Home Physical Sciences 2,5-Disubstituted 1,3,4-oxadiazole derivatives of chromeno[4,3-b]pyridine: synthesis and study of antimicrobial potency
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2,5-Disubstituted 1,3,4-oxadiazole derivatives of chromeno[4,3-b]pyridine: synthesis and study of antimicrobial potency

  • Ghanshyam R. Jadhav , Dattatray G. Deshmukh , Vijay J. Medhane EMAIL logo , Vishwas B. Gaikwad and Avinash D. Bholay
Published/Copyright: May 13, 2016
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 22 Issue 3

Abstract

A convenient synthesis of 1,3,4-oxadiazole containing derivatives of chromeno[4,3-b]pyridine (6a–e, 8a–e and 9a–e) starting from 4-hydroxycoumarin is presented. The synthesized compounds were screened for in vitro antimicrobial activity against representative bacterial and fungal species. The MIC (minimum inhibitory concentration) of the synthesized compounds ranges between 5 and 15 μg/mL, which is comparable with MIC of standard drugs. Compounds 6c, 8c–e, 9c and 9e have the highest potency for certain bacteria and fungi.

Keywords: antimicrobial activity; coumarin; multistep synthesis; 1,3,4-oxadiazole; pyridine

Introduction

The era of antibiotics began in the 1940s with the widespread introduction of penicillin and streptomycin which provided effective treatment for the most prevalent disease of the time [1–3]. Today, additional antimicrobial drugs [4–6] such as cephalosporins, oxazolidinones, fluconazole and ketoconazole are available. However, many of these agents have diverse limitations. For example, the antibacterial drug vancomycin is resistant to the bacteria Enterococcus faecium, which causes serious problems [7]. This scenario highlights the need of intense efforts to develop new class of compounds with promising antimicrobial activity.

Many naturally occurring coumarin derivatives such as novobiocin, chloromycin and coumermycin A1 are potent antibiotics [8, 9]. Coumarins are structurally similar to quinolone drugs which can inhibit ATPase activity of bacterial DNA gyrase by competing with ATP thereby exhibiting antibacterial activity [10]. Coumarin derivatives are known to also exhibit anticoagulant [11], anti-HIV [12], anti-inflammatory [13], antioxidant [14], anticancer [15, 16] and antifungal activities [17, 18].

Oxadiazoles are bioisoesters of amides and esters that can engage in hydrogen bonding interactions with receptors [19]. The oxadiazoles exhibit antimicrobial, antitubercular [20, 21], anti-inflammatory [22, 23], anticancer [24] and antidepressant activities [25]. Some examples of oxadiazole containing drugs are zibotentan, used in cancer therapy [26], and raltegravir, an antiretroviral agent used in treatment of HIV infections [27].

Pyridine is a versatile bioactive heterocycle featured in enzymes [28] and in numerous alkaloids [29]. Pyridine derivatives are antimicrobial agents [30], potassium channel activators [31] and analgesic drugs [32].

Examples of biologically active compounds containing an oxadiazole, coumarin or pyridine entity are shown in Figure 1. In the present study we designed and synthesized some oxadiazole containing derivatives of chromeno[4,3-b]pyridine and studied the effect on biological activity of various substituents at the phenyloxadiazole moiety. The aim was to find an antimicrobial agent with enhanced activity.

Figure 1 Biological activities of some 1,3,4-oxadiazole, coumarin and pyridine incorporated compounds.
Figure 1

Biological activities of some 1,3,4-oxadiazole, coumarin and pyridine incorporated compounds.

Results and discussion

Chemistry

4-Amino-2-oxo-2H-chromene (2) was obtained from 4-hydroxy-2H-chromen-2-one (1) using a standard literature procedure [35, 36]. Vilsmeyer-Haack formylation of compound 2 furnished 4-amino-2-oxo-2H-chromene-3-carbaldehyde (3). Friedlander condensation of compound 3 with ethyl acetoacetate yielded chromeno[4,3-b]pyridine-3-carboxylate (4) in good yield (76%). The key intermediate carbohydrazide 5 was obtained in 72% yield by nucleophilic displacement of the ethoxy group in compound 4 by reaction with hydrazine hydrate (Scheme 1).

Scheme 1 Reagents and conditions: (i) ammonium acetate, 130°C, 3 h; (ii) DMF-POCl3, 0–25°C, 10 h; (iii) ethyl acetoacetate, EtOH, piperidine, reflux for 4 h; (iv) hydrazine hydrate, MeOH, reflux for 13 h.
Scheme 1

Reagents and conditions: (i) ammonium acetate, 130°C, 3 h; (ii) DMF-POCl3, 0–25°C, 10 h; (iii) ethyl acetoacetate, EtOH, piperidine, reflux for 4 h; (iv) hydrazine hydrate, MeOH, reflux for 13 h.

Carbohydrazide 5 was cyclized with various carboxylic acids in phosphorus oxychloride under reflux condition to furnish 1,3,4-oxadiazole derivatives 6a–e in 69–80% yield. The precursor 5 was also utilized for the synthesis of oxadiazole derivatives 8a–e and 9a–e. Thus, treatment of 5 with aldehydes yielded Schiff bases 7a–e, the cyclization of which with acetic anhydride or trifluoroacetic anhydride under reflux furnished 1,3,4-oxadiazole derivatives 8a–e and 9a–e, respectively, in 64–79% yield (Scheme 2). Structures of all these compounds were confirmed by IR, 1H NMR, 13C NMR and MS analysis.

Scheme 2 Reagents and conditions: (i) Ar-CO2H/POCl3, reflux for 2–4 h; (ii) Ar-CHO/EtOH catalytic AcOH, 25°C, 4–5 h; (iii) Ac2O, reflux for 4–4.5 h; (iv) trifluoroacetic anhydride, reflux for 2–2.5 h.
Scheme 2

Reagents and conditions: (i) Ar-CO2H/POCl3, reflux for 2–4 h; (ii) Ar-CHO/EtOH catalytic AcOH, 25°C, 4–5 h; (iii) Ac2O, reflux for 4–4.5 h; (iv) trifluoroacetic anhydride, reflux for 2–2.5 h.

Antimicrobial activity

The antimicrobial activity was assessed by agar-well diffusion method using Mueller Hinton agar medium [37]. Zone of inhibition and MIC’s were measured for compounds 6a–e, 8a–e and 9a–e against bacterial strains Staphylococcus areus (Gram-positive), Escherichia coli (Gram-negative) and fungal strains Candida albicans and Aspergillus niger with reference to standard drugs (streptomycin and griseofulvin). The results are presented in Table 1. Compounds 6c, 8c, and 9e possess good antibacterial activity at 5 μg/mL against the tested strains of Gram-positive S. areus as close lead when compared with standard drug streptomycin at 3 μg/mL, whereas other derivatives are moderately active. Compounds 9c and 9e display good potency (5 μg/mL) with respect to streptomycin (3 μg/mL) whereas compounds 6a and 6e show moderate activity against Gram-negative bacteria E. coli. For fungal strains, compounds 8d and 9e show good inhibitory activity (5 μg/mL) against C. albicans, whereas compounds 8e and 6e shows moderate inhibition with respect to standard drug griseofulvin (3 μg/mL). Compounds 8e and 9e are moderately active (10 μg/mL) against the tested strain of A. niger, whereas other compounds are less active with respect to griseofulvin (3 μg/mL). In summary, the structure-activity relationship (SAR) analysis of antimicrobial screening shows that compound with R1 as p-chloro and p-fluoro substituents display good antimicrobial activity for S. aureus. Against E. coli, compounds containing R1 as p-chloro and p-fluoro along with N-substituted COCF3 group on the oxadiazole ring display good activity. For the same organism, moderate activity is displayed when the R group is hydrogen or p-chloro. For C. albicans, compounds containing R1 as p-NO2, N-substituted COCH3 or p-fluoro group display good antimicrobial activity. Compounds containing R1 as p-fluoro substituent display good to moderate antimicrobial activity against A. niger.

Table 1

In vitro antimicrobial activity of compounds 6a–e, 8a–e and 9a–e as zone of inhibition (mm); the MIC values (μg/mL) are given in parentheses.a,b

EntryR/R1Staphylococcus aureus ATCC 25923Escherichia coli ATCC 25922Candida albicans MTCC 277Aspergillus niger MCIM 545
6aH12.5 (05)12.9 (05)11.8 (15)14.1 (15)
6b2-OCH312.9 (05)12.7 (10)12.3 (15)13.8 (15)
6c3-Cl15.1 (05)13.8 (10)11.2 (10)10.8 (10)
6d4-NO213.3 (05)11.5 (10)14.6 (10)13.2 (10)
6e4-F14.5 (05)11.9 (05)12.7 (05)14.3 (10)
8aH14.2 (05)12.3 (10)15.1 (10)12.8 (15)
8b3,4-di-OCH316.4 (10)12.4 (10)10.9 (10)13.7 (10)
8c4-Cl15.9 (05)12.2 (10)11.5 (10)14.7 (10)
8d4-NO214.4 (05)14.9 (15)14.4 (05)13.7 (10)
8e4-F14.8 (05)15.8 (15)13.9 (05)15.5 (10)
9aH12.7 (05)13.6 (15)15.3 (15)13.4 (10)
9b3,4-di-OCH313.3 (05)14.2 (10)13.2 (10)17.4 (15)
9c4-Cl14.5 (05)14.6 (05)13.5 (10)15.1 (10)
9d4-NO212.5 (05)15.1 (15)13.7 (10)13.8 (10)
9e4-F16.2 (05)15.8 (05)14.3 (05)15.3 (10)
Strept–17.9 (03)17.6 (03)ntnt
Gris–ntnt16.8 (03)16.4 (03)

aThe abbreviations used are Strept for streptomycin (100 μg/disc), Gris for griseofulvin (100 μg/disc) and nt for not tested. bTest compounds were applied as 100 μg/disc.

Conclusions

The 1,3,4-oxadiazole containing derivatives of chromeno [4,3-b]pyridine 6a–e, 8a–e and 9a–e were synthesized with good yields. Most of the synthesized compounds exhibit good antimicrobial activity. Structure-activity relationship (SAR) analysis suggests that compounds with R/R1 as p-chloro or p-fluoro groups enhance the activity against Gram positive, Gram negative bacteria and one fungi Aspergillus niger. Against Candida albicans, compounds containing a p-nitro group display good potency. The present study may be useful in generating new lead compounds as antimicrobial agents.

Experimental

All reactions were monitored by thin layer chromatography (TLC) on 25 mm silica gel 60 F254 plates (Merck, Darmstardt, Germany) using UV light (254 and 366 nm) for detection. Melting points are uncorrected. The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were measured on a Varian NMR Mercury 300 spectrometer. IR spectra were recorded in potassium bromide pellets using a Schimadzu IR 8400 S spectrophotometer. Mass spectra were recorded on an Agilent 1100 LC-Q-TOF mass spectrometer with an ionization potential of 70 eV.

Synthesis of 4-amino 2-oxo-2H-chromene (2)

4-Amino-2-oxo-2H-chromene (2) was synthesized using 4-hydroxy 2-oxo-2H-chromene (1) and ammonium acetate at 130°C according to literature methods [35, 36].

Synthesis of 4-amino-2-oxo-2H-chromene-3-carbaldehyde (3)

To a solution of compound 2 (0.161 g, 1 mmol) in DMF (2 mL), the Vilsmeyer adduct prepared from DMF (1.2 mmol) and POCl3 (50 mmol) was added at 0°C. The mixture was stirred at 0–25°C for 8 h (TLC, chloroform: ethanol, 9:1) and then poured over crushed ice. The yellowish solid was collected, washed, dried and crystallized from ethanol/water (8:2): yield 84%; mp 183–185°C; IR: υmax 3342, 3259, 2748, 1745, 1708, 1540 cm-1; 1H NMR (DMSO-d6): δ 7.09–7.38 (m, 2H, Ar–H), 7.58–7.71 (m, 1H, Ar–H), 8.25 (dd, J = 8.1, 1.3Hz, 1H), 9.30 (bs, 1H, –NH), 9.94 (s, 1H, CHO), 10.27 (bs, 1H, -NH); 13C NMR (DMSO-d6): δ 94.9, 113.3, 117.3, 124.1, 124.6, 134.8, 153.8, 157.9, 161.9, 191.5; MS: m/z 190 (M+H). Anal. Calcd for C10H7NO3: C, 63.49; H, 3.73; N, 7.40; O, 25.37. Found: 63.32; H, 3.65; N, 7.23; O, 25.29.

Synthesis of ethyl 2-methyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (4)

To a suspension of 4-amino-2-oxo-2H-chromene-3-carbaldehyde (3) (0.189 g, 1 mmol) in absolute ethanol (15 mL), was added ethyl acetoacetate (1.2 mmol) and piperidine (2–3 drops), and the mixture was heated under reflux for 4 h (TLC, ethyl acetate/n-hexane, 1:1). The solvent was removed in vacuo and the residue was poured on cold water. The solid was collected, washed, dried and crystallized from ethanol/water (9:1): a white solid; yield 76%; mp 159–161°C; IR: υmax 1743, 1726, 1555, 1470 cm-1; 1H NMR (CDCl3): δ 1.45 (t, 3H, J = 7.2 Hz, –CH3), 3.04 (s, 3H, Ar–CH3), 4.44 (q, J = 7.2 Hz, 2H, –OCH2), 7.41(m, 2H, Ar–H), 7.63 (m, 1H, Ar–H), 8.65 (dd, J =1.2, 6.6 Hz, 1H, Ar–H), 9.09 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 13.8, 25.4, 61.3, 114.2, 116.7, 118.1, 124.4, 124.8, 125.1, 132.50, 140.2, 152.1, 152.7, 159.9, 164.4, 166.4; MS: m/z 284 (M+H). Anal. Calcd for C16H13NO4: C, 67.84; H, 4.63; N, 4.94; O, 22.59. Found: C, 67.69; H, 4.54; N, 4.81; O, 22.46.

Synthesis of 2-methyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carbohydrazide (5)

A mixture of ethyl 2-methyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carboxylate (4) (0.283 g, 1 mmol) and hydrazine hydrate (1.2 mmol) in methanol (15 mL), was heated under reflux for 6 h (TLC, ethyl acetate: hexane, 2:1), then concentrated in vacuo and poured over crushed ice. The separated solid was collected, washed, dried and crystallized from DMF: a white solid; yield 72%; mp 221–223°C; IR: υmax 3342, 3257, 3221, 1739, 1657, 1536 cm-1; 1H NMR (DMSO-d6): δ 3.05 (s, 3H, Ar–CH3), 4.36 (bs, 2H, –NH2), 7.42 (m, 2H, Ar–H), 7.63 (m, 1H, Ar–H), 8.60 (m, 1H, Ar–H), 8.92 (bs, 1H, –NH), 9.11 (s, 1H, Ar–H); 13C NMR (DMSO-d6): δ 25.7, 114.4, 116.3, 117.6, 123.9, 124.4, 127.1, 132.2, 140.5, 151.2, 152.1, 159.7, 163.1, 173.2; MS: m/z 270 (M+H). Anal. Calcd for C14H11N3O3: C, 62.45; H, 4.12; N, 15.61; O, 17.83. Found: C, 62.29; H, 4.03; N, 15.54; O, 17.72.

Synthesis of 2-methyl-3-(5-aryl-1,3,4-oxadiazol-2-yl)-5H-chromeno[4,3-b]pyridin-5-ones 6a–e

Compounds 6a–e were synthesized by refluxing carbohydrazide 5 (0.269 g, 1 mmol) and aryl acid (1.1 mmol) in phosphoryl oxychloride (15 mL) for 2–4 h. The mixture was poured over crushed ice and the precipitated product 6 was filtered, dried and purified by silica gel column chromatography eluting with n-hexane/ethyl acetate, 8:2.

2-Methyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5H-chromeno[4,3-b]pyridin-5-one (6a)

A white solid; yield 74%; mp 187–188°C; IR: υmax 1736, 1643, 1453 cm-1; 1H NMR (CDCl3): δ 3.25 (s, 3H, Ar–CH3) 7.40–7.60 (m, 6H, Ar–H), 8.20 (s, 2H, Ar–H), 8.70 (d, J = 7.2 Hz, 1H, Ar–H), 9.20 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 26.3, 115.7, 116.4, 117.6, 118.30, 119.1, 125.0, 125.8, 128.1, 128.6, 131.2, 132.7, 137.5, 151.4, 152.4, 153.1, 159.2, 161.4, 163.3, 164.2, 168.3; MS: m/z 356 (M+H). Anal. Calcd for C21H13N3O3: C, 70.98; H, 3.69; N, 11.83; O, 13.51. Found: C, 70.79; H, 3.58; N, 11.73; O, 13.39.

3-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (6b)

A white solid; yield: 69%; mp 220–221°C; IR: υmax 1738, 1646, 1457 cm-1; 1H NMR (CDCl3): δ 3.10 (s, 3H, Ar–CH3), 3.78 (s, 3H, –OCH3), 7.12 (m, 2H, Ar–H), 7.39–7.51 (m, 4H, Ar–H), 7.62 (m, 1H, Ar–H), 8.64 (d, J = 8.0 Hz, 1H, Ar–H), 8.95 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 26.85, 30.1, 115.1, 116.1, 117.4, 118.7, 119.9, 125.1, 125.3, 128.6, 128.7, 131.8, 133.1, 138.3, 151.9, 153.1, 153.2, 160.5, 162.7, 164.7, 165.1, 168.1; MS: m/z 386 (M+H). Anal. Calcd for C22H15N3O4: C, 68.57; H, 3.92; N, 10.90; O, 16.61. Found: C, 68.41; H, 3.83; N, 10.79; O, 16.48.

3-(5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (6c)

A white solid; yield 77%; mp 233–234°C; IR: υmax 1742, 1651, 1447 cm-1; 1H NMR (CDCl3): δ 3.27 (s, 3H, Ar–CH3), 7.45 (dd, J = 8.0, 4.0 Hz, 2H, Ar–H), 7.57 (dd, J = 8.0 Hz, 2H, Ar–H), 7.65 (d, J = 8.0 Hz, 1H, Ar–H), 8.10 (d, J = 8.0 Hz, 1H, Ar–H), 8.19 (s, 1H, Ar–H), 8.70 (d, J = 8.0 Hz, 1H, Ar–H), 9.19 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 26.1, 115.1, 115.8, 117.5, 118.3, 118.6, 125.0, 125.8, 128.3, 129.2, 131.2, 133.6, 138.1, 151.0, 152.7, 153.5, 159.8, 162.5, 163.1, 164.2, 166.8; MS: m/z 390 (M+H), 392 (M+3). Anal. Calcd for C21H12ClN3O3: C, 63.49; H, 3.73; N, 7.40; O, 25.37. Found: C, 63.36; H, 3.62; N, 7.28; O, 25.24.

2-Methyl-3-(5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)-5H-chromeno[4,3-b]pyridin-5-one (6d)

A yellowish solid; yield 80%; mp 181–182°C; IR: υmax 1744, 1641, 1456 cm-1; 1H NMR (CDCl3): δ 3.27 (s, 3H, Ar–CH3) 7.44 (m, 1H, Ar–H), 7.63 (d, J = 16.0 Hz, 4H, Ar–H), 8.21 (s, 2H, Ar–H), 8.69 (d, J = 8.0 Hz, 1H, Ar–H), 9.19 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 25.9, 114.4, 115.8, 117.5, 118.0, 120.4, 124.6, 125.5, 126.4, 128.3, 132.2, 132.5, 137.3, 151.9, 152.1, 153.2, 158.4, 161.4, 162.8, 164.6, 167.3; MS: m/z 401 (M+H). Anal. Calcd for C21H12N4O5: C, 63.00; H, 3.02; N, 13.99; O, 19.98. Found: C, 62.84; H, 2.91; N, 13.87; O, 19.89.

3-(5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (6e)

A white solid; yield 79%; mp 246–247°C; IR: υmax 1741, 1652, 1454 cm-1; 1H NMR (CDCl3): δ 3.24 (s, 3H, Ar–CH3), 7.09 (m, 3H, Ar–H), 7.40 (m, 2H, Ar–H), 7.64 (dd, J = 8.1, 7.5 Hz, 1H, Ar–H), 8.19 (m, 1H, Ar–H), 8.68 (d, J = 8.1 Hz, 1H, Ar–H), 9.18 (s, 1H, Ar–H); MS: m/z 374 (M+H). Anal. Calcd for C21H12FN3O3: C, 67.56; H, 3.24; F, 5.09; N, 11.26; O, 12.86. Found: C, 67.41; H, 3.11; F, 4.93; N, 11.09; O, 12.74.

Synthesis of N′-arylidene-2-methyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carbohydrazides 7a–e

Equimolar quantities of 2-methyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carbohydrazide (5) and an aryl aldehyde were allowed to react in absolute ethanol with 2–3 drops of glacial acetic acid for 4–5 h (TLC, ethyl acetate: hexane, 2.5:1). Solvent was evaporated in vacuo and the mixture was poured into cold water. The separated solid was filtered, washed and crystallized from DMF.

N′-Benzylidene-2-methyl-5-oxo-5H-chromeno[4,3-b]pyridine-3-carbohydrazide (7a)

A white solid; yield 82%; mp 211–212°C; IR: υmax 3263, 1753, 1669, 1630, 1553 cm-1; 1H NMR (DMSO-d6): δ 3.24 (s, 3H, Ar–CH3), 7.50–7.67 (m, 2H, Ar–H), 7.72 (s, 1H, Ar–H), 7.74 (s, 1H, N=CH), 8.04 (d, J = 8.0 Hz, 1H, Ar–H), 8.16 (d, J = 8.0 Hz, 1H, Ar–H), 8.25 (s, 1H, Ar–H), 8.34 (d, J = 8.0 Hz, 1H, Ar–H), 8.52 (m, 2H, Ar–H), 8.66 (s, 1H, Ar–H), 11.47 (s, 1H, –NH); 13C NMR (DMSO-d6): δ 26.4, 113.3, 117.6, 121.4, 124.4, 125.1, 128.5, 131.9, 133.6, 137.3, 141.3, 143.2, 148.2, 150.18, 150.9, 151.5, 156.6, 158.7, 162.1, 166.4, 168.3; MS: m/z 358 (M+H). Anal. Calcd for C21H15N3O3: C, 70.58; H, 4.23; N, 11.76; O, 13.43. Found: C, 70.40; H, 4.12; N, 11.64; O, 13.31.

Synthesis of 3-(4-acetyl-4,5-dihydro-5-aryl-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridine-5-ones 8a–e

A mixture of compound 7a–e (1 mmol) and acetic anhydride (15 mL) was heated under reflux for 4–4.5 h. Reaction progress was monitored by TLC (ethyl acetate/n-hexane, 1:3). After cooling to room temperature, the excess acetic anhydride was decomposed by addition of water and the mixture was stirred for further 45 min. The separated product was filtered, washed with water, dried and purified by silica gel column chromatography eluting with chloroform/methanol (8:2).

3-(4-Acetyl-4,5-dihydro-5-phenyl-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (8a)

A white solid; yield 71%; mp 138–139°C; IR: υmax 1740, 1668 cm-1; 1H NMR (CDCl3): δ 2.33 (s, 3H, –COCH3), 3.23 (s, 3H, Ar–CH3), 6.49 (s, 1H, –CH–N), 7.33–7.78 (m, 7H, Ar–H), 7.99 (s, 1H, Ar–H), 8.67 (d, J = 4.0 Hz, 1H, Ar–H), 9.11 (d, J = 4.0 Hz, 1H, Ar–H); 13C NMR (CDCl3): δ 22.8, 25.1, 76.5, 112.6, 116.4, 122.1, 123.8, 126.3, 129.4, 130.8, 136.9, 139.2, 140.6, 143.7, 145.6, 146.9, 150.97, 158.2, 161.1, 163.5, 165.9, 170.3; MS: m/z 400 (M+H). Anal. Calcd for C23H17N3O4: C, 69.17; H, 4.29; N, 10.52; O, 16.02. Found: C, 69.02; H, 4.18; N, 10.43; O, 15.88.

3-(4-Acetyl-4,5-dihydro-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (8b)

A white solid; yield 79%; mp: 144–145°C; IR: υmax 1742, 1672 cm-1; 1H NMR (CDCl3): δ 2.40 (s, 3H, –COCH3), 3.10 (s, 3H, Ar–CH3), 3.82 (s, 6H, 2CH3O), 6.49 (s, 1H, –CH–N), 7.26 (m, 2H, Ar–H), 7.40 (m, 3H, Ar–H), 7.61 (m, 1H, Ar–H), 8.64 (d, J = 4.0 Hz, 1H, Ar–H), 8.92 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 23.2, 24.6, 57.9, 58.5, 77.3, 115.1, 123.3, 124.1, 126.6, 129.7, 129.9, 137.4, 138.5, 141.8, 143.3, 145.9, 146.5, 150.2, 154.2, 158.6, 159.2, 164.2, 165.5, 171.3; MS: m/z 460 (M+H). Anal. Calcd for C25H21N3O6: C, 65.35; H, 4.61; N, 9.15; O, 20.89. Found: C, 65.19; H, 4.53; N, 9.03; O, 20.76.

3-(4-Acetyl-5-(4-chlorophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (8c)

A white solid; yield 68%; mp 155–156°C; IR: υmax 1748, 1666 cm-1; 1H NMR (CDCl3): δ 2.32 (s, 3H, –COCH3), 3.30 (s, 3H, Ar–CH3), 6. 73 (s, 1H, –CH–N), 7.25–7.73 (m, 7H, Ar–H), 8.48 (d, J = 8.0 Hz, 1H, Ar–H), 8.58 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 23.2, 26.4, 77.2, 114.2, 117.6, 124.6, 125.8, 128.7, 129.8, 131.4, 137.3, 139.7, 140.8, 144.8, 144.9, 147.1, 151.2, 156.2, 159.5, 160.8, 164.5, 167.3, 170.6; MS: m/z 434 (M+H), 436 (M+3). Anal. Calcd for C23H16ClN3O4: C, 63.67; H, 3.72; Cl, 8.17; N, 9.69; O, 14.75. Found: C, 63.49; H, 3.64; Cl, 8.04; N, 9.53; O, 14.61.

3-(4-Acetyl-4,5-dihydro-5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (8d)

A yellowish solid; yield: 76%; mp 141–142°C; IR: υmax 1741, 1671 cm-1; 1H NMR (CDCl3): δ 2.41 (s, 3H, –COCH3) 3.09 (s, 3H, Ar–CH3), 7.17 (s, 1H, –CH–N), 7.41 (m, 2H, Ar–H), 7.61–7.72 (m, 3H, Ar–H), 8.29 (d, J = 8.1 Hz, 2H, Ar–H), 8.64 (d, J = 8.1 Hz, 1H, Ar–H), 8.95 (s, 1H, Ar–H); MS: m/z 445 (M+H). Anal. Calcd for C23H16N4O: C, 62.16; H, 3.63; N, 12.61; O, 21.60. Found: C, 61.97; H, 3.51; N, 12.54; O, 21.49.

3-(4-Acetyl-5-(4-fluorophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (8e)

A creamy solid; yield 69%; mp 176–177°C; IR: υmax 1744, 1672 cm-1; 1H NMR (CDCl3): δ 2.40 (s, 3H, –COCH3), 3.09 (s, 3H, Ar–CH3), 6.49 (s, 1H, –CH–N), 7.27 (d, J = 8.0 Hz, 2H, Ar–H), 7.42 (m, 4H, Ar–H), 8.64 (dd, J = 8.0 Hz, 1H, Ar–H), 8.91 (s, 1H, Ar–H), 9.15 (s, 1H, Ar–H); MS: m/z 418 (M+H). Anal. Calcd for C23H16FN3O4: C, 66.18; H, 3.86; F, 4.55; N, 10.07; O, 15.33. Found: C, 66.03; H, 3.73; F, 4.39; N, 9.91; O, 15.21.

Synthesis of 3-(4-(2,2,2-trifluoroacetyl)-4,5-dihydro-5-aryl-1,3,4-oxadiazol-2-yl)-2 methyl-5H-chromeno[4,3-b]pyridin-5-ones 9a-e

A mixture of compound 7a–e (1 mmol) and trifluoroacetic anhydride (15 mL) was heated under reflux for 2–2.5 h. Reaction progress was monitored by TLC (ethyl acetate/n-hexane, 1:2.5). The mixture was cooled to room temperature, poured into cold water and stirred for 30 min. The precipitate was filtered, washed with water, dried and purified by silica gel column chromatography eluting with chloroform/methanol, 8:2.

3-(4-(2,2,2-Trifluoroacetyl)-4,5-dihydro-5-phenyl-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (9a)

A white solid; yield 68%; mp 221–222°C; IR: υmax 1778, 1749 cm-1; 1H NMR (CDCl3): δ 3.09 (s, 3H, Ar–CH3), 6.49 (s, 1H, –CH–N), 7.27 (d, J = 8.0 Hz, 2H, Ar–H), 7.39–7.44 (m, 5H, Ar–H), 8.67 (d, J = 8.0 Hz, 1H, Ar–H), 8.90 (s, 1H, Ar–H), 9.15 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 26.8, 78.2, 114.9, 117.1, 118.7, 125.1, 125.7, 128.5, 130.5, 133.8, 135.3, 142.1, 144.5, 147.7, 148.4, 148.9, 150.6, 154.3, 157.5, 161.8, 166.5, 167.3, 188.7; MS: m/z 454 (M+H). Anal. Calcd for C23H14F3N3O4: C, 60.93; H, 3.11; F, 12.57; N, 9.27; O, 14.12. Found: C, 60.78; H, 3.03; F, 12.45; N, 9.14; O, 14.03.

3-(4-(2,2,2-Trifluoroacetyl)-4,5-dihydro-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (9b)

A white solid; yield 64%; mp 235–236°C; IR: υmax 1773, 1751 cm-1; 1H NMR (CDCl3): δ 3.10 (s, 3H, Ar–CH3), 3.82 (s, 6H, 2CH3O), 6.49 (s, 1H, –CH–N), 7.23–7.29 (m, 2H, Ar–H), 7.38–7.42 (m, 3H, Ar–H), 7.61 (m, 1H, Ar–H), 8.64 (d, J = 4.0 Hz, 1H, Ar–H), 8.92 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 26.6, 57.1, 57.4, 78.5, 114.6, 117.9, 118.7, 124.2, 126.2, 128.8, 131.4, 134.7, 138.4, 142.7, 144.9, 147.2, 148.8, 149.3, 150.8, 155.1, 162.3, 158.7, 166.6, 168.1, 189.4; MS: m/z 514 (M+H). Anal. Calcd for C25H18F3N3O6: C, 58.48; H, 3.53; F, 11.10; N, 8.18; O, 18.70. Found: C, 58.31; H, 3.42; F, 11.04; N, 8.08; O, 18.56.

3-(5-(4-Chlorophenyl)-4-(2,2,2-trifluoroacetyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (9c)

A white solid; yield 70%; mp 246–247°C; IR: υmax 1776, 1744 cm-1; 1H NMR (CDCl3): δ 3.30 (s, 3H, Ar–CH3), 6. 73 (s, 1H, –CH–N), 7.25–7.73 (m, 7H, Ar–H), 8.48 (d, J = 8.0 Hz, 1H, Ar–H), 8.58 (s, 1H, Ar–H); 13C NMR (CDCl3): δ 27.4, 78.6, 115.2, 118.2, 118.9, 125.4, 126.1, 128.2, 131.6, 133.7, 142.4, 143.3, 145.4, 148.1, 148.8, 149.6, 151.3, 155.1, 156.2, 160.2, 166.3, 167.4, 189.1; MS: m/z 488 (M+H), 490 (M+3). Anal. Calcd for C23H13ClF3N3O4: C, 56.63; H, 2.69; Cl, 7.27; F, 11.68; N, 8.61; O, 13.12. Found: C, 56.45; H, 2.59; Cl, 7.16; F, 11.52; N, 8.49; O, 13.05.

3-(4-(2,2,2-Trifluoroacetyl)-4,5-dihydro-5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (9d)

A yellowish solid; yield 73%; mp 203–204°C; IR: υmax 1769, 1741 cm-1; 1H NMR (CDCl3): δ 3.09 (s, 3H, Ar–CH3), 7.17 (s, 1H, –CH–N), 7.38–7.45 (m, 2H, Ar–H), 7.61–7.72 (m, 3H, Ar–H), 8.29 (d, J = 8.1 Hz, 2H, Ar–H), 8.64 (d, J = 8.1 Hz, 1H, Ar–H), 8.95 (s, 1H, Ar–H); MS: m/z 499 (M+H). Anal. Calcd for C23H13F3N4O6: C, 55.43; H, 2.63; F, 11.44; N, 11.24; O, 19.26. Found: 55.29; H, 2.55; F, 11.32; N, 11.10; O, 19.26.

3-(4-(2,2,2-Trifluoroacetyl)-5-(4-fluorophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-5H-chromeno[4,3-b]pyridin-5-one (9e)

A creamy solid; yield 65%; mp 261–263°C; IR: υmax 1773, 1746 cm-1; 1H NMR (CDCl3): δ 3.09 (s, 3H, Ar–CH3), 6.49 (s, 1H, –CH–N), 7.27 (d, J = 8.0 Hz, 2H, Ar–H), 7.39–7.44 (m, 4H, Ar–H), 8.64 (dd, J = 8.0 Hz, 1H, Ar–H), 8.91 (s, 1H, Ar–H), 9.15 (s, 1H, Ar–H); MS: m/z 472 (M+H). Anal. Calcd for C23H13F4N3O4: C, 58.61; H, 2.78; F, 16.12; N, 8.91; O, 13.58. Found: C, 58.43; H, 2.64; F, 15.97; N, 8.78; O, 13.41.

Antimicrobial assay

The antimicrobial activity of the synthesized compounds was evaluated by agar-well diffusion method. The antibacterial and antifungal assays were performed in Muller-Hinton broth and Czapek Dox broth, respectively. Evaluation was performed using the bacteria reseeded in broth for 24 h at 37°C, and the fungi were reseeded in broth for 48 h at 25°C. The antibacterial activity of test samples were studied against one Gram-positive bacterium Styphalococcus aureus ATCC 25923, one Gram-negative bacterium Escherichia Coli ATCC 25922, while Candida albicans MTCC 277 and Aspergillus niger MCIM 545 were used as standard fungal strains. The pathogens were obtained from National Chemical Laboratory (NCIM), Pune, India. The compounds were diluted in DMF for required concentration for bioassay. DMF was also loaded as control. Streptomycin and griseofluvin were used as standards to evaluate the potency of the tested compounds under similar conditions. The zone of inhibition was determined from the diameter of the zone of inhibition using a caliper. Each inhibition zone was measured three times to get an average value. The minimum inhibitory concentration (MIC) values were determined on MH agar plates by pouring the molten agar in Petri dishes according to National Committee for Clinical Laboratory Standards (NCCLS, M7-A5 January 2000), containing the following sample concentrations (μg/mL.): 0 (control), 3, 5, 10, 15, 20, 30, 40. The MIC is defined as the lowest concentration of the tested sample showing no visible bacterial growth after 24 h incubation period at 37°C [38].

Acknowledgments

The authors thank UGC, New Delhi [File no.40-27/2011 (SR)] and BCUD, S. P. Pune University [OSD/BCUD/230/89] for financial support.

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Received: 2015-10-22
Accepted: 2016-3-16
Published Online: 2016-5-13
Published in Print: 2016-6-1

©2016 by De Gruyter

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  2. Research Articles
  3. TiCl2·2H2O catalyzed one-pot synthesis of highly functionalized tetrahydropiperidines and evaluation of their antimicrobial activities
  4. 2,5-Disubstituted 1,3,4-oxadiazole derivatives of chromeno[4,3-b]pyridine: synthesis and study of antimicrobial potency
  5. Catalytic synthesis and antimicrobial activity of N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides
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https://doi.org/10.1515/hc-2015-0215
Keywords for this article
antimicrobial activity; coumarin; multistep synthesis; 1,3,4-oxadiazole; pyridine
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Research Articles
  3. TiCl2·2H2O catalyzed one-pot synthesis of highly functionalized tetrahydropiperidines and evaluation of their antimicrobial activities
  4. 2,5-Disubstituted 1,3,4-oxadiazole derivatives of chromeno[4,3-b]pyridine: synthesis and study of antimicrobial potency
  5. Catalytic synthesis and antimicrobial activity of N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides
  6. Benzo[e][1,2,4]triazino[2,3-c][1,2,3]triazin-2-ones electro-deficient heterocyclic compounds with promising anticancer activity
  7. Synthesis and biological activity studies of some new hybrid compounds derived from antipyrine
  8. Diastereoselective synthesis of dispiro[indoline-3,1′-cyclobutane-2′,3″-indolines] via visible light catalyzed cyclodimerization of 3-phenacylideneoxindoles
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  10. Lactic acid-catalyzed fusion of ninhydrin and enamines for the solvent-free synthesis of hexahydroindeno[1,2-b]indole-9,10-diones
  11. Efficient synthesis of N-arylsulfonyl-1,2,3-triazoles from 1,1-dibromo-2-arylethylenes
  12. A direct synthetic route to fused tricyclic quinolones from 2,3-diaminoquinolin-4(1H)one
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