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Synthesis and goat pulmonary vasodilatory activity of some novel 1,3,4-oxadiazoles
*Corresponding author padmpramod@rediffmail.com (Pramodkumar J. Shirote)
-
Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer-review under responsibility of King Saud University.
Available online 16 July 2010
Abstract
A novel series of[(1Z)-1-(2,2-disubstituted-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl) ethylidene] (PSMB1–PSMB15) were synthesized as title compounds. The synthesis route included the cyclization of carbonyl hydrazone in the presence of excess of acetic anhydride and subsequent condensation with various aromatic amines. All the title compounds were characterized by IR, 1H NMR, MS and elemental analysis. They were screened for their goat pulmonary vein relaxant activity. Compound PSMB9 was found the most active derivative exhibiting 83.33% relaxation. Isosorbide dinitrate was used as the standard drug for goat pulmonary vein relaxant activity.
Keywords
1,3,4-Oxadiazole
Isosorbide dinitrate
Goat pulmonary vein relaxant activity
1 Introduction
Research on 1,3,4-oxadiazole skeleton derivatives has attracted sizeable interest because of their assorted biological activity, including anti-HIV activity, (Taoa et al., 2006), antibacterial (Sahin and Palaska, 2002; Ates et al., 1998; Kocabalkanli et al., 2001), antifungal, analgesic and anti-inflammatory activities (Palaska et al., 2002; Mishrah et al., 1995; Maccari et al., 2005; Demirbas, 2005) and, smooth muscle relaxant (Ahulwalia et al., 1989; Dhiman et al., 2001). Moreover, they are also effective in conjunction with imines and nitric oxide and display diverse potent physiological actions (Sad, 1996; Ram, 1988; Misra et al., 1996; Shah et al., 1998; Amir and Kumar, 2004). With regard to the cardiovascular system, it helps to maintain micro- and macro-vascular homeostasis through several mechanisms including vasodilatation, inhibition of platelet aggregation, and modulation of platelet and leukocyte adhesion to the endothelium (Mogilaiah and Sakram, 2004; Gasco et al., 2004). Based on the fact, it is envisioned that the attachment of imines to the 1,3,4-oxadiazole can enhance the pulmonary vein relaxation which may contribute to maintain the homeostasis and in continuation of our research on synthesis of pharmacological active oxadiazole and imines, herein we report the synthesis of a novel series of 5-(pyridyl)-1,3,4-oxadiazole. All the title compounds were evaluated for goat pulmonary vein relaxation (Chand, 1981; Chand et al., 1979) using force transducer multichannel physiograph (BIOPAC MP35 SYSTEM). The synthesis route is outlined in Fig. 1.
Synthesis route of compounds PSMB1–PSMB15. Key: (a) acetophenones–methanol; (b) acetic anhydride; (c) aromatic amines.
2 Experimental
2.1 General
Melting points were determined by open capillary method and were uncorrected. IR spectra (KBr wafer technique) were recorded on a Nicolet Impact-410 FT (Nicolet Instrumentation Corporation, Madison, WI, USA), 1H NMR spectra were recorded in CDCl3 on a Brucker 300 MHz (Brucker Magnetics AG, Faellanden, Switzerland) using TMS as the internal standard. Mass spectra were obtained with a HPLC/MS LCQDECA spectrometer. HRMS-FAB was obtained with Mass Spectrometers JoelSX-102. Elemental analysis was performed on a Perkin–Elmer model 240C analyzer and the data were within ±0.4% of the theoretical values. The purity of the compounds was confirmed by TLC on silica gel ‘G’ (60-120 mesh size) coated glass plates.
2.1.1 Typical procedure for synthesis of (2E)-2-[(Z)-2-aminovinyl]-N′-[1-(aryl)ethylidene]penta-2,4-dienehydrazide 1(a–f)
A solution of 0.01 mol of isoniazid and an equimolar amount of appropriate acetophenones were added in 25 ml methanol with a drop of glacial acetic acid, consecutively; the reaction mixture was refluxed for about 2 h until the disappearance of the starting material which was ascertained by TLC. The precipitate obtained was filtered-off; washed with cold methanol and was then recrystallized from methanol to give 1(a–f). Analytical and spectral data was obtained for all the compounds.
2.1.2 (2E)-2-[(Z)-2-aminovinyl]-N′-[1-(phenyl)ethylidene]penta-2,4-dienehydrazide 1(a)
Yield 84%; m.p. 187–188 °C; IR (KBr) Vmax/cm−1: 3280 (N–H), 3010 (Ar, C–H), 1685 (C⚌O), 1589 (C⚌C), 1575 (C⚌N); 1H NMR (CDCl3) δ: 2.37 (s, 3H, CH3), 5.23 (s, 1H, NH), 7.2–7.62 (m, 5H, aromatic). 7.65–8.43 (m, 4H, pyridinyl).
2.1.3 (2E)-2-[(Z)-2-aminovinyl]-N′-[1-(4-chlorophenyl)ethylidene]penta-2,4-dienehydrazide 1(b)
Yield 79%; m.p. 205–206 °C; IR (KBr) Vmax/cm−1: 3295 (N–H), 2980 (Ar, C–H), 1684 (C⚌O), 1589 (C⚌C), 1579 (C⚌N), 670 (C–Cl); 1H NMR (CDCl3) δ: 2.33 (s, 3H, CH3), 5.30 (s, 1H, NH), 6.92–7.42 (m, 4H, aromatic). 7.63–8.45 (m, 4H, pyridinyl).
2.1.4 (2E)-2-[(Z)-2-aminovinyl]-N′-[1-(4-bromophenyl)ethylidene]penta-2,4-dienehydrazide 1(c)
Yield 86%; m.p. 207–208 °C; IR (KBr) Vmax/cm−1: 3290 (N–H), 2985 (Ar, C–H), 1690 (C⚌O), 1595 (C⚌C), 1576 (C⚌N), 430 (C–Br).
2.1.5 (2E)-2-[(Z)-2-aminovinyl]-N′-[1-(4-methoxyphenyl)ethylidene]penta-2,4-dienehydrazide 1(d)
Yield 76%; m.p. 195–196 °C; IR (KBr) Vmax/cm−1: 3293 (N–H), 2988 (Ar, C–H), 1693 (C⚌O), 1610 (C⚌C), 1587 (C⚌N); 1H NMR (CDCl3) δ: 3.67 (s, 3H, OCH3), 2.42 (s, 3H, CH3), 5.34 (s, 1H, NH), 7.2–7.42 (m, 4H, aromatic). 7.58–8.33 (m, 4H, pyridinyl).
2.1.6 (2E)-2-[(Z)-2-aminovinyl]-N′-[1-(4-nitrophenyl)ethylidene]penta-2,4-dienehydrazide 1(e)
Yield 83%; m.p. 209–210 °C; IR (KBr) Vmax/cm−1: 3320 (N–H), 2994 (Ar, C–H), 1688 (C⚌O), 1609 (C⚌C), 1578 (C⚌N), 1510 (N⚌O); 1H NMR (CDCl3) δ: 2.38 (s, 3H, CH3), 5.28 (s, 1H, NH), 7.34–7.62 (m, 4H, aromatic). 7.52–8.3 (m, 4H, pyridinyl).
2.1.7 (2E)-2-[(Z)-2-aminovinyl]-N′-[1-(3-nitrophenyl)ethylidene]penta-2,4-dienehydrazide 1(f)
Yield 80%; m.p. 207–208 °C; IR (KBr) Vmax/cm−1: 3335 (N–H), 2998 (Ar, C–H), 1689 (C⚌O), 1610 (C⚌C), 1588 (C⚌N), 1505 (N⚌O).
2.1.8 Typical procedure for synthesis of 1-acetamido-1-(Aryl) ethyl(1Z,2E,3Z)-2-(2-imino ethylidene)-N-methylpent-3-enimidoate 2(a–f)
A mixture of 0.01 mol of the appropriate compound 1(a–f) and an excess of acetic anhydride was refluxed for 2 h until the completion of the reaction which was monitored by TLC. Excess of acetic anhydride was distilled off and the residue was poured onto crushed ice. The solid thus obtained was filtered; washed with water and was then recrystallized with aqueous methanol to obtain 2(a–f). Analytical and spectral data was obtained for all the compounds.
2.1.9 1-Acetamido-1-(phenyl) ethyl(1Z,2E,3Z)-2-(2-iminoethylidene)-N-methylpent-3-enimidoate 2(a)
Yield 78%; m.p. 154–155 °C; IR (KBr) Vmax/cm−1: 2995 (Ar, C–H), 1695 (C⚌O), 1587 (C⚌C), 1595 (C⚌N, oxadiazolyl), 1586 (C⚌N, pyridinyl); 1H NMR (CDCl3) δ: 2.32 (s, 3H, CH3), 2.18 (s, 3H, COCH3), 6.9–7.58 (m, 5H, aromatic). 7.62–8.23 (m, 4H, pyridinyl).
2.1.10 1-Acetamido-1-(4-chlorophenyl) ethyl(1Z,2E,3Z)-2-(2-iminoethylidene)-N-methylpent-3-enimidoate 2(b)
Yield 87%; m.p. 162–163 °C; IR (KBr) Vmax/cm−1: 2983 (Ar, C–H), 1689 (C⚌O), 1588 (C⚌C), 1592 (C⚌N, oxadiazolyl), 157 (C⚌N), 655 (C–Cl); 1H NMR (CDCl3) δ: 2.31 (s, 3H, CH3), 2.09 (s, 3H, COCH3), 6.91–7.32 (m, 4H, aromatic). 7.58–8.35 (m, 4H, pyridinyl).
2.1.11 1-Acetamido-1-(4-bromophenyl) ethyl(1Z,2E,3Z)-2-(2-iminoethylidene)-N-methylpent-3-enimidoate 2(c)
Yield 78%; m.p. 175–176 °C; IR (KBr) Vmax/cm−1: 2984 (Ar, C–H), 1690 (C⚌O), 1586 (C⚌C), 1593 (C⚌N, oxadiazolyl), 1576 (C⚌N), 465 (C–Br).
2.1.12 1-Acetamido-1-(4-methoxyphenyl)ethyl(1Z,2E,3Z)-2-(2-iminoethylidene)-N-methylpent-3-enimidoate 2(d)
Yield 78%; m.p. 165–166 °C; IR (KBr) Vmax/cm−1: 2986 (Ar, C–H), 1698 (C⚌O), 1589 (C⚌C), 1598 (C⚌N, oxadiazolyl), 1587 (C⚌N); 1H NMR (CDCl3) δ: 3.65 (s, 3H, –OCH3), 2.39 (s, 3H, CH3), 2.09 (s, 3H, COCH3), 6.98–7.27 (m, 4H, aromatic). 7.38–7.98 (m, 4H, pyridinyl).
2.1.13 1-Acetamido-1-(4-nitrophenyl)ethyl(1Z,2E,3Z)-2-(2-iminoethylidene)-N-methylpent-3-enimidoate 2(e)
Yield 78%; m.p. 123–124 °C; IR (KBr) Vmax/cm−1: 2984 (Ar, C–H), 1689 (C⚌O), 1580 (C⚌C), 1594 (C⚌N, oxadiazolyl), 1578 (C⚌N), 1508 (N⚌O); 1H NMR (CDCl3) δ: 2.32 (s, 3H, CH3), 2.07 (s, 3H, COCH3), 7.44–7.67 (m, 4H, aromatic). 7.72–8.14 (m, 4H, pyridinyl).
2.1.14 1-Acetamido-1-(3-nitrophenyl)ethyl(1Z,2E,3Z)-2-(2-iminoethylidene)-N-methylpent-3-enimidoate 2(f)
Yield 78%; m.p. 128–129 °C; IR (KBr) Vmax/cm−1: 2983 (Ar, C–H), 1688 (C⚌O), 1584 (C⚌C), 1593 (C⚌N, oxadiazolyl), 1575 (C⚌N), 1510 (N⚌O).
2.1.15 General procedure for synthesis of N-{(1Z)-1-[2-methyl-2-(aryl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-aromatic amines (PSMB1–PSMB15)
A mixture of 0.01 mol of 2(a–f) and an equimolar amount of appropriate aromatic amines was added to 25 ml ethanol with a drop of glacial acetic acid, was heated under reflux for 5–6 h. The precipitate obtained was filtered-off; washed with cold ethanol and recrystallized from ethanol to give PSMB1–PSMB15. Physical properties are given in Table 1 and Analytical and spectral data were obtained from all the compounds.
| Compound | Ar | Ar1 | Molecular formula | Molecular weight | Color | Yield (%) |
|---|---|---|---|---|---|---|
| PSMB1 |
|
|
C22H20N4O | 356.43 | Light yellow | 68 |
| PSMB2 |
|
|
C22H19N5O3 | 401.43 | Yellow | 69 |
| PSMB3 |
|
|
C22H18ClN5O3 | 435.87 | Light brown | 72 |
| PSMB4 |
|
|
C22H18BrN5O3 | 480.32 | Dark yellow | 73 |
| PSMB5 |
|
|
C23H21BrN4O2 | 465.35 | Light yellow | 65 |
| PSMB6 |
|
|
C23H21N5O4 | 431.45 | Yellowish brown | 68 |
| PSMB7 |
|
|
C22H19N5O3 | 401.43 | Light brown | 72 |
| PSMB8 |
|
|
C22H18N6O5 | 446.43 | Yellow | 70 |
| PSMB9 |
|
|
C23H21N5O4 | 431.45 | Brown | 67 |
| PSMB10 |
|
|
C26H21N5O3 | 451.49 | Yellowish -white | 68 |
| PSMB11 |
|
|
C22H19N5O3 | 401.43 | Light brown | 69 |
| PSMB12 |
|
|
C22H18N6O5 | 446.43 | Dark-yellow | 73 |
| PSMB13 |
|
|
C23H21N5O3 | 415.46 | Brown | 70 |
| PSMB14 |
|
|
C23H21N5O4 | 431.45 | Brown | 63 |
| PSMB15 |
|
|
C26H21N5O3 | 451.49 | Yellowish -white | 64 |
2.1.16 N-[(1Z)-1-(2-methyl-2-phenyl-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl)ethylidene]aniline (PSMB1)
Yield 68%, m.p. 205–206 °C; found: C, 73.85; H, 5.10; N, 15.65. Calc. for C22H20N4O (356.43): C, 74.14; H, 5.66; N, 15.72; IR (KBr) Vmax/cm−1: 2983 (Ar, C–H), 1584 (C⚌C), 1593 (C⚌N, oxadiazolyl), 1575 (C⚌N); 1H NMR (CDCl3) δ: 2.30 (s, 3H, CH3), 2.02 (s, 3H, N⚌C–CH3), 7.2–7.38 (m, 10H, aromatic), 7.45–8.10 (m, 4H, pyridinyl); MS (m/z): 357 (M+1), 358 (M+2).
2.1.17 N-[(1Z)-1-(2-methyl-2-phenyl-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl)ethylidene]-4-nitroaniline (PSMB2)
Yield 69%, m.p. 210–211 °C; found: C, 64.83; H, 4.85; N, 16.25. Calc. for C22H19N5O3 (401.43): C, 65.83; H, 4.77; N, 17.45; IR (KBr) Vmax/cm−1: 2985 (Ar, C–H), 1586 (C⚌C), 1595 (C⚌N, oxadiazolyl), 1510 (N⚌O), 1573 (C⚌N); 1H NMR (CDCl3) δ:2.31 (s, 3H, CH3), 2.01 (s, 3H, N⚌C–CH3), 7.1–7.23 (m, 9H, aromatic), 7.55–8.12 (m, 4H, pyridinyl); MS (m/z): 402 (M+1), 403 (M+2).
2.1.18 N-{(1Z)-1-[2-(4-chlorophenyl)-2-methyl-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-nitroaniline (PSMB3)
Yield 72%, m.p. 233–234 °C; found: C, 61.55; H, 4.10; N, 9.65. Calc. for C22H18ClN5O3 (435.87): C, 60.62; H, 4.16; N, 8.13; IR (KBr) Vmax/cm−1: 2963 (Ar, C–H), 1574 (C⚌C), 1599 (C⚌N, oxadiazolyl), 1517 (N⚌O), 1574 (C⚌N); 1H NMR (CDCl3) δ: 2.28 (s, 3H, CH3), 2.03 (s, 3H, N⚌C–CH3), 6.9–7.18 (m, 8H, aromatic). 7.15–8.0 (m, 4H, pyridinyl); MS (m/z): 437 (M+1), 438 (M+2) (HRMS calcd for C22H18ClN5O3 435.8735, found 435.8741).
2.1.19 N-{(1Z)-1-[2-(4-bromophenyl)-2-methyl-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-nitroaniline (PSMB4)
Yield 73%, m.p. 236–237 °C; found:C, 54.85;H, 4.10; N, 14.65. Calc. for C22H18BrN5O3 (480.32): C, 55.01; H, 3.78; N, 14.58; IR (KBr) Vmax/cm−1: 2963 (Ar, C–H), 1578 (C⚌C), 1597 C⚌N, oxadiazolyl), 1516 (N⚌O), 1569 (C⚌N); 1H NMR (CDCl3) δ: 2.35 (s, 3H, CH3), 2.10 (s, 3H, N⚌C–CH3), 7.4–7.60 (m, 8H, aromatic). 7.65–8.10 (m, 4H, pyridinyl); MS (m/z): 481 (M+1), 482 (M+2) (HRMS calcd for C22H18BrN5O3 480.3245, found 480.3250).
2.1.20 N-{(1Z)-1-[2-(4-bromophenyl)-2-methyl-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-methoxyaniline (PSMB5)
Yield 65%, m.p. 208–209 °C; found: C, 60.15; H, 4.45; N, 12.55. Calc. for C23H21BrN4O2 (465.35): C, 59.36; H, 4.55; N, 12.04; IR (KBr) Vmax/cm−1: 3010 (Ar, C–H), 1576 (C⚌C), 1591 (C⚌N, oxadiazolyl), 1572 (C⚌N); 1H NMR (CDCl3) δ: 2.30 (s, 3H, CH3), 2.04 (s, 3H, N⚌C–CH3), 3.70 (s, 3H, OCH3), 7.1–7.40 (m, 8H, aromatic). 7.45–7.90 (m, 4H, pyridinyl); MS (m/z): 466 (M+1), 467 (M+2) (HRMS calcd for C23H21BrN4O2 465.3534, found 465.3539).
2.1.21 N-{(1Z)-1-[2-methyl-2-(4-methoxyphenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-nitroaniline (PSMB6)
Yield 68%, m.p. 210–211 °C; found: C, 63.89; H, 4.95; N, 15.65. Calc. for C23H21N5O4 (431.45): C, 64.03; H, 4.91; N, 16.23; IR (KBr) Vmax/cm−1: 2993 (Ar, C–H), 1586 (C⚌C), 1598 (C⚌N, oxadiazolyl), 1515 (N⚌O), 1569 (C⚌N); 1H NMR (CDCl3) δ: 2.32 (s, 3H, CH3), 2.01 (s, 3H, N⚌C–CH3), 3.65 (s, 3H, OCH3), 6.5–7.23 (m, 8H, aromatic). 7.35–7.98 (m, 4H, pyridinyl); MS (m/z): 432 (M+1), 433 (M+2).
2.1.22 N-{(1Z)-1-[2-methyl-2-(4-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-aniline (PSMB7)
Yield 72%, m.p. 179–180 °C; found: C, 64.94; H, 4.76; N, 17.85. Calc. for C22H19N5O3 (401.43): C, 65.83; H, 4.77; N, 17.45; IR (KBr) Vmax/cm−1: 2988 (Ar, C–H), 1579 (C⚌C), 1596 (C⚌N, oxadiazolyl), 1518 (N⚌O), 1577 (C⚌N); 1H NMR (CDCl3) δ: 2.29 (s, 3H, CH3), 2.03 (s, 3H, N⚌C–CH3), 7.1–7.23 (m, 9H, aromatic). 7.35–8.12 (m, 4H, pyridinyl); MS (m/z): 402 (M+1), 403 (M+2).
2.1.23 N-{(1Z)-1-[2-methyl-2-(4-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-nitroaniline (PSMB8)
Yield 70%, m.p. 194–195 °C; found: C, 60.25; H, 4.12; N, 19.15. Calc. for C22H18N6O5 (446.43): C, 59.19; H, 4.06; N, 18.83; IR (KBr) Vmax/cm−1: 2983 (Ar, C–H), 1584 (C⚌C), 1593 (C⚌N, oxadiazolyl), 1522 (N⚌O), 1575 (C⚌N); 1H NMR (CDCl3) δ: 2.27 (s, 3H, CH3), 2.1 (s, 3H, N⚌C–CH3), 7.4–7.60 (m, 8H, aromatic). 7.66–8.13 (m, 4H, pyridinyl); MS (m/z) 447 (M+1), 448 (M+2).
2.1.24 N-{(1Z)-1-[2-methyl-2-(4-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-methoxyaniline (PSMB9)
Yield 67%, m.p. 178–179 °C; found: C, 63.94; H, 5.04; N, 16.65. Calc. for C23H21N5O4 (431.45): C, 64.03; H, 4.91; N, 16.23; IR (KBr) Vmax/cm−1: 2983 (Ar, C–H), 1584 (C⚌C), 1593 (C⚌N, oxadiazolyl), 1524 (N⚌O), 1575 (C⚌N); 1H NMR (CDCl3) δ: 2.31 (s, 3H, CH3), 2.04 (s, 3H, N⚌C–CH3), 3.75 (s, 3H, OCH3), 7.2–7.5 (m, 8H, aromatic). 7.6–7.9 (m, 4H, pyridinyl); MS (m/z): 432 (M+1), 433 (M+2).
2.1.25 N-{(1Z)-1-[2-methyl-2-(4-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-1-napthylamine (PSMB10)
Yield 68%, m.p. 172–173 °C; found: C, 69.45; H, 4.56; N, 15.75. Calc. for C26H21N5O3 (451.49): C, 69.17; H, 4.69; N, 15.51; IR (KBr) Vmax/cm−1: 2979 (Ar, C–H), 1579 (C⚌C), 1590 (C⚌N, oxadiazolyl), 1519 (N⚌O), 1573 (C⚌N); 1H NMR (CDCl3) δ: 2.30 (s, 3H, CH3), 2.02 (s, 3H, N⚌C-CH3), 7.34–7.68 (m, 11H, aromatic), 7.74–8.23 (m, 4H, pyridinyl); MS (m/z): 452 (M+1), 453 (M+2).
2.1.26 N-{(1Z)-1-[2-methyl-2-(3-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-aniline (PSMB11)
Yield 69%, m.p. 185–186 °C; found: C, 64.65; H, 4.67; N, 17.65. Calc. for C22H19N5O3 (401.43): C, 65.83; H, 4.77; N, 17.45; IR (KBr) Vmax/cm−1: 2988 (Ar, C–H), 1578 (C⚌C), 1596 (C⚌N, oxadiazolyl), 1528 (N⚌O), 1578 (C⚌N); 1H NMR (CDCl3) δ: 2.31 (s, 3H, CH3), 2.03 (s, 3H, N⚌C-CH3), 7.2–7.38 (m, 9H, aromatic), 7.4–8.2 (m, 4H, pyridinyl); MS (m/z): 402 (M+1), 403 (M+2).
2.1.27 N-{(1Z)-1-[2-methyl-2-(3-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-nitroaniline (PSMB12)
Yield 73%, m.p. 199–200 °C; found: C, 58.45; H, 4.16; N, 17.85. Calc. for C22H18N6O5 (446.43): C, 59.19; H, 4.06; N, 18.83; IR (KBr) Vmax/cm−1: 3012 (Ar, C–H), 1586 (C⚌C), 1598 (C⚌N, oxadiazolyl), 1533 (N⚌O), 1575 (C⚌N); 1H NMR (CDCl3) δ: 2.32 (s, 3H, CH3), 2.01 (s, 3H, N⚌C–CH3), 7.2–7.38 (m, 8H, aromatic), 7.45–8.10 (m, 4H, pyridinyl); MS (m/z): 447 (M+1) 448 (M+2).
2.1.28 N-{(1Z)-1-[2-methyl-2-(3-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-p-toludine (PSMB13)
Yield 70%, m.p. 205–206 °C; found: C, 67.09; H, 5.10; N, 16.65. Calc. for C23H21N5O3 (415.46): C, 66.49; H, 5.09; N, 16.86; IR (KBr) Vmax/cm−1: 2987 (Ar, C–H), 1578 (C⚌C), 1599 (C⚌N, oxadiazolyl), 1575 (C⚌N), 1535 (N⚌O); 1H NMR (CDCl3) δ: 2.32 (s, 3H, CH3), 2.35 (s, 3H, Ar–CH3), 2.05 (s, 3H, N⚌C–CH3), 7.12–7.45 (m, 8H, aromatic). 7.48–7.97 (m, 4H, pyridinyl); MS (m/z): 416 (M+1), 417 (M+2).
2.1.29 N-{(1Z)-1-[2-methyl-2-(3-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-4-methoxyaniline (PSMB14)
Yield 63%, m.p. 184–185 °C; found: C, 63.85; H, 5.10; N, 16.35. Calc. for C23H21N5O4 (431.45): C, 64.03; H, 4.91; N, 16.23; IR (KBr) Vmax/cm−1: 2986 (Ar, C–H), 1583 (C⚌C), 1597 (C⚌N, oxadiazolyl), 1529 (N⚌O), 1576 (C⚌N); 1H NMR (CDCl3) δ:2.34 (s, 3H, CH3), 2.04 (s, 3H, N⚌C–CH3), 3.76 (s, 3H, OCH3), 7.3–7.67 (m, 8H, aromatic), 7.7–8.2 (m, 4H, pyridinyl); MS (m/z): 432 (M+1), 433 (M+2).
2.1.30 N-{(1Z)-1-[2-methyl-2-(3-nitrophenyl)-5-pyridin-4-yl-1,3,4-oxadiazol-3(2H)-yl]ethylidene}-1-napthylamine (PSMB15)
Yield 64%, m.p. 169–170 °C; found: C, 70.85; H, 5.10; N, 15.62. Calc. for C26H21N5O3 (451.49): C, 69.17; H, 4.69; N, 15.51; IR (KBr) Vmax/cm−1: 2989 (Ar, C–H), 1587 (C⚌C), 1599 (C⚌N, oxadiazolyl), 1517 (N⚌O), 1572 (C⚌N); 1H NMR (CDCl3) δ: 2.29 (s, 3H, CH3), 2.04 (s, 3H, N⚌C–CH3), 7.37–7.71 (m, 11H, aromatic), 7.74–8.28 (m, 4H, pyridinyl); MS (m/z): 452 (M+1), 453 (M+2).
2.2 Pulmonary vein relaxant activity
The synthesized compounds PSMB1–PSMB15 were tested in vitro for their pulmonary vein relaxant activity. Pulmonary veins and arteries of adult goat of either sex were brought from a local slaughterhouse. The Media used to carry the muscle was ice-cold Krebs–Henseleit solution. These were cut into spiral strips and were used within 12–24 h. These strips were mounted in 15 ml isolated organ baths, containing Krebs–Henseleit solution, mixed with 95% O2 and 5% CO2 at 37 °C. The composition of the Krebs–Henseleit solution was (mmol/l): NaCl (118), KCI (4.70), and CaCI2, 2H2O (2.5), KH2PO4 (1.2), MgSO4, 7H2O (1.2), NaHCO3 (25.0) and glucose 10.0. The strip was allowed to equilibrate for 2 h under a resting load of 2 g. Relaxation of muscle strip was recorded for each drug using force transducer multichannel physiograph (BIOPAC MP35 SYSTEM). The title compounds were compared with isosorbide dinitrate, a standard drug used for relaxation. Alcohol was used as control. Significance was calculated by using ANOVA followed by the Dunnet ‘t’ test. The relaxation activity data for all compounds are given in Table 2.
| Compounds | Difference in tension (grams)mean ± SEM | % Relaxation (compared with standard) |
|---|---|---|
| PSMB1 | 0.04 ± 0.0070 | 22.2 |
| PSMB2 | 0.02 ± 0.0031 | 11.1 |
| PSMB3 | 0.026 ± 0.004 | 14.44 |
| PSMB4 | 0.028 ± 0.0037 | 15.55 |
| PSMB5 | 0.042 ± 0.0066 | 23.33 |
| PSMB6 | 0.03 ± 0.0031 | 16.66 |
| PSMB7 | 0.082 ± 0.0037 | 45.55 |
| PSMB8 | 0.082 ± 0.0037 | 45.55 |
| PSMB9 | 0.15 ± 0.0037* | 83.33* |
| PSMB10 | 0.028 ± 0. 0037 | 15.55 |
| PSMB11 | 0.038 ± 0.0037 | 21.11 |
| PSMB12 | 0.04 ± 0.0070 | 22.22 |
| PSMB13 | 0.07 ± 0.0044 | 38.88 |
| PSMB14 | 0.05 ± 0.0031 | 27.77 |
| PSMB15 | 0.032 ± 0.0058 | 17.77 |
3 Result and discussion
The various title compounds PSMB1–PSMB15 were synthesized cleanly and in fairly good yields. Their structures were confirmed by an elemental analysis and spectral data. The IR spectrum of these compounds showed C⚌N str. at around 1575 and 1595 cm−1 and alkyl stretching at 3010 cm−1. The compound also exhibited appropriate peaks at the corresponding δ (ppm) (see spectral data) in their 1H NMR spectra, thus confirming their structures. All the synthesized compounds were screened for their pulmonary vein relaxation activity using goat pulmonary vein. As seen in Table 2, compound PSMB9 was found to be the most potent, demonstrating 83.33% relaxation as that of isosorbide dinitrate where as compound PSMB2 was the least potent, exhibiting 11.1% relaxation. The results of the relaxant activity indicate that the presence of parasubstituted aryl ring, with electron withdrawing groups such as 4-nitrophenyl, at C2 atom of oxadiazole, along with the moderate electron donating substituent at N3 position appear to be essential for pulmonary vein relaxation.
Acknowledgments
The authors wish to express their thanks to Dr. F.V. Manvi, Principal, K.L.E.’s College of Pharmacy, Belguam (India) for encouragement and Dr. H.N. More, Principal, Bharati Vidyapeeth College of Pharmacy, Morewadi, Kolhapur (India), for providing the necessary facilities and excellent support. The authors wish to express thanks to IIT, Mumbai and CDRI, Lucknow for the spectral analysis.
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