of these compounds has been carried out against the pathogenic strains A. fumigatus and C. albicans.

Results and discussion

In our continuous effort to discover potent antifungal agents, 24 novel quinoline derivatives were synthesized and purified. 2-Aryl-2H-1,2,4-triazol-3(4H)-ones 3a,b were prepared from the corresponding N-arylsydnones 1a,b through the intermediary of 5-methyl-3-aryl-1,3,4-oxadiazol-2(3H)-ones 2a,b (Scheme 1) [24], [25]. 6-Substituted-2-chloro-3-formylquinolines 4c–f were prepared by Meth-Cohns’ Vilsmeir-Haack approach and then converted to 6-substituted-2-aryloxy-quinoline-3-carbaldehydes 5g–r. Reduction of the formyl group with NaBH4 followed by treatment with PBr3 yielded 6-substituted-3-(bromomethyl)-2-aryloxyquinolines 7g–r [27]. The reaction of compounds 3a,b with compounds 7g–r in the presence of anhydrous K2CO3 afforded the final products 2-aryl-4[{(6-substituted-2-(aryloxy)quinolin-3-yl)methyl}]-2H-1,2,4-triazol-3(4H)-ones 8–31 (Scheme 2). Predicted structures of the newly synthesized compounds were in good agreement with their IR, 1H NMR, 13C NMR, MS and elemental analysis data.

Scheme 1 Synthesis of 1,2,4-triazole derivatives 3a,b from 3-arylsydnones 1a,b.
Scheme 1

Synthesis of 1,2,4-triazole derivatives 3a,b from 3-arylsydnones 1a,b.

Scheme 2 Synthesis of 1,2,4-triazole hybrids of 2-(aryloxy)quinolines 8–31.
Scheme 2

Synthesis of 1,2,4-triazole hybrids of 2-(aryloxy)quinolines 8–31.

Docking simulation

Molecular docking was used to determine the orientation of inhibitors bound in the active sites of NMT and DHFR. The docking studies are in agreement with the experimental findings that compounds 22, 24 and 29 are good antifungal agents. As depicted in Figures 1 and 2, compound 24 forms four hydrogen bonds at the active site of the enzyme NMT. The nitrogen atom of the quinoline forms hydrogen bond with hydrogen of SER378 (N-----H-SER378), the methoxy group present at ortho position of the phenoxyphenyl group and the methoxy group at para position of the phenyl ring attached to a triazole ring form two respective hydrogen bonds with hydrogen of ASN434 and ASN152 (H3CO-----H-ASN434 and H-ASN152) and the last hydrogen bond is the result of the interaction of the nitrogen atom of a triazole ring with hydrogen of GLY455 (N-----H-GLY455). As depicted in Figures 1 and 2, compound 29 makes two hydrogen bonds with the active site of the enzyme DHFR. These are interaction of the triazole with hydrogen of GLU116 (N-----H-GLU116) and interaction of the carbonyl group at the triazole with hydrogen of THR58 (C=O-----H-THR58). The docking study corroborates the experimental findings (Tables 1 and 2). As can be seen from the scores listed in Tables 1 and 2, all molecules preferentially bind in the active sites of the enzymes in comparison with the references 4CAW and 1AI9. As depicted in Figures 3 and 4, compound 22 is involved in three hydrogen bonding interactions with the enzyme (PDB ID: 1AI9). One is N-----H- GLU116 and the remaining two interactions involve the oxygen atom of a carbonyl group present at position 5 of the triazole ring with hydrogens of THR58 and GLY114 (C=O-----H-THR58 and C=O-----H-GLY114).

Figure 1 Interactions of compounds 24 and 29 with NMT (PDB ID: 4CAW; A-chain) and DHFR (PDB ID: 1AI9). Interaction of compound 24 with NMT: a–c. Interaction of compound 29 with DHFR: d–f.
Figure 1

Interactions of compounds 24 and 29 with NMT (PDB ID: 4CAW; A-chain) and DHFR (PDB ID: 1AI9). Interaction of compound 24 with NMT: a–c. Interaction of compound 29 with DHFR: d–f.

Figure 2 Hydrogen bonding interactions of compounds 24 and 29 at the active site of 4CAW and 1AI9, respectively. Hydrogen bonds are indicated by dashed lines. Amino acid residues involved in weak van der Waals interactions are shown in box.
Figure 2

Hydrogen bonding interactions of compounds 24 and 29 at the active site of 4CAW and 1AI9, respectively. Hydrogen bonds are indicated by dashed lines. Amino acid residues involved in weak van der Waals interactions are shown in box.

Table 1

Surflex docking score (kcal/mol) for NMT (A. fumigatus).

CompoundC scoreaCrash scorebPolar scorecD scoredPMF scoreeG scorefChem scoreg
84.86−0.830.70−236.10−97.44−184.70−37.41
164.21−0.450.02−216.78−92.19−170.42−34.61
248.05−1.183.53−390.92−87.14−207.73−40.62
296.40−1.051.33−426.32−8.11−200.17−32.94
225.27−0.931.12−337.38−23.00−211.47−33.75
304.72−1.000.49−361.72−60.33−194.47−33.22
314.06−0.611.06−356.20−74.26−133.76−34.80

  1. aC score (consensus score) integrates popular scoring functions for ranking the affinity of ligands bound to the active site of a receptor and reports the output of total score.

  2. bCrash-score reveals the inappropriate penetration into the binding site. Crash scores close to 0 are favorable. Negative numbers indicate penetration.

  3. cContribution of the polar interactions to the total score. The polar score may be useful for excluding docking results that make no hydrogen bonds.

  4. dD score for charge and van der Waals interactions between the protein and the ligand.

  5. ePMF-score indicates the Helmholtz free energies of interactions for protein-ligand atom pairs (potential of mean force, PMF).

  6. fG-score shows hydrogen bonding, complex (ligand-protein), and internal (ligand-ligand) energies.

  7. gChem-score points for H-bonding, lipophilic contact, and rotational entropy, along with an intercept term.

Table 2

Surflex docking score (kcal/mol) for DHFR (C. albicans).

CompoundC scoreaCrash scorebPolar scorecD scoredPMF scoreeG scorefChem scoreg
86.52−2.151.12−226.44−22.24−255.71−29.09
165.11−0.720.01−274.64−58.08−212.02−28.47
245.94−1.561.04−385.98−22.63−266.74−27.93
297.44−2.711.74−417.89−78.48−266.01−33.81
226.53−2.422.11−334.25−81.34−256.82−28.74
305.78−1.941.36−351.72−27.62−249.56−30.51
316.23−1.931.88−385.48−5.30−236.86−28.65

  1. a−gFor definitions of footnotes, see Table 1.

Figure 3 Interaction of compound 22 with DHFR (PDB ID: 1AI9).
Figure 3

Interaction of compound 22 with DHFR (PDB ID: 1AI9).

Figure 4 Interactions of compound 22 at the active site of 1AI9 (DHFR). Hydrogen bonds are indicated by dashed lines. Amino acid residues involved in weak van der Waals interactions are shown in box.
Figure 4

Interactions of compound 22 at the active site of 1AI9 (DHFR). Hydrogen bonds are indicated by dashed lines. Amino acid residues involved in weak van der Waals interactions are shown in box.

In vitro antifungal activity

The compounds were subjected to in vitro antifungal screening against pathogenic strains A. fumigatus and C. albicans using fluconazole as a standard drug (Table 3). The experimental activity results parallel the results of docking simulation.

Table 3

Antifungal activity of the synthesized compounds (MIC in μg/mL).a

CompoundA. fumigatus (MIC)C. albicans (MIC)
180.200.20
220.200.40
240.400.20
251.600.40
290.400.20
Fluconazole0.200.20

  1. aThe MIC values of the tested compounds 10, 14, 16, 17, 19, 26, 28 and 31 are higher than 1.5 μg/mL.

Conclusions

A series of 2-aryl-4[{(6-substituted-2-(aryloxy)quinolin-3-yl)-methyl}]-2H-1,2,4-triazol-3(4H)-ones 8–31 were synthesized and screened for their antifungal activities. Docking studies results support the experimental findings that compounds 22, 24 and 29 are potent antifungal agents.

Experimental

Melting points were determined in open capillary tubes and are uncorrected. All reactions were monitored by thin layer chromatography using silica gel pre-coated aluminium sheets (Merck TLC 60 F254) and visualized in a UV light chamber. 2-Chloro-3-formyl-quinolines 4c–f and N-arylsydnones 1a,b were prepared according to the reported methods indicated in the text. IR spectra were recorded in KBr discs on a Nicolet 170 SX FT-IR spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker Advance FT NMR spectrometer in DMSO-d6 with TMS as an internal standard. Mass spectra were recorded using a Finnegan MAT 8200 spectrometer.

General procedure for synthesis of compounds 8–31

A mixture of compound 3a,b (1.0 mmol), 7g–r (1.6 mmol) and anhydrous K2CO3 (1.6 mmol) in DMF was stirred for 20 min at room temperature. After completion, ice-cold water was added and the resultant solid mass was filtered and recrystallized from ethyl acetate.

[2-Phenyl-4[-{(2-(p-tolyloxy)quinolin-3-yl)-methyl}]-2H-1,2,4-triazol-3(4H)-one (8) This compound was obtained from 3a and 7g; pale yellow solid; yield 81%; mp 142–144°C; IR: ν 1704 (C=O), 1626 (C=N) cm−1; 1H NMR: δ 8.35 (s, 1H, ArH), 8.28 (s, 1H, C5H), 7.25–7.97 (m, 13H, ArH), 5.14 (s, 2H, CH2), 2.33 (s, 3H, CH3); 13C NMR: δ 159.1, 151.7, 150.7, 145.0, 138.6, 138.3, 137.7, 136.0, 134.0, 130.0, 129.8, 129.0, 127.7, 126.6, 125.3, 125.1, 121.5, 119.9, 117.9, 41.51, 20.4; MS: m/z 408 [M+]. Anal. Calcd for C25H20N4O2: C, 73.1; H, 4.94; N, 13.72. Found: C, 73.4; H, 5.01; N, 13.80.

[4-{(6-Methyl-2-(p-tolyloxy)-quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (9)

This compound was obtained from 3a and 7h; buff solid; yield 93%; mp 118–120°C; IR: ν 1709 (C=O), 1628 (C=N) cm−1; 1H NMR: δ 8.92 (s, 1H, ArH), 8.31 (s, 1H, C5H), 7.19–8.21 (m, 12H, ArH), 5.30 (s, 2H, CH2), 2.43 (s, 3H, CH3), 2.45 (s, 3H, CH3); 13C NMR: δ 156.0, 144.0, 141.0, 136.0, 135.0, 133.0, 132.0, 131.5, 130.5, 130.0, 128.0, 127.3, 125.7, 125.4, 124, 123.1, 123.0, 119.0, 118.0, 41.1, 20.8, 20.7; MS: m/z 422 [M+]. Anal. Calcd for C26H22N4O2: C, 73.92; H, 5.25; N, 13.26. Found: C, 73.98; H, 5.28; N, 13.32.

[4-{(6-Chloro-2-(p-tolyloxy)quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (10)

This compound was obtained from 3a and 7i; pale yellow solid; yield 88%; mp 153–155°C; IR: ν 1703 (C=O), 1620 (C=N) cm−1; 1H NMR: δ 8.99 (s, 1H, ArH), 8.34 (s, 1H, C5H), 7.21–8.25 (m, 12H, ArH), 5.12 (s, 2H, CH2), 2.49 (s, 3H, CH3); 13C NMR: δ 158.0, 145.0, 143.0, 138.0, 137.0, 134.0, 132.0, 131.0, 129.3, 129.0, 128.2, 126.7, 126.4, 125.0, 123.7, 123.5, 119.8, 117.8, 117.0, 41.4, 20.8; MS: m/z 444 [M+2], 442 [M+]. Anal. Calcd for C25H19N4ClO2: C, 67.80; H, 4.32; N, 12.65. Found: C, 67.92; H, 4.40; N, 12.80.

[4-{(6-Methoxy-2-(p-tolyloxy)quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (11)

This compound was obtained from 3a and 7j; buff solid; yield 89%; mp 188–190°C; IR: ν 1710 (C=O), 1627 (C=N) cm−1; 1H NMR: δ 8.32 (s, 1H, ArH), 8.26 (s, 1H, C5H), 7.81–8.23 (m, 12H, ArH), 5.12 (s, 2H, CH2), 3.83 (s, 3H, OCH3 ), 2.47 (s, 3H, CH3); 13C NMR: δ 159.0, 152.0, 149.0, 144.0, 141.5, 139.1, 138.6, 138.3, 135.9, 134.4, 132.0, 131.0, 129.6, 128.7, 126.7, 124.5, 123.6, 122.0, 121.5, 119.4, 41.2, 20.4; MS: m/z 438 [M+]. Anal. Calcd for C26H22N4O3: C, 71.22; H, 5.06; N, 12.78. Found: C, 71.40; H, 5.20; N, 12.82.

[4-{(2-(2-Methoxyphenoxy)quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (12)

This compound was obtained from 3a and 7k; yellow solid; yield 97%; mp 178–180°C; IR: ν 1706 (C=O), 1623 (C=N) cm−1; 1H NMR: δ 8.36 (s, 1H, ArH), 8.33 (s, 1H, C5H), 7.21–7.99 (m, 13H, ArH), 5.14 (s, 2H, CH2), 2.40 (s, 3H, OCH3); 13C NMR: δ 159.2, 153.0, 150.9, 147.0, 143.5, 140.1, 139.6, 139.3, 137.9, 136.4, 135.0, 132.0, 130.0, 129.7, 127.6, 125.9, 125.6, 125.0, 123.5, 120.9, 119.4, 42.5, 20.7; MS: m/z 424 [M+]. Anal. Calcd for C25H20N4O3: C, 70.74; H, 4.75; N, 13.20. Found: C, 70.80; H, 5.01; N, 13.54.

[4-{(2-(2-Methoxyphenoxy)-6-methylquinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (13)

This compound was obtained from 3a and 7l; buff solid; yield 65%; mp 132–134°C; IR: ν 1715 (C=O), 1620 (C=N) cm−1; 1H NMR: δ 8.33 (s, 1H, ArH), 8.31 (s, 1H, C5H), 7.19–7.75 (m, 12H, ArH), 5.12 (s, 2H, CH2), 2.39 (s, 3H, OCH3), 2.44 (s, 3H, CH3); 13C NMR: δ 158.0, 152.0, 149.0, 145.0, 144.0, 143.0, 138.3, 138.0, 136.6, 135.2, 134.0, 131.0, 129.3, 129.0, 128.4, 124.1, 124.0, 123.8, 123.0, 119.3, 119.0, 42.4, 20.0; MS: m/z 438 [M+]. Anal. Calcd for C26H22N4O3: C, 71.22; H, 5.06; N, 12.78. Found: C, 71.47; H, 5.12; N, 12.82.

[4-{(6-Chloro-2-(2-methoxyphenoxy)quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (14)

This compound was obtained from 3a and 7m; pale yellow solid; yield 71%; mp 192–194°C; IR: 1708 (C=O), 1624 (C=N) cm−1; 1H NMR: δ 8.56 (s, 1H, ArH), 8.48 (s, 1H, C5H), 7.21–8.32 (m, 12H, ArH), 5.28 (s, 2H, CH2), 2.39 (s, 3H, OCH3); 13C NMR: δ 160.0, 156.0, 152.0, 147.0, 146.0, 145.0, 139.6, 139.0, 137.0, 136.1, 135.0, 133.0, 131.0, 130.0, 129.0, 125.4, 125.0, 124.2, 124.0, 120.5, 120.0, 42.5; MS: m/z 460 [M+2], 458 [M+]. Anal. Calcd for C25H19N4ClO3: C, 65.43; H, 4.17; N, 12.21. Found: C, 65.63; H, 4.23; N, 12.48.

[4-{(6-Methoxy-2-(2-methoxyphenoxy)quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (15)

This compound was obtained from 3a and 7n; buff solid; yield 65%; mp 132–134°C; IR: ν 1701 (C=O), 1620 (C=N) cm−1; 1H NMR: δ 8.35 (s, 1H, ArH), 8.33 (s, 1H, C5H), 7.21–7.87 (m, 12H, ArH), 5.18 (s, 2H, CH2), 2.39 (s, 3H, OCH3), 2.44 (s, 3H, OCH3); 13C NMR: δ 159.0, 154.0, 150.0, 146.0, 145.0, 144.0, 139.0, 138.5, 137.3, 136.2, 135.0, 132.0, 130.0, 129.9, 129.7, 125.4, 125, 124.6, 124.0, 121.0, 120.8, 42.5, 41.7; MS: m/z 454 [M+]. Anal. Calcd for C26H22N4O4: C, 68.71; H, 4.88; N, 12.33. Found: C, 68.82; H, 4.91; N, 12.76.

[4-{(2-(4-Chlorophenoxy)quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (16)

This compound was obtained from 3a and 7o; brown crystalline solid; yield 72%; mp 120–122°C; IR: ν 1713 (C=O), 1622 (C=N) cm−1; 1H NMR: δ 8.39 (s, 1H, ArH), 8.37 (s, 1H, C5H), 7.30–8.23 (m, 10H, ArH), 5.16 (s, 2H, CH2), 2.43 (s, 3H, CH3); 13C NMR: δ 166.0, 167.0, 162.0, 157.0, 145.5, 138.3, 135.9, 135.7, 133.0, 132.7, 129.8, 127.7, 126.2, 125.3, 124.1, 123.9, 122.0, 121.0, 43.5, 21.0; MS: m/z 430 [M+2], 428 [M+]. Anal. Calcd for C24H17N4ClO2: C, 67.21; H, 4; N, 13.06. Found: C, 67.52; H, 4.3; N, 13.4.

[4-{(2-(4-Chlorophenoxy)-6-methylquinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (17)

This compound was obtained from 3a and 7p; yellow solid; yield 78%; mp 168–170°C; IR: ν 1706 (C=O), 1628 (C=N) cm−1; 1H NMR: δ 8.34 (s, 1H, ArH), 8.22–8.25 (s, 1H, C5H ), 7.21–7.91 (m, 12H, ArH), 5.12 (s, 2H, CH2), 2.43 (s, 3H, CH3); 13C NMR: δ 158.2, 151.1, 150.7, 145.7, 143.2, 138.3, 137.7, 134.6, 132.1, 131.1, 129.3, 129.0, 126.7, 126.4, 125.1, 123.7, 123.6, 119.8, 117.8, 41.4, 20.8; MS: m/z 444 [M+2], 442 [M+]. Anal. Calcd for C25H19N4ClO2: C, 67.80; H, 4.32; N, 12.65. Found: C, 67.92; H, 4.40; N, 12.80.

[4-{(6-Chloro-2-(4-chlorophenoxy)quinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (18)

This compound was obtained from 3a and 7q; pale brown solid; yield 90%; mp 134–136°C; IR: ν 1712 (C=O), 1630 (C=N) cm−1; 1H NMR δ 8.37 (s, 1H, ArH), 8.32 (s, 1H, C5H), 7.12–8.15 (m, 12, ArH), 5.16 (s, 2H, CH2); 13C NMR: δ 159.9, 151.6, 144.0, 143.3, 138.8, 135.0, 134.7, 130.8, 129.9, 129.1, 128.7, 127.1, 126.7, 125.6, 124.4, 122.1, 121.8, 121.5, 118.4, 41.9; MS: m/z 466 [M+4], 464 [M+2], 463 [M+1], 462 [M+]. Anal. Calcd for C24H16N4Cl2O2: C, 62.22; H, 3.48; N, 12.09. Found to be C, 62.50; H, 3.52; N, 12.12.

[4-{(2-(4-Chlorophenoxy)-6-methoxyquinolin-3-yl)methyl}]-2-phenyl-2H-1,2,4-triazol-3(4H)-one (19)

This compound was obtained from 3a and 7r; pale yellow solid; yield 79%; mp 175–177°C; IR: ν 1707 (C=O), 1625 (C=N) cm−1; 1H NMR: δ 8.34 (s, 1H, ArH), 8.31 (s, 1H, C5H), 7.85–8.08 (m, 12H, ArH ), 4.93 (s, 2H, CH2), 3.83 (s, 3H, OCH3 ); 13C NMR: δ 159.2, 155.7, 153.9, 147.9 145.7, 144.0, 142.0, 140.0, 137.1, 135.7, 132.0, 129.5, 128.6, 127.8, 123.6, 119.2, 118.0, 116.0, 115.0, 114.0, 113.0, 55.9, 43.9; MS: m/z 460 [M+2], 458 [M+]. Anal. Calcd for C25H19N4ClO3: C, 65.43; H, 4.17; N, 12.21. Found: C, 65.52; H, 4.22; N, 12.5.

[2-{(4-Methoxyphenyl)-4-((2-(p-tolyloxy)quinolin-3-yl)methyl}]-2H-1,2,4-triazol-3(4H)-one (20)

This compound was obtained from one 3b and 7g; light brown solid; yield 87%; mp 126–128°C; IR: ν 1719 (C=O), 1623 (C=N) cm−1; 1H NMR: δ 8.54 (s, 1H, ArH), 8.29 (s, 1H, C5H), 7.20–8.12 (m, 12H, ArH), 5.06 (s, 2H, CH2), 3.81 (s, 3H, OCH3), 2.43 (s, 3H, CH3); 13C NMR: δ 156.1, 142.0, 139.0, 136.0, 134.0, 131.0, 130.0, 129.0, 128.1, 128.0, 127.0, 124.7, 123.0, 122.0, 121.0, 119.0, 118.7, 118.0, 116.0, 41.0, 55.9, 20.7; MS: m/z 438 [M+]. Anal. Calcd for C26H22N4O3: C, 71.22; H, 5.06; N, 12.78. Found: C, 71.43; H, 5.20; N, 12.91.

2-{(4-Methoxyphenyl)-4-[(6-methyl-2-(p-tolyloxy)quinolin-3-yl)methyl}]-2H-1,2,4-triazol-3(4H)-one (21)

This compound was obtained from 3b and 7h; beige solid; yield 90%; mp 144–146°C; IR: ν 1711 (C=O), 1620 (C=N) cm−1; 1H NMR: δ 8.63 (s, 1H, ArH), 8.31 (s, 1H, C5H ), 7.21–8.19 (m, 11H, ArH), 5.09 (s, 2H, CH2) 3.82 (s, 3H, OCH3), 2.44 (s, 3H, CH3); 13C NMR: δ 156.0, 141.0, 138.0, 135.0, 133.0, 130.0, 129.1, 129.5, 128.2, 128.1, 126.0, 123.7, 123.0, 121.9, 120.6, 118.1, 118.9, 117.3, 117.0, 41.1, 55.0, 20.9, 20.6; MS: m/z 452 [M+]. Anal. Calcd for C27H24N4O3: C, 71.67; H, 5.35; N, 12.38. Found: C, 71.92; H, 5.43; N, 12.45.

[4-(6-Chloro-2-(p-tolyloxy)quinolin-3-yl)methyl]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (22)

This compound was obtained from 3b and 7i; pale yellow solid; yield 78%; mp 128–130°C; IR: ν 1717 (C=O), 1621 (C=N) cm−1; 1H NMR: δ 8.50 (s, 1H, ArH), 8.47 (s, 1H, C5H), 6.9–8.11 (m, 11H, ArH), 5.15 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 2.36 (s, 3H, CH3); 13C NMR: δ 162.3, 159.9, 157.2, 151.1, 144.3, 138.3, 137.9, 135.0, 134.7, 131.5, 130.8, 129.8, 127.0, 126.7, 123.5, 122.1, 121.9, 120.4, 114.6, 55.8, 41.8, 20.9; MS: m/z 475 [M+2], 473 [M+1], 472 [M+]. Anal. Calcd for C26H21N4ClO3: C, 66.03; H, 4.48; N, 11.85. Found: C, 66.72; H, 4.6; N, 12.2.

[4-(6-Methoxy-2-(p-tolyloxy)quinolin-3-yl)methyl]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (23)

This compound was obtained from 3b and 7j; buff crystalline solid; yield 77%; mp 162–164°C; IR: ν 1700 (C=O), 1623 (C=N) cm−1; 1H NMR: δ 8.87 (s, 1H, ArH), 8.30 (s, 1H, C5H), 7.21–8.17 (m, 11H, ArH), 5.23 (s, 2H, CH2), 3.71 (s, 3H, OCH3), 3.68 (s, 3H, OCH3 ), 2.52 (s, 3H, CH3); 13C NMR: δ 157.0, 143.0, 141.0, 137.0, 136.0, 135.5, 134.2, 133.0, 131.3, 130.0, 129.2, 128.7, 127.4, 124.8, 123.4, 121.1, 119.6, 118.0, 117.5, 55.8, 55.7, 41.0, 20.1; MS: m/z 468 [M+]. Anal. Calcd for C27H24N4O4: C, 69.22; H, 5.16; N, 11.96. Found: C, 69.40; H, 5.27; N, 12.32.

[4-(2-(2-Methoxyphenoxy)quinolin-3-yl)methyl]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (24)

This compound was obtained from 3b and 7k; light brown solid; yield 80%; mp 154–156°C; IR: ν 1721 (C=O), 1627 (C=N) cm−1; 1H NMR: δ 8.31 (s, 1H, ArH), 8.24 (s, 1H, C5H), 7.83–8.05 (m, 12H, ArH), 5.10 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 3.80 (s, 3H, OCH3); 13C NMR: δ 162.2, 159.0, 156.6, 151.2, 150.9, 145.2 141.6, 138.9, 137.9, 131.1, 130.0, 127.8, 127.4, 126.5, 125.3, 124.9, 123.3, 120.7, 119.7, 114.1, 113.1, 55.6, 55.2, 41.5; MS: m/z 455 [M+1], 454 [M+]. Anal. Calcd for C26H22N4O4: C, 68.71; H, 4.88; N, 12.33. Found C, 68.82; H, 5.02 N, 12.62.

[4-(2-(2-Methoxyphenoxy)-6-methylquinolin-3-yl)methyl]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (25)

This compound was obtained from 3b and 7l; yellow solid; yield 77%; mp 187–189°C; IR: ν 1719 (C=O), 1628 (C=N) cm−1; 1H NMR: δ 8.27 (s, 1H, ArH), 8.22 (s, 1H, C5H), 7.80–8.00 (m, 11H, ArH), 5.04 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 2.47 (s, 3H, CH3); 13C NMR: δ 158.0, 153.1, 150.0, 143.9 142.7, 142.0, 139.0, 137.0, 132.8, 131.1, 129.8, 127.1, 126.4, 125.0, 124.0, 118.5, 116.1, 114.4, 113.3, 112.8, 111.0, 55.8, 55.7, 43.7, 20.6; MS: m/z 468 [M+]. Anal. Calcd for C27H24N4O4: C, 69.22; H, 5.16; N, 11.96. Found: C, 68.82; H, 5.20; N, 12.62.

[4-(6-Chloro-2-(2-methoxyphenoxy)quinolin-3-yl)methyl]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (26)

This compound was obtained from 3b and 7m; brown solid; yield 82%; mp 110–112°C; IR: ν 1724 (C=O), 1629 (C=N) cm−1; 1H NMR: δ 8.39 (s, 1H, ArH), 8.28 (s, 1H, C5H), 7.92–8.18 (m, 11H, ArH), 5.16 (s, 2H, CH2), 3.88 (s, 3H, OCH3), 3.86 (s, 3H, OCH3); 13C NMR: δ 162, 155.0, 153.0, 147.0, 145.1, 144.0, 143.0, 139.2, 136.1, 134.1, 132.5, 129.2, 128.1, 127.0, 122.0, 119.6, 118.0, 117.6, 115.4, 114.8, 113.0, 55.9, 55.8, 43.9; MS: m/z 490 [M+2], 488 [M+]. Anal. Calcd for C26H21N4ClO4: C, 63.87; H, 4.33; N, 11.46. Found: C, 63.92; H, 4.45; N, 11.67.

4-(6-Methoxy-2-(2-methoxyphenoxy)quinolin-3-yl)methyl]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (27)

This compound was obtained from 3b and 7n; pale yellow solid; yield 74%; mp 145–147°C; IR: ν 1722 (C=O),1628 (C=N) cm−1; 1H NMR: δ 8.30 (s, 1H, ArH), 8.22 (s, 1H, C5H), 7.82–8.21 (m, 12H, ArH), 5.06 (s, 2H, CH2), 3.82 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 2.49 (s, 3H, CH3); 13C NMR: δ 159.0, 154.2, 152.3, 144.4, 143.0, 143.0, 140.0, 138.0, 133.0, 132.0, 130.0, 128.0, 127.5, 126.0, 125.0, 119.1, 117.6, 115.0, 114.8, 113.3, 112.0, 55.6, 55.5, 43.8, 20.7; MS: m/z 484 [M+]. Anal. Calcd for C27H24N4O5: C, 66.93; H, 4.99; N, 11.56. Found: C, 67.02; H, 5.07; N, 11.69.

[4-{(2-(4-Chlorophenoxy)quinolin-3-yl)methyl}]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (28)

This compound was obtained from 3b and 7o; brown solid; yield 93%; mp 186–188°C; IR: ν 1716 (C=O), 1621 (C=N) cm−1; 1H NMR: δ 8.78 (s, 1H, ArH), 8.30 (s, 1H, C5H), 7.12–8.02 (m, 12H, ArH), 5.08 (s, 2H, CH2), 3.83 (s, 3H, OCH3); 13C NMR: δ 157.0, 143.0, 141.0, 137.0, 135.0, 132.1, 131.0, 130.0, 129.1, 129.0, 128.3, 125.7, 125.2, 124.0, 123.2, 122.0, 118.0, 117.1, 117.0, 55.9, 41.0; MS: m/z 460 [M+2], 458 [M+]. Anal. Calcd for C25H19N4ClO3: C, 65.43; H, 4.17; N, 12.21. Found: C, 65.51; H, 4.41; N, 12.32.

[4-{(2-(4-Chlorophenoxy)-6-methylquinolin-3-yl)methyl}]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (29)

This compound was obtained from 3b and 7p; pale brown solid; yield 71%; mp 128–130°C; IR: ν 1727 (C=O), 1621 (C=N) cm−1; 1H NMR: δ 8.29 (s, 1H, ArH), 8.20 (s, 1H, C5H), 6.99–7.85 (m, 11H, ArH), 5.11 (s, 2H, CH2), 3.76 (s, 3H, OCH3), 2.44 (s, 3H, CH3); 13C NMR: δ 158.2, 156.6, 151.8, 150.9, 143.2, 138.3, 137.7, 134.6, 132.1, 130.9, 129.3, 128.8, 126.6, 125.4, 123.6, 123.4, 122.9, 119.89, 114.3, 55.2, 41.3, 20.7. MS: m/z 475 [M+2], 473 [M+1], 472 [M+]. Anal. Calcd for C26H21N4ClO3: C, 66.03; H, 4.48; N, 11.85. Found: C, 66.72; H, 4.60; N, 12.20.

[4-{(6-Chloro-2-(4-chlorophenoxy)quinolin-3-yl)methyl}]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (30)

This compound was obtained from 3b and 7q; yellow solid; yield 85%; mp 141–143°C; IR: ν 1711 (C=O), 1629 (C=N) cm−1; 1H NMR: δ 9.17 (s, 1H, ArH), 8.41 (s, 1H, C5H), 7.30–8.31 (m, 11H, ArH), 5.27 (s, 2H, CH2), 3.82 (s, 3H, OCH3 ); 13C NMR: δ 160.0, 152.0, 149.0, 147.9, 143.0, 145.0, 138.0, 136.0, 135.1, 133.0, 128.0, 127.0, 125.2, 124.9, 122.0, 120.0, 118.0, 117.9, 56.0, 42.3; MS: m/z 496 [M+4], 494 [M+2], 492 [M+]. Anal. Calcd for C25H18N4Cl2O3: C, 60.86; H, 3.68; N, 11.36. Found: C, 60.92; H, 3.72; N, 11.47.

[4-{(2-(4-Chlorophenoxy)-6-methoxyquinolin-3-yl)methyl}]-2-(4-methoxyphenyl)-2H-1,2,4-triazol-3(4H)-one (31)

This compound was obtained from 3b and 7r; brown solid; yield 80%; mp 187–189°C; IR: ν 1718 (C=O), 1630 (C=N) cm−1; 1H NMR: δ 8.82 (s, 1H, ArH), 8.30 (s, 1H, C5H), 7.31–8.09 (m, 11H, ArH), 5.10 (s, 2H, CH2), 3.68 (s, 3H, OCH3), 3.67 (s, 3H, OCH3); 13C NMR: δ 157.5, 145.0, 144.0, 139.0, 138.0, 137.0, 136.0, 135.0, 133.4, 132.0, 130.0, 129.0, 128.1, 127.8, 125.0, 123.0, 120.0, 119.0, 55.7, 55.6, 41.3; MS: m/z 490 [M+2], 488 [M+]. Anal. Calcd for C26H21N4ClO4: C, 63.87; H, 4.33; N, 11.46 Found: C, 63.92; H, 4.45; N, 11.72.

Molecular docking studies

The crystal structures of NMT (A. fumigatus) in complex with myristoyl CoA and pyrazole sulphonamide ligand (PDB ID: 4CAW; A-Chain) and DHFR (PDB ID: 1AI9) (C. albicans) were used for the docking studies. These data were obtained from the Protein Data Bank. The proteins were prepared for docking by adding polar hydrogen atom with Gasteiger-Hückel charges and water molecules were removed. The 3D structure of the ligands was generated by the SKETCH module implemented in the SYBYL program (Tripos Inc., St. Louis, MO, USA) and its energy-minimized conformation was obtained with the help of the Tripos force field using Gasteiger-Hückel charges [28]. Molecular docking was performed with Surflex-Dock program that interfaced with Sybyl-X 2.0 [29] and other miscellaneous parameters were assigned to the default values given by the software.

In vitro antifungal activity assay

Dilutions of each sample are done with BHI (brain heart infusion) for MIC. In the initial tube, drug (20 μL) was added into the BHI (380 μL) broth. For dilutions, BHI broth (200 μL) was added into the next nine tubes separately. Then from the initial tube 200 μL was transferred to the first tube containing BHI broth (200 μL). This was a 10−1 dilution. From 10−1 diluted tube, 200 μL was transferred to the second tube to make 10−2 dilution. The serial dilution was repeated up to 10−9 dilution for each drug. From the maintained stock cultures of required organisms, a 5 μL-culture was taken and added into BHI (02 mL) broth. To each serially diluted tube, above culture suspension (200 μL) was added. The tubes were incubated for 24 h and observed for turbidity [30].

Acknowledgements

The authors wish to thank the University Grants Commission (UGC), New Delhi [Grant 14-3/2012 (NS/PE), 14-03-2012] for providing financial support. SMS acknowledges the UGC for providing fellowship under focused area of UPE programme.

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Supplemental Material:

The online version of this article (DOI: https://doi.org/10.1515/hc-2016-0073) offers supplementary material.

Received: 2016-6-4
Accepted: 2017-3-20
Published Online: 2017-7-19
Published in Print: 2017-8-28

©2017 Walter de Gruyter GmbH, Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2016-0073
Keywords for this article
antifungal; dihydrofolate reductase; N-myristoyl transferase; quinoline
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Chemical and pharmacological research on the plants from genus Ajuga
  4. Research Articles
  5. One-pot synthesis of annulated 1,8-naphthyridines
  6. Visible-light mediated regioselective (phenylsulfonyl)difluoromethylation of fused imidazoles with iododifluoromethyl phenyl sulfone
  7. Synthesis of thienopyrimidine-pyrazolo[3,4-b]pyridine hybrids
  8. Regioselective 1,4-conjugate aza-Michael addition of dienones with benzotriazole
  9. A simple one-pot synthesis of 2,4-diaryl- 9H-pyrido[2,3-b]indoles under solvent-free conditions
  10. Cyclodimerization of 3-phenacylideneoxindolines with amino esters for the synthesis of dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines]
  11. An efficient approach to the synthesis of coumarin-fused dihydropyridinones
  12. Halogenoheterocyclization of terminally substituted 2-allylthio(seleno)quinolin- 3-carbaldehydes
  13. A new synthetic route to benzophenone derivatives
  14. Design, synthesis, docking and in vitro antifungal study of 1,2,4-triazole hybrids of 2-(aryloxy)quinolines
  15. Synthesis, antimicrobial activity and anti-biofilm activity of novel tetrazole derivatives
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