Journal of the Korean Chemical Society (대한화학회지)

Korean Chemical Society (대한화학회)
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One Pot Synthesis of Bioactive Novel Cyanopyridones

  • Received : 2013.04.09
  • Accepted : 2013.07.15
  • Published : 2013.08.20
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Abstract

Cyanopyridone was prepared by the condensation of cyanoacetamide, substituted arylaldehydes and malononitrile in presence of pipyridine. The structure of the synthesized compound CP 1-20 was assigned on the basis of elemental analysis, IR, $^1H$-NMR and mass spectroscopy. These compounds were also screened for antimicrobial activity. The Minimum Inhibitory Concentration (MIC) of all the synthesized compounds was compared with standard drugs.

Keywords

INTRODUCTION

Pyridone and their derivatives play an essential role in several biological processes and have considerable chemical and pharmacological importance.1−3 The 2-pyridones represent a unique class of pharmacophore, which are observed in various therapeutic agents4 and antibiotics.5 The 3-cyanopyridin-2-one nucleus is the structural basis of the alkaloid ricinine (I), the first known alkaloid containing a cyano-group. Cheney et al. reported 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles (II), as inhibitors of the oncogenic serine/threonine kinas PIM-1, which plays a role in cancer cell survival, differentiation and proliferation.6 Wendt et al. showed that several compounds with the same general formula as above (II) but with higher lipophilic properties (III) can inhibit surviving which is a member of the inhibitor of apoptosis family (IAP).7

The thienopyridone agonist (IV) showed modest AMPK (adenosine monophosphate-activated protein kinase) activity8 (Fig. 1). These heterocycles attracted attention because of their applications as bioactive compounds for example as a promising class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs)9 as antibacterial,10 antifungal,11 sedative,12 andcardiotonic agent.13 Moreover, such derivatives have recently become important due to their structural similarity to nucleosides.14

They are also versatile precursors for the construction of complex natural products15 pyridines16 and larger pyridone systems such as those found in the nitro guanidine insecticide Imidacloprid17 and subtype selective GABA receptor agonists. Consequently, methodologies for the preparation of pyridones have attracted much attention from both industrial and academic areas.

Figure 1.Some reported potent cynopyridones.

 

EXPERIMENTAL

Melting points were determined in open capillary tubes and are uncorrected. Formation of the compounds was routinely checked by TLC on silica gel-G plates of 0.5 mm thickness and spots were located by iodine. IR spectra were recorded Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe technique. 1H-NMR was determined using DMSO-d6 as asolvent on a Bruker Ac 400 MHz spectrometer. Elemental analysis of the all the synthesized compounds was carried out on Elemental Vario EL III Carlo Erba 1108 model and the results are in agreements with the structures assigned.

Scheme 1.Synthesis of 2-cyano-N-(substituted) acetamides.

Preparations of Cyanoacetamide Derivatives

The disubstituted aniline (10 mmol) and ethyl 2-cyanoacetate (10 mmol) were refluxed on sand bath for 3−4 hours to yield 2-cyano-N-(substituted) acetamides18 (3) in good yields (Scheme 1).

General Procedure for Synthesis of Cyanopyridones (CP 1−20)

A mixture of substituted 10 mmol of cyanoacetamide (3), 10 mmol substituted aldehyde (4) and 10 mmol of malononitrile (5) were dissolve in 30 ml of methanol, catalytic amount of pipyridine was added. The reaction mixture was heated under reflux on water bath for 20−22 h (under TLC analysis). After completion of the reaction, filtered product was washed with methanol and recrystalized from ethanol (Scheme 2).

6-Amino-1-(2,5-dichlorophenyl)-2-oxo-4-phenyl-1,2- dihydro pyridine-3,5-dicarbonitrile (CP-1): MP: 272−274℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.01−7.11 (t, 1H, Ar−H), 7.10−7.12 (t, 2H, Ar−H, J = 11.6 Hz), 7.52−7.55 (t, 2H, Ar−H, J = 11.6 Hz), 7.68−7.69 (d, 1H, Ar−diCl), 7.75−7.78 (d, 1H, Ar−diCl), 7.85 (s, 1H, Ar−diCl), 8.20 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−H), 2218 (C≡N), 1639 (C=O), 774 (C−Cl); MS m/z (%): 380 (M+), 364 (100), 329 (6), 304 (14), 288 (31), 210 (16), 187 (23), 152 (8), 77 (32). Elemental Analysis for C19H10Cl2N4O: Calculated: C, 59.86; H, 2.64; N, 14.70. Found: C, 59.40; H, 2.30; N, 14.35%.

Scheme 2.One spot synthesis of CP 1−20.

6-Amino-1-(2,5-dichlorophenyl)-4-(4-methoxyphenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-2): MP: 280−284 ℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 3.85 (s, 3H, OCH3), 7.12−7.15 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.52−7.55 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.68−7.69 (d, 1H, diCl−Ar−H), 7.75−7.78 (d, 1H, diCl− Ar−H), 7.85 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−H), 2218 (C≡N), 1639 (C=O), 1173 (C−O−C), 774 (C−Cl); MS m/z (%): 410 (M+), 394 (16), 375 (100), 360 (4), 332 (6), 196 (4), 187 (16), 152 (8), 109 (7), 75 (4). Elemental Analysis for C20H12Cl2N4O2: Calculated: C, 58.41; H, 2.94; N, 13.62. Found: C, 58.21; H, 2.45; N, 13.33%.

6-Amino-1-(2,5-dichlorophenyl)-4-(2-methoxyphenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-3): MP: 280−284 ℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 3.87 (s, 3H, OCH3), 7.10−7.13 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.54−7.57 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.22−7.28 (t, 2H, 4-OCH3−Ar−H,), 7.65−7.67 (d, 1H, diCl−Ar−H), 7.71−7.74 (d, 1H, diCl−Ar−H), 7.84 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−C−H), 2218 (C≡N), 1639 (C=O), 1173 (C−O−C), 774 (C−Cl); MS m/z (%): 410 (M+), 394 (45), 375 (100), 360 (6), 332 (9), 196 (8), 187 (21), 152 (6), 109 (11), 75 (8). Elemental Analysis for C20H12Cl2N4O2: Calculated: C, 58.41; H, 2.94; N, 13.62. Found: C, 58.26; H, 2.54; N, 13.46%.

6-Amino-1-(2,5-dichlorophenyl)-4-(4-nitrophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-4): MP: 245−250℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.12−8.15 (d, 2H, 4-NO2−Ar−H, J = 11.6 Hz), 7.52−7.55 (d, 2H, 4-NO2−Ar−H, J = 11.6 Hz), 7.68−7.69 (d, 1H, diCl−Ar−H), 7.75−7.78 (d, 1H, diCl−Ar−H), 7.85 (s, 1H, diCl−Ar− H), 8.38 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−C−H), 2218 (C≡N), 1639 (C=O), 1355− 1315 (NO2), 774 (C−Cl); MS m/z (%): 425 (M+), 304 (25), 288 (100), 237 (15), 210 (12), 187 (5), 152 (7), 126 (13), Elemental Analysis for C19H9Cl2N5O3: Calculated: C, 53.54; H, 2.13; N, 16.43. Found: C, 53.22; H, 2.04; N, 16.18%.

6-Amino-1-(2,5-dichlorophenyl)-4-(2-nitrophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-5): MP: 234−236℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.10−8.13 (d, 2H, 2-NO2−Ar−H, J = 11.6 Hz), 7.22−7.25 (d, 2H, 2-NO2−Ar−H, J = 11.6 Hz), 7.54−7.57 (t, 2H, 2-NO2−Ar−H), 7.65−7.67 (d, 1H, diCl−Ar−H), 7.71−7.74 (d, 1H, diCl−Ar−H), 7.84 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−H), 2218 (C≡N), 1639 (C=O), 1355−1315 (NO2), 774 (C−Cl); MS m/z (%): 425(M+), 304 (25), 288 (100), 237 (15), 210 (12), 187 (5), 152 (7), 126 (13). Elemental Analysis for C19H9Cl2N5O3: Calculated: C, 53.54; H, 2.13; N, 16.43. Found: C, 53.20; H, 2.08; N, 16.26%.

6-Amino-1-(2,5-dichlorophenyl)-2-oxo-4-(p-tolyl)-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-6): MP: 284−286℃; 1H-NMR (400MHz, DMSO-d6) δ ppm: 2.05 (s, 3H, CH3), 7.10−7.13 (d, 2H, CH3−Ar−H, J = 11.6 Hz), 7.42−7.45 (d, 2H, OCH3−Ar−H, J = 11.6 Hz), 7.68− 7.69 (d, 1H, diCl−Ar−H), 7.75−7.78 (d, 1H, diCl−Ar−H), 7.85 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 2870 (CH3), 3194 (Ar−C−H), 2218 (C≡N), 1639 (C=O), 774 (C−Cl); MS m/z (%): 394 (M+), 380 (10), 359 (95), 282 (5), 254 (8), 233 (9), 202 (12), 142 (18), 91 (13), 77 (27). Elemental Analysis forC20H12Cl2N4O: Calculated: C, 60.78; H, 3.06; N, 14.18. Found: C, 60.68; H, 3.00; N, 14.10%.

6-Amino-1-(2,5-dichlorophenyl)-4-(4-bromophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-7): MP: 298−300℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.53−7.56 (d, 2H, 4-Br−Ar−H, J = 11.6 Hz), 7.79−7.82 (d, 2H, 4-Br−Ar−H, J = 11.6 Hz), 7.68−7.69 (d, 1H, diCl−Ar−H), 7.75−7.78 (d, 1H, diCl−Ar−H), 7.85 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−H), 2218 (C≡N), 1639 (C=O), 774 (C−Cl), 642 (C−Br); MS m/z (%): 460 (M+), 425 (95), 401 (23), 323 (18), 293 (10), 205 (12), 218 (8), 164 (9), 77 (65). Elemental Analysis for C19H9BrCl2N4O: Calculated: C, 49.60; H, 1.97; N, 12.18. Found: C, 49.37; H, 1.85; N, 12.07%.

6-Amino-1-(2,5-dichlorophenyl)-4-(3-bromophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-8): MP: 305−308℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38−7.41 (m, 3H, 3-Cl−Ar−H), 7.49 (s, 1H, 3-Cl−Ar−H), 7.68−7.69 (d, 1H, diCl−Ar−H), 7.75−7.78 (d, 1H, diCl− Ar−H), 7.85 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−C−H), 2218 (C≡N), 1639 (C=O), 774 (C−Cl), 642 (C−Br); MS m/z (%): 460 (M+), 425 (95), 401 (23), 323 (18), 293 (10), 205 (12), 218 (8), 164 (9), 77 (65). Elemental Analysis for C19H9BrCl2N4O: Calculated: C, 49.60; H, 1.97; N, 12.18. Found: C, 49.27; H, 1.90; N, 12.11%.

6-Amino-1-(2,5-dichlorophenyl)-4-(4-chlorophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-9): MP: 278−282℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.50−7.53 (d, 2H, 4-Cl−Ar−H, J = 11.6 Hz), 7.75−7.78 (d, 2H, 4-Cl−Ar−H, J = 11.6 Hz), 7.68−7.69 (d, 1H, diCl−Ar−H), 7.75−7.78 (d, 1H, diCl−Ar−H), 7.85 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−H), 2218 (C≡N), 1639 (C=O), 774 (C−Cl); MS m/z (%): 414 (M+), 379 (90), 304 (21), 288 (25), 254 (5), 210 (15), 142 (8), 77 (29). Elemental Analysis for C19H9Cl3N4O: Calculated: C, 54.90; H, 2.18 N, 13.48. Found: C, 54.70; H, 2.10 N, 13.25%.

6-Amino-1-(2,5-dichlorophenyl)-4-(3-chlorophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-10): MP: 285−288℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.28−7.31 (m, 3H, 3-Cl−Ar−H), 7.45 (s, 1H, 3-Cl−Ar−H), 7.68−7.69 (d, 1H, diCl−Ar−H), 7.75−7.78 (d, 1H, diCl−Ar−H), 7.85 (s, 1H, diCl−Ar−H), 8.28 (s, 2H, NH2); IR (KBr, υ/cm−1): 3665 and 3522 (NH2), 3194 (Ar−H), 2218 (C≡N), 1639 (C=O), 774 (C−Cl); MS m/z (%): 414 (M+), 379 (90), 304 (21), 288 (25), 254 (5), 210 (15), 142 (8), 77 (29). Elemental Analysis for C19H9Cl3N4O: Calculated: C, 54.90; H, 2.18 N, 13.48. Found: C, 54.55; H, 2.08N, 13.14%.

6-Amino-1-(2,5-dimethylphenyl)-2-oxo-4-phenyl-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-11): MP: 283−285℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 7.55 (s, 5H, Ar−H), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.12−7.15 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.52−7.55 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.10 (s, 1H, diCH3−Ar−H), 7.90 (s, 2H, NH2), IR (KBr, υ/cm−1): 3641 and 3447 (N−H), 3206 (Ar−H), 2870 (CH3), 2215 (C≡N), 1631 (C=O), 774 (C− Cl); MS m/z (%): 340 (M+, 24), 325 (100), 309 (20), 164 (24), 107 (18), 103 (28), 91 (45), 77 (36). Elemental Analysis for C21H16N4O: Calculated: C, 74.10; H, 4.74; N, 16.46. Found: C, 74.06; H, 4.64; N, 16.56%.

6-Amino-1-(2,5-dimethylphenyl)-4-(4-methoxyphenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-12): MP: 255−260℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.12−7.15 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.52−7.55 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.10 (s, 1H, diCH3−Ar−H), 7.90 (s, 2H, NH2); IR (KBr, υ/cm−1): 3651 and 3457 (N−H), 3206 (Ar−H), 2870 (CH3), 2215 (C≡N), 1631 (C=O), 1172 (C−O−C symmetrical stretching OCH3 group); MS m/z (%): 370(M+, 20), 355 (95), 324 (17), 205 (20), 164 (17), 107 (15), 103 (24), 91 (40), 77 (30). Elemental Analysis for C22H18N4O2: Calculated: C, 71.34; H, 4.90; N, 15.13.Found: C, 71.30; H, 4.87; N, 15.08%.

6-Amino-1-(2,5-dimethylphenyl)-4-(2-methoxyphenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-13): MP: 225−228℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 7.10−7.13 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.54−7.57 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.22−7.28 (t, 2H, 4- OCH3−Ar−H), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.10 (s, 1H, diCH3−Ar−H), 7.90 (s, 2H, NH2); IR (KBr, υ/cm−1): 3650 and 3440 (N−H), 3206 (C−H aromatic), 2870 (CH3), 2215 (C≡N), 1631 (C=O), 1172 (C−O−C symmetrical stretching OCH3 group); MS m/z (%): 370 (M+, 22), 355 (96), 324 (14), 205 (19), 164 (5), 107 (10), 103 (32), 91 (30), 77 (35). Elemental Analysis for C22H18N4O2: Calculated: C, 71.34; H, 4.90; N, 15.13. Found: C, 71.31; H, 4.85; N, 15.10%.

6-Amino-1-(2,5-dimethylphenyl)-4-(4-nitrophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-14): MP: 195−198℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 7.11 (s, 1H, diCH3−Ar− H), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.58−7.61 (d, 2H, 4Br−Ar−H, J = 11.2 Hz), 7.79−7.82 (d, 2H, 4Br−Ar−H, J = 11.6 Hz), 7.91 (s, 2H, NH2); IR (KBr, υ/cm−1): 3644 and 3446 (N−H), 3200 (C−H aromatic), 2855 (CH3), 2250 (C≡N), 1631 (C=O), 1350−1310 (NO2); MS m/z (%): 385 (M+, 31), 370 (100), 339 (28), 205 (15), 164 (8), 122 (30), 103 (30), 77 (30). Elemental Analysis for C21H15N5O3: Calculated: C, 65.45; H, 3.92; N, 18.17.Found: C, 65.40; H, 3.91; N, 18.15%.

6-Amino-1-(2,5-dimethylphenyl)-4-(2-nitrophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-15): MP: 228−230℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.90 (s, 3H, CH3), 2.02 (s, 3H, CH3), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.10 (s, 1H, diCH3−Ar−H), 7.90 (s, 2H, NH2), 8.10−8.13 (d, 2H, 2-NO2−Ar−H, J = 11.6 Hz), 7.22−7.25 (d, 2H, 2-NO2−Ar−H, J = 11.6 Hz), 7.54−7.57 (t, 2H, 2-NO2−Ar−H); IR (KBr, υ/cm−1): 3351 and 3457 (N− H), 3206 (C−H aromatic), 2870 (CH3), 2215 (C≡N), 1631 (C=O), 1355−1315 (NO2); MS m/z (%): 385 (M+, 29), 370 (98), 339 (30), 205 (14), 164 (6), 122 (21), 91 (8), 77 (45). Elemental Analysis for C21H15N5O3: Calculated: C, 65.45; H, 3.92; N, 18.17. Found: C, 65.35; H, 3.88; N, 18.10%.

6-Amino-1-(2,5-dimethylphenyl)-2-oxo-4-(p-tolyl)-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-16): MP: 220−222℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.90 (s, 3H, CH3), 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.12−7.15 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.52− 7.55 (d, 2H, 4-OCH3−Ar−H, J = 11.6 Hz), 7.10 (s, 1H, diCH3−Ar−H), 7.90 (s, 2H, NH2); IR (KBr, υ/cm−1): 3650 and 3450 (N−H), 3205 (C−H aromatic), 2868 (CH3), 2340 (C≡N), 1629 (C=O); MS m/z (%): 354 (M+, 36), 339 (92), 308 (26), 205 (13), 164 (11), 103 (22), 91 (10), 77 (42). Elemental Analysis for C22H18N4O: Calculated: C, 74.56; H, 5.12; N, 15.81. Found: C, 74.50; H, 5.11; N, 15.71%.

6-Amino-1-(2,5-dimethylphenyl)-4-(4-bromophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-17): MP: 275−279℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 7.11 (s, 1H, diCH3−Ar−H), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.53−7.56 (d, 2H, 4Br−Ar−H J = 11.2 Hz), 7.79−7.82 (d, 2H, 4Br−Ar−H, J = 11.6 Hz), 7.93 (s, 2H, NH2); IR (KBr, υ/cm−1): 3640 and 3438 (N−H), 3206 (C−H aromatic), 2870 (CH3), 2215 (C≡N), 1631 (C=O), 642 (C−Br); MS m/z (%): 418 (M+, 61), 403 (100), 323 (18), 309 (10), 205 (12), 164 (14), 103 (32), 91 (20), 77 (65). Elemental Analysis for C21H15BrN4O: Calculated: C, 60.16; H, 3.61; N, 13.36. Found: C, 60.11; H, 3.51; N, 13.31%.

6-Amino-1-(2,5-dimethylphenyl)-4-(3-bromophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-18): MP: 290−292℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 7.11 (s, 1H, diCH3−Ar−H), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.42−7.55 (m, 4H, 3Br−Ar−H), 7.93 (s, 2H, NH2); IR (KBr, υ/cm−1): 3635 and 3420 (N−H), 3206 (C−H aromatic), 2872 (CH3), 2215 (C≡N), 1631 (C=O), 642 (C−Br); MS m/z (%): 418 (M+, 57), 403 (100), 323 (20), 309 (10), 205 (9), 164 (14), 103 (30), 91 (18), 77 (65). Elemental Analysis for C21H15BrN4O: Calculated: C, 60.16; H, 3.61; N, 13.36. Found: C, 60.13; H, 3.57; N, 13.31%.

6-Amino-1-(2,5-dimethylphenyl)-4-(4-chlorophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-19): MP: 235−238℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 7.11 (s, 1H, diCH3−Ar−H), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.50−7.53 (d, 2H, 4Br−Ar−H, J = 11.2Hz), 7.77−7.80 (d, 2H, 4Br−Ar−H, J = 11.6Hz), 7.91 (s, 2H, NH2); IR (KBr, υ/cm−1): 3635 and 3440 (N−H), 3202 (C−H aromatic), 2870 (CH3), 2211 (C≡N), 1641 (C=O), 772 (C−Cl); MS m/z (%): 374 (M+, 52), 359 (100), 276 (21), 309 (8), 205 (11), 164 (15), 103 (25), 91 (15), 77 (60). Elemental Analysis for C21H15ClN4O: Calculated: C, 67.29; H, 4.03; N, 14.95. Found: C, 67.25; H, 3.95; N, 14.89%.

6-Amino-1-(2,5-dimethylphenyl)-4-(3-chlorophenyl)-2-oxo-1,2-dihydro pyridine-3,5-dicarbonitrile (CP-20): MP: 258−260℃; 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 2.32 (s, 3H, CH3), 7.11 (s, 1H, diCH3−Ar−H), 7.25−7.35 (d, 2H, diCH3−Ar−H), 7.42−7.55 (m, 4H, 3Br−Ar−H), 7.93 (s, 2H, NH2); IR (KBr, υ/cm−1): 3590 and 3457 (N−H), 3200 (C−H aromatic), 2860 (CH3), 2210 (C≡N), 1621 (C=O), 774 (C−Cl); MS m/z (%): 374 (M+, 55), 359 (98), 276 (16), 309 (6), 205 (10), 164 (12), 103 (28), 91 (18), 77 (58). Elemental Analysis for C21H15ClN4O: Calculated: C, 67.29; H, 4.03; N, 14.95. Found: C, 67.25; H, 4.00; N, 14.92%.

Antimicrobial Screening

The synthesized compound were tested for their antibacterial and antifungal activity (MIC) in vitro by broth dilution method19−21 with two Gram-positive bacteria Staphylococcus aureus (S.a.) MTCC 96, Streptococcus pyogenes (S.p.) MTCC 443, two Gram-negative bacteria Escherichia coli (E.c.) MTCC 442, Pseudomonas aeruginosa (P.a.) MTCC 441 and three fungal strains Candida albicans (C.a.) MTCC 227, Aspergillus niger (A.n.) MTCC 282, Aspergillus clavatus (A.c.) MTCC 1323 taking ampicillin, chloramphenicol, ciprofloxacin, norfloxacin, nystatin, and griseofulvin as standard drugs.

Serial dilutions of the test compounds and reference drugs were prepared in Muellere-Hinton agar. Drugs (10 mg) were dissolved in dimethylsulfoxide (DMSO, 1 mL). Further progressive dilutions with melted Muellere-Hinton agar were performed to obtain the required concentrations of 1.56, 3.12, 6.25, 10, 12.5, 25, 50, 62.5, 100, 125, 250, 500 and 1000 μg mL−1. The tubes were inoculated with 108 cfu mL−1 (colony forming unit mL−1) and incubated at 37 ℃ for 24 h. The MIC was the lowest concentration of the tested compound that yields no visible growth (turbidity) on the plate. To ensure that the solvent had no effect on the bacterial growth, a control was performed with the test medium supplemented with DMSO at the same dilutions as used in the experiments and it was observed that DMSO had no effect on the microorganisms in the concentrations studied.

 

RESULTS AND DISCUSSION

The compound 1 and 2 reacted in a solvent free condition to provide the starting materials (3) in good yields for the synthesis of desired product (CP 1−20).

As shown in the reaction (Scheme 2) the synthesis of the target molecules CP 1−20 was carried out. The compound 3 was reacted with the various substituted 4 and 5 compounds to give different target molecules. All the molecules have been synthesized under the conventional method using methanol as a solvent and pipyridine as a catalyst.

The physical data like molecular formula, molecular weight, melting point, and percentage of yield of all the synthesized target molecules are shown in Table 1.

The purity of all the synthesized compound was checked by TLC (8:2:n-hexane:ethylacetate). The target molecules were conformed on the basis of 1H-NMR, IR, Mass Spectrometry. The 1H-NMR spectra showed the broad peak in between 7.5−8.0 ppm which showed the presence of an −NH2 functional group. The aromatic ring protons and J values were found to be in accordance with substitution pattern on phenyl ring. The sharp band near 2250 cm−1 in IR spectra indicates the presence of −CN group. Systematic fragmentation pattern was observed in mass spectral analysis for all the synthesized compounds. Molecular ion peak was observed in agreement with molecular weight of respective compound. All the synthesized target molecules showed screening in vitro studies on the selected microorganism and fungal species. Among the tested compounds CP-1, CP-2, CP-7 and CP-15 exhibited more antimicrobial activity against gram positive and gram negative bacteria and CP-9, CP-10 and CP-17 exhibited comparatively moderate anti fungal activity (Table 2).

 

CONCLUSION

In summary we have developed a simple, one pot method for the preparation of a series of 6-amino-1-(2,5-disubstituted phenyl)-2-oxo-4-substituted phenyl-1,2-dihydropyridine-3,5-dicarbonitrile. All the synthesized compounds were characterized by FT-IR, 1H-NMR, mass spectroscopy and elemental analysis. The compounds were subjected for different biological activities and all the synthesized compounds showed good to moderate antimicrobial activity, results of other activities are awaiting. Further efforts toward this end will be reported in due course.

Table 1.Physical data of all the synthesized compounds

Table 2.Minimal inhibitory concentration (MIC) of all synthesized compounds

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