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Journal of Chemistry
Volume 2018, Article ID 8536063, 11 pages
https://doi.org/10.1155/2018/8536063
Research Article

Synthesis, Characterization, and Antibacterial and Anti-Inflammatory Activities of New Pyrimidine and Thiophene Derivatives

1Department of Chemistry, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
2Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
3Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt

Correspondence should be addressed to Siham Lahsasni; as.ude.usk@insashals

Received 17 May 2018; Revised 1 July 2018; Accepted 10 July 2018; Published 1 August 2018

Academic Editor: Gabriel Navarrete-Vazquez

Copyright © 2018 Siham Lahsasni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Substituted[4,5]thieno[2,3-d]thiazolo[3,2-a]pyrimidin-5-one (3a–b) and pyrimidin-5(6H)-imine (3c–e) were synthesized via reaction of the starting compounds, ethyl 2-amino-substituted[b]thiophene-3-carboxylate (2a–c) and 2-amino-substituted [b]thiophene-3-carbonitrile (2d–f), respectively, with 2-bromothiazole. Synthesis of (bromo-substituted[b]thiophen-2-yl)alkanamide derivatives (4a–e) and thieno[2,3-d][1,3]oxazin-4-imine derivative (5) was accomplished via reaction of the starting compounds with bromoalkyl chloride through nucleophilic substitution; however, for the synthesis of compound 5, nucleophilic substitution was followed by nucleophilic addition to a nitrile group to form the oxazinimine ring. 1-(3-cyano-substituted[b]thiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)thiourea derivatives (6a–c) were obtained via reaction of the starting compounds (2d–f) and 4-(trifluoromethyl phenyl)isothiocyanate. The lead compounds (2d–f) rapidly reacted with 4-(trifluoromethyl)benzaldehyde or 4-(2-pyridyl)benzaldehyde in acidic medium to yield compounds (7a–f) in large quantities. X-ray crystallography of compounds 4c and 7e confirmed their structures. Antimicrobial studies revealed that compound 6a was equally potent to ampicillin against Bacillus strains. Moreover, compounds 3e, 4d, and 6a possessed greater anti-inflammatory potency than that of the standard drug.

1. Introduction

Thiophene, thiazole, and pyrimidine derivatives have been used as therapeutic drugs over years. Figure 1 shows some potent drugs containing thiazole or thiophene ring.

Figure 1: Some drugs containing thiazole, pyrimidine, or thiophene ring.

Dasatinib is a dual Src/Abl [1] and pan-Src [2] kinase inhibitor, zopolrestat [3] and lidorestat [4] are aldose reductase inhibitors used for the treatment of diabetic complications, and raloxifene is the first clinically available selective estrogen receptor modulator (SERM) used to prevent both osteoporosis and breast cancer [58]. In addition, clopidogrel is an antiplatelet agent used to inhibit blood clots in coronary artery disease and to prevent heart attacks and strokes in patients with heart or circulatory diseases [911].

The most efficient protocol for the synthesis of these thiophene derivatives is intramolecular cyclization via nucleophilic displacement [1215], Gewald method [16, 17], thio-Claisen rearrangement [18], and dehydrophotocyclization [19, 20].

Within the scope of these diverse synthetic methods and utility of thiophene-based systems and in continuation to our interest in the design of bioactive heterocycles [2123], we aimed at developing novel heterocyclic compounds containing thiophene, thiazole, and pyrimidine rings, identifying their structures using infrared (IR), 1H nuclear magnetic resonance (1H NMR), 13C NMR spectroscopy, and X-ray, and evaluating their biological effects, in particular, their antimicrobial and anti-inflammatory activities.

2. Materials and Methods

2.1. General Information

Melting points (mp) were determined using an electrothermal digital melting point apparatus and were uncorrected. IR spectra (KBr discs) were recorded using FTIR plus 460 or Pye Unicam SP-1000 spectrophotometer. 1H NMR spectra were recorded using Varian Gemini-200 (200 MHz) and Jeol AS (500 MHz) instruments. Dimethyl sulfoxide- (DMSO-) d6 was used as a solvent, and tetramethylsilane (TMS) was used as an internal standard. Chemical shifts were expressed as δ ppm. Mass spectra were recorded using Hewlett Packard 5988 A GC/MS system and GCMS-QP 1000 Ex Shimadzu instrument. Vario EL III Elemental CHNS analyzer at the Microanalytical Data Unit of Cairo University was used to obtain the analytical data.

2.2. Chemistry
2.2.1. Synthetic Procedure for Substituted [4,5]Thieno[2,3-d]thiazolo[3,2-a]pyrimidine Derivatives (3a–e)

A mixture of the appropriate lead compound (2b–f) (5 mmol), an excess amount of 2-bromothiazole (approximately 1 mL), and few drops of hydrochloric acid in absolute ethanol (3 mL) was refluxed for 3–5 h. The product started to precipitate shortly once the reaction started (within approximately 15 min). The precipitate was filtered, washed with absolute ethanol, dried, and recrystallized from absolute ethanol.

6,7,8,9-Tetrahydro-5H-benzo[4,5]thieno[2,3-d]thiazolo[3,2-a]pyrimidin-5-one (3a). White solid; yield: 30%; mp: 221–222°C; IR (KBr, υmax, cm−1): 3079.1 (CH aromatic), 2930.47 (CH aliphatic), 1675.45 (C=O), and 1563.55, 1516.11 (C=C aromatic); 1H NMR (δ, ppm, CDCl3): 1.878 (m, 4H, J = 6 Hz, H7-8), 2.77 (t, 2H, J = 6 Hz, H9), 3.049 (t, 2H, J = 6 Hz, H6), 6.87 (d, 1H, J = 4.8 Hz, H2), and 7.98 (d, 1H, J = 4.8 Hz, H3); 13C NMR (δ, ppm, CDCl3): 22.253, 22.95, 25.158, 25.618 (C6-9), 109.571 (C2), 116.155 (C5a), 121.652 (C5a′), 130.973 (C3), 131.479 (C9a), 154.951 (C10a), 157.419 (C11a), and 163.835 (C5); and DART-TOF-MS (m/z): 263.03 [M + H]+; anal. calcd. for C12H10N2OS2 (262.02): C, 54.94; H, 3.84; N, 10.68; O, 6.10; and S, 24.44; found: C, 55.04; H, 3.74; N, 10.60; O, 6.17; and S, 24.53.

7,8,9,10-Tetrahydrocyclohepta[4,5]thieno[2,3-d]thiazolo[3,2-a]pyrimidin-5(6H)-one (3b). White solid; yield: 38%; mp: 145–147°C; IR (KBr, υmax, cm−1): 3130.08 (CH aromatic), 2917.76 (CH aliphatic), 1674.41 (C=O), and 1563.5, 1509.46 (C=C aromatic); 1H NMR (δ, ppm, CDCl3): 1.72 (m, 4H, H7, H9), 1.897 (m, 2H, H8), 2.838 (t, 2H, J = 5.4 Hz, H10), 3.365 (t, 2H, J = 4.8 Hz, H6), 6.855 (d, 1H, J = 4.8 Hz, H2), and 7.984 (d, 1H, J = 4.8 Hz, H3); 13C NMR (δ, ppm, CDCl3): 27.212, 27.672, 27.925, 29.895, 32.486 (C6-10), 109.494 (C2), 116.853 (C5a), 121.667 (C5a′), 135.634 (C3), 136.438 (C10a), 155.403 (C11a), 156.982 (C12a), and 162.317 (C5); and DART-TOF-MS (m/z): 277.05 [M + H]+; anal. calcd. for C13H12N2OS2 (276.04): C, 56.50; H, 4.38; N, 10.14; O, 5.79; and S, 23.20; found: C, 56.43; H, 4.40; N, 10.18; O, 5.73; and S, 23.29.

7,8-Dihydrocyclopenta[4,5]thieno[2,3-d]thiazolo[3,2-a]pyrimidin-5(6H)-imine (3c). Dark green solid; yield: 22%; mp < 300°C; IR (KBr υmax, cm−1): 3241.38 (NH), 3073.4 (CH aromatic), 1643.81 (C=N), and 1590.95, 1509.8 (C=C aromatic); 1H NMR (δ, ppm, DMSO-d6): 2.469 (m, 2H, H7), 3.005 (t, 2H, H8), 3.15 (t, 2H, H6), 8.05 (d, 1H, J = 4.8 Hz, H2), 8.653 (d, 1H, J = 4.8 Hz, H3), and 9.172 (s, 1H, NH); and 13C NMR (δ, ppm, DMSO-d6): 27.664, 29.496, 29.971 (C6-8), 108.682 (C2), 118.210 (C5a), 122.395 (C5a′), 136.416 (C8a), 141.138 (C9a), 148.359 (C3), 157.121 (C5), and 168.972 (10a); and DART-TOF-MS (m/z): 248.03 [M + H]+; anal. calcd. for C11H9N3S2 (247.02): C, 53.42; H, 3.67; N, 16.99; and S, 25.92; found: C, 53.47; H, 3.64; N, 17.05; and S, 25.89.

6,7,8,9-Tetrahydro-5H-benzo[4,5]thieno[2,3-d]thiazolo[3,2-a]pyrimidin-5-imine (3d). Yellow solid; yield: 88%; mp < 300°C; IR (KBr, υmax, cm−1): 3281.42 (NH), 3080.16 (CH aromatic), 2929.63 (CH aliphatic), 1643.47 (C=N), and 1564.15, 1504.9 (C=C aromatic); 1H NMR (δ, ppm, DMSO-d6): 1.835 (s, 4H, H7, H8), 2.824 (s, 2H, H6), 2.993 (s, 2H, H9), 8.002 (d, 1H, J = 4.8 Hz, H2), 8.619 (d, 1H, J = 4.8 Hz, H3), and 9.002 (s, 1H, NH); 13C NMR (δ, ppm, DMSO-d6): 21.945, 22.144, 25.471, 25.931 (C6-9), 111.372 (C2), 118.003 (C5a), 122.319 (C5a′), 128.091 (C9a), 135.664 (C10a), 148.596 (C3), 157.573 (C5), and 164.303 (C11a); and DART-TOF-MS (m/z): 262.05 [M + H]+; anal. calcd. for C12H11N3S2 (261.04): C, 55.15; H, 4.24; N, 16.08; and S, 24.53; found: C, 55.09; H, 4.31; N, 16.13; and S, 24.57.

7,8,9,10-Tetrahydrocyclohepta[4,5]thieno[2,3-d]thiazolo[3,2-a]pyrimidin-5(6H)-imine (3e). Light brown solid; yield: 70%; mp < 300°C; IR (KBr, υmax, cm−1): 3270.42 (NH), 3053.25 (CH aromatic), 2906.04 (CH aliphatic), 1639.62 (C=N), and 1556.71, 1501.3 (C=C aromatic); 1H NMR (δ, ppm, DMSO-d6): 1.714, 1.866, 2.953, 3.12 (m, 10H, H6-10), 8.02 (d, 1H, H2), 8.63 (d, 1H, H3), and 9.186 (s, 1H, NH); 13C NMR (δ, ppm, DMSO-d6): 26.485, 26.914, 28.838, 28.93, 30.67 (C6-10), 112.192 (C2), 117.865 (C5a), 122.434 (C5a′), 133.319 (C10a), 139.765 (C11a), 148.941 (C3), 157.204 (C5), and 163.107 (C12a); and DART-TOF-MS (m/z): 276.07 [M + H]+; anal. calcd. for C13H13N3S2 (275.06): C, 56.70; H, 4.76; N, 15.26; and S, 23.28; found: C, 56.74; H, 4.72; N, 15.34; and S, 23.33.

2.2.2. Synthetic Procedure for Compounds (4a–e, 5)

Compounds 2b–f (1.7 mmol) were refluxed in bromoalkanoyl chloride for 2–3 h. Then, the mixture was left at room temperature until the product precipitated. The precipitate was filtered, washed with absolute ethanol, dried, and recrystallized from a mixture of absolute ethanol and methanol.

Ethyl-2-(5-bromopentanamido)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (4a). Greenish white solid; yield: 25%; mp: 57–59°C; IR (KBr, υmax, cm−1): 3271.77 (NH), 2944.81 (CH aliphatic), 1669.36 (C=O), and 1558.46, 1520.71 (C=C aromatic); 1H NMR (δ, ppm, CDCl3): 1.353 (t, 3H, J = 6.6 Hz, -CH2CH3), 1.916 (m, 4H, H3′-4′), 2.356 (m, 2H, J = 6.6 Hz, H5), 2.491 (t, 2H, J = 6.6 Hz, H2′), 2.82 (t, 2H, H6), 2.867 (t, 2H, H4), 3.419 (t, 2H, J = 5.4 Hz, H5′), 4.29 (q, 2H, J = 6.6 Hz, -CH2CH3), and 11.004 (s, 1H, NH); 13C NMR (δ, ppm, CDCl3): 14.271 (-CH2CH3), 22.481, 23.731, 27.908, 28.828, 30.262, 31.940, 32.929, 35.589 (C4-6, C2′-5′), 60.441 (-CH2CH3), 108.083 (C3), 132.169 (C6a), 141.214 (C3a), 151.341 (C=O ester), 166.143 (C=O amide), and 169.11 (C2); and DART-TOF-MS (m/z): 374.04 [M + H]+; anal. calcd. for C15H20BrNO3S (373.03): C, 48.13; H, 5.39; Br, 21.35; N, 3.74; O, 12.82; and S, 8.57; found: C, 48.18; H, 5.24; Br, 21.41; N, 3.69; O, 12.77; and S, 8.52.

5-Bromo-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)pentanamide (4b). White solid; yield: 74%; mp: 149–150°C; IR (KBr, υmax, cm−1): 3468.26 (NH), 2935.12 (CH aliphatic), 2214.8 (CN), 1699.82 (C=O), and 1548.87, 1455.74 (C=C aromatic); 1H NMR (δ, ppm, CDCl3): 1.818–1.967 (m, 8H, H5-6, H3′-4′) 2.569, 2.614 (m, 4H, H4, H7), 2.533 (t, 2H, H2′), 3.433 (t, 2H, H5′), and 9.277 (s, 1H, NH); 13C NMR (δ, ppm, CDCl3): 22.115, 23.065, 23.74, 23.885, 23.954, 31.942, 32.946, 34.794 (C4-7, C2′-5′), 92.316 (C3), 114.814 (CN), 128.083 (C7a), 130.689 (C3a), 147.507 (C2), and 169.829 (C=O amide); and DART-TOF-MS (m/z): 341.03 [M + H]+; anal. calcd. for C14H17BrN2OS (340.02): C, 49.27; H, 5.02; Br, 23.41; N, 8.21; O, 4.69; and S, 9.39; found: C, 49.32; H, 4.98; Br, 23.49; N, 8.17; O, 4.73; and S, 9.31.

5-Bromo-N-(3-cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-2-yl)pentanamide (4c). Beige solid; yield: 82%; mp: 127–129°C; IR (KBr, υmax, cm−1): 3486.48 (NH), 2924.92 (CH aliphatic), 2213.55 (CN), 1696.13 (C=O), and 1544.89, 1441.07 (C=C aromatic); 1H NMR (δ, ppm, CDCl3): 1.656 (m, 4H, H5, H7), 1.85–1.951 (m, H2′-4′), 2.507 (m, 2H, H6), 2.697 (s, 4H, H4, H8), 3.431, 3.567 (m, 2H, H5′), and 8.575 (s, 1H, NH); 13C NMR (δ, ppm, CDCl3): 22.483, 23.725, 27.32, 27.994, 29.044, 31.758, 31.888, 32.003, 34.947 (C4-8, C2′-5′), 95.106 (C3), 115.159 (CN), 131.77 (C8a), 135.465 (C3a), 145.031 (C2), and 169.623 (C=O amide); and DART-TOF-MS (m/z): 355.05 [M + H]+; anal. calcd. for C15H19BrN2OS (354.04): C, 50.71; H, 5.39; Br, 22.49; N, 7.88; O, 4.50; and S, 9.02; found: C, 50.78; H, 5.34; Br, 22.41; N, 7.93; O, 4.47; and S, 8.96.

Ethyl-2-(6-bromohexanamido)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate (4d). White solid; yield: 43%; mp: 66–67°C; IR (KBr, υmax, cm−1): 3360.95 (NH), 2915.27 (CH aliphatic), 1675.80 (C=O), and 1529.22 (C=C aromatic); 1H NMR (δ, ppm, CDCl3): 1.379 (t, 3H, J = 7.2 Hz, -CH2CH3), 1.508 (m, 2H, H4′), 1.594, 1.638 (4H, H5, H7), 1.756 (m, 2H, H3′), 1.826 (s, 2H, H6), 1.888 (m, 2H, H5′), 2.456 (t, 2H, J = 7.2 Hz, H2′), 2.699 (m, 2H, H8), 3.015 (m, 2H, H4), 3.396 (t, 2H, J = 6.6 Hz, H6′), 4.33 (q, 2H, J = 7.2 Hz, -CH2CH3), and 11.2 (s, 1H, NH); 13C NMR (δ, ppm, CDCl3): 14.25 (-CH2CH3), 24.442, 26.936, 27.688, 27.795, 28.247, 28.561, 32.21, 32.417, 33.444, 36.564 (C4-8, C2′-6′), 60.649 (-CH2CH3), 112.668 (C3), 130.843 (C8a), 136.270 (C3a), 145.484 (C=O ester), 166.748 (C=O amide), and 169.554 (C2); and DART-TOF-MS (m/z): 416.09 [M + H]+; anal. calcd. for C18H26BrNO3S (415.08): C, 51.92; H, 6.29; Br, 19.19; N, 3.36; O, 11.53; and S, 7.70; found: C, 51.88; H, 6.34; Br, 19.25; N, 3.31; O, 11.47; and S, 7.79.

6-Bromo-N-(3-cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-2-yl)hexan-amide( 4e). Brown solid; yield: 69%; mp: 104–106°C; IR (KBr, υmax, cm−1): 3420.51 (NH), 2925.32 (CH aliphatic), 2217.32 (CN), 1688.82 (C=O), and 1552.66, 1439.5 (C=C aromatic); 1H NMR (δ, ppm, CDCl3): 1.529 (m, 2H, H4′), 1.66 (m, 4H, H5, H7), 1.765 (m, 2H, H3′), 1.85 (m, 2H, H6), 1.899 (m, 2H, H5′), 2.496 (t, 2H, J = 7.2 Hz, H2′), 2.694 (m, 4H, H4, H8), 3.409 (t, 2H, J = 6.6 Hz, H6′), and 8.91 (s, 1H, NH); 13C NMR (δ, ppm, CDCl3): 24.322, 27.327, 27.665, 27.994, 29.044, 29.067, 31.996, 32.364, 33.406, 35.706 (C4-8, C2′-6′), 95.075 (C3), 115.151 (CN), 131.716 (C8a), 135.411 (C3a), 145.07 (C2), and 169.921 (C=O amide); and DART-TOF-MS (m/z): 369.07 [M + H]+; anal. calcd. for C16H21BrN2OS (368.06): C, 52.03; H, 5.73; Br, 21.64; N, 7.59; O, 4.33; and S, 8.68; found: C, 52.08f H, 5.64; Br, 21.69; N, 7.51; O, 4.37; and S, 8.62.

2-(5-Bromopentyl)-5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,3]oxazin-4-imine (5). White solid; yield: 40%; mp: 174–175°C; IR (KBr, υmax, cm−1): 2936.82 (CH aliphatic), 1664.9 (C=N), and 1588.12 (C=C); 1H NMR (δ, ppm, DMSO-d6): 1.376 (m, 2H, H3′), 1.641–1.816 (m, 8H, H2′, H4′, H7-8), 2.553 (t, 2H, J = 6.6 Hz, H1′), 2.686 (s, 2H, H6), 2.821 (s, 2H, H6), 3.508 (t, 2H, J = 6.6 Hz, H5), and 12.177 (s, 1H, NH); 13C NMR (δ, ppm, DMSO-d6): 22.246, 22.966, 24.821, 25.726, 26.4, 27.343, 32.264, 34.058, 35.469 (C6-9, C1′-5′), 120.778 (C4a), 130.965 (C4a′), 131.395 (C9a), 157.787 (C10a), 159.013 (C4), and 163.559 (C2); and DART-TOF-MS (m/z): 355.05 [M + H]+; anal. calcd. for C15H19BrN2OS (354.04): C, 50.71; H, 5.39; Br, 22.49; N, 7.88; O, 4.50; and S, 9.02; found: C, 50.76; H, 5.32; Br, 22.52; N, 7.85; O, 4.53; and S, 8.96.

2.2.3. General Synthetic Procedure for 1-(3-Cyano-substituted[b]thiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (6a–c)

A mixture of the appropriate compound 2d–f (1.3 mmol) with 1 equivalent of 4-(trifluoromethyl)phenyl isothiocyanate in absolute ethanol was stirred at room temperature for 2–7 h. The precipitate was filtered, washed with absolute ethanol, and dried.

1-(3-Cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (6a). Light brown solid; yield: 31%; mp: 172–174°C; IR (KBr, υmax, cm−1): 3327.76, 3234.11 (NH), 2212.49 (CN), and 1589.8, 1560.47 (C=C); 1H NMR (δ, ppm, DMSO-d6): 2.323 (s, 2H, H5), 2.72 (s, 2H, H6), 2.814 (s, 2H, H4), 7.701 (s, 2H, H2′, H6′), 7.818 (s, 2H, H3′, H5′), 10.71 (s, 1H, NH), and 10.95 (s, 1H, NH); 13C NMR (δ, ppm, DMSO-d6): 27.786, 28.039, 29.649 (C4-5), 115.036 (CN), 123.139 (C3′, C5′), 126.236 (C2′, C6′), and 130.613 (C3a); and DART-TOF-MS (m/z): 368.05 [M + H]+; anal. calcd. for C16H12F3N3S2 (367.04): C, 52.31; H, 3.29; F, 15.51; N, 11.44; and S, 17.45; found: C, 52.27; H, 3.35; F, 15.55; N, 11.38; and S, 17.40.

1-(3-Cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (6b). Light beige solid; yield: 49%; mp: 187–189°C; IR (KBr, υmax, cm−1): 3328.78, 3235.86 (NH), 2210.19 (CN), and 1590.92, 1560.13 (C=C); 1H NMR (δ, ppm, DMSO-d6): 1.74 (s, 4H, H5-6), 2.498 (m, 2H, H7), 2.585 (s, 2H, H4), 7.715 (d, 2H, J = 7.8 Hz, H2′, H6′), 7.838 (d, 2H, J = 7.8 Hz, H3′, H5′), 10.765 (s, 1H, NH), and 11.016 (s, 1H, NH); 13C NMR (δ, ppm, DMSO-d6): 22.146, 23.05, 23.809, 23.848 (C4-7), 96.041 (C3), 114.791 (CN), 123.07 (C3′, C5′), 123.775 (CF3), 125.584 (C4′), 126.297 (C2′, C6′), 128.581 (C3a), 130.988 (C7a), 142.862 (C1′), 148.895 (C2), and 176.728 (C=S); and DART-TOF-MS (m/z): 382.07 [M + H]+ anal. calcd. for C17H14F3N3S2 (381.06): C, 53.53; H, 3.70; F, 14.94; N, 11.02; and S, 16.81; found: C, 53.57; H, 3.64; F, 15.0; N, 11.06; and S, 16.75.

1-(3-Cyano-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-2-yl)-3-(4-(trifluoro-methyl)phenyl)thiourea (6c). Dark beige solid; yield: 32%; mp: 169–171°C; IR (KBr, υmax, cm−1): 3326.54 (NH), 2211.97 (CN), and 1582.92, 1554.87 (C=C); 1H NMR (δ, ppm, DMSO-d6): 1.572 (s, 4H, H5, H7), 1.781 (s, 2H, H6), 2.633–2.674 (m, 4H, H4, H8), 7.705 (d, 2H, J = 8.4 Hz, H2′, H6′), 7.828 (d, 2H, J = 8.4 Hz, H3′, H5′), 10.777 (s, 1H, NH), and 10.937 (s, 1H, NH);13C NMR (δ, ppm, DMSO-d6): 27.334, 28.07, 28.783, 31.78 (C4-8), 98.241 (C3), 115.266 (CN), 122.955 (C3′, C5′), 123.77 (CF3), 125.577 (C4′), 126.274 (C2′, C6′), 131.947(C3a), 135.634 (C8a), 142.855 (C1′), 146.787 (C2), and 176.507 (C=S); DART-TOF-MS (m/z): 396.08 [M + H]+; anal. calcd. for C18H16F3N3S2 (395.07): C, 54.67; H, 4.08; F, 14.41; N, 10.63; and S, 16.21; found: C, 54.77; H, 3.99; F, 14.46; N, 10.68; and S, 16.16.

2.2.4. General Synthetic Procedure for Compounds (7a–f)

Few drops of sulfuric acid were added to a mixture of the appropriate lead compound 2d–f (5.6 mmol) and 1 equivalent of 4-(trifluoromethyl)benzaldehyde or 4-(2-pyridyl)benzaldehyde in absolute ethanol. Precipitation occurred once sulfuric acid was added. The precipitate was filtered, washed with absolute ethanol, and dried.

2-((4-(Trifluoromethyl)benzylidene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (7a). Dark brown solid; yield: 41%; mp: 150–152°C; IR (KBr, υmax, cm−1): 2219.12 (CN), 1678.47 (C=N), and 1567.51, 1536.64 (C=C); 1H NMR (δ, ppm, CDCl3): 2.444 (m, 2H, H5), 2.873 (t, 2H, H6), 2.946 (t, 2H, H4), 7.704 (d, 2H, J = 7.8 Hz, H3′, H5′), 8.033 (d, 2H, J = 7.8 Hz, H2′, H6′), and 8.468 (s, 1H, N=CH); 13C NMR (δ, ppm, CDCl3): 27.379, 28.169, 30.239 (C4-6), 103.913 (C3), 114.492 (CN), 124.611 (CF3), 125.814 (C3′, C5′), 129.44 (C2′, C6′), 133.441 (C4′), 138.087 (C3a), 139.007 (C1′), 145.108 (C6a), 155.649 (C2), and 163.744 (N=CH); and DART-TOF-MS (m/z): 321.07 [M + H]+; anal. calcd. for C16H11F3N2S (320.06): C, 59.99; H, 3.46; F, 17.79; N, 8.75; and S, 10.01; found: C, 60.07; H, 3.39; F, 17.84; N, 8.80; and S, 9.97.

2-((4-(Trifluoromethyl)benzylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (7b). Yellow solid; yield: 78%; mp: 146–147°C; IR (KBr, υmax, cm−1): 2216.15 (CN), 1659.53 (C=N), and 1563.09, 1514.72 (C=C); 1H NMR (δ, ppm, CDCl3): 1.861 (m, 4H, H5, H6), 2.664 (s, 2H, H7), 2.711 (s, 2H, H4), 7.696 (d, 2H, J = 7.8 Hz, H3′, H5′), 8.026 (d, 2H, J = 7.8 Hz, H2′, H6′), and 8.422 (s, 1H, N=CH); 13C NMR (δ, ppm, CDCl3): 21.914, 22.987, 24.282, 25.271 (C4-7), 108.39 (C3), 114.201 (CN), 124.618 (CF3), 125.799 (C3′, C5′), 129.448 (C2′, C6′), 133.426 (C4′), 133.832 (C3a), 135.572 (C1′), 138.102 (C7a), 156.73 (C2), and 158.569 (N=CH); and DART-TOF-MS (m/z): 335.09 [M + H]+; anal. calcd. for C17H13F3N2S (334.08): C, 61.07; H, 3.92; F, 17.05; N, 8.38; and S, 9.59; found: C, 61.12; H, 3.86; F, 16.98; N, 8.42; and S, 9.55.

2-((4-(Trifluoromethyl)benzylidene)amino)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (7c). Yellow solid; yield: 99%; mp: 113–114°C; IR (KBr, υmax, cm−1): 2221.48 (CN), 1684.98 (C=N), and 1547.17, 1517.48 (C=C); 1H NMR (δ, ppm, CDCl3): 1.7 (m, 4H, H5, H7), 1.882 (s, 2H, H6), 2.804 (t, 4H, H4, H8), 7.7 (d, 2H, J = 7.8 Hz, H3′, H5′), 8.026 (d, 2H, J = 7.8 Hz, H2′, H6′), and 8.438 (s, 1H, N=CH); 13C NMR (δ, ppm, CDCl3): 27.073, 27.755, 29.142, 30.691, 31.956 (C4-8), 110.605 (C3), 114.729 (CN), 122.824 (CF3), 125.776 (C3′, C5′), 129.356 (C2′, C6′), 133.150 (C4′), 137.558 (C3a), 138.186 (C1′), 140.624 (C8a), 156.538 (C2), and 156.576 (N=CH); and DART-TOF-MS (m/z): 349.1 [M + H]+; anal. calcd. for C18H15F3N2S (348.09): C, 62.06; H, 4.34; F, 16.36; N, 8.04; and S, 9.20; found: C, 62.12; H, 4.30; F, 16.45; N, 8.0; and S, 9.25.

2-((4-(Pyridin-2-yl)benzylidene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (7d). Yellow solid; yield: 29%; mp: 191–193°C; IR (KBr, υmax, cm−1): 2219.27 (CN), and 1581.62, 1548.56 (C=C); 1H NMR (δ, ppm, CDCl3): 2.433 (m, 2H, J = 7.2 Hz, H5), 2.869 (t, 2H, J = 7.2 Hz, H6), 2.934 (t, 2H, J = 7.2 Hz, H4), 7.273 (t, 1H, H4″), 7.794 (m, 2H, J = 7.2 Hz, H5″, H6″), 8.032 (d, 2H, J = 7.8 Hz, H2′, H6′), 8.106 (d, 2H, J = 7.8 Hz, H3′, H5′), 8.488 (s, 1H, N=CH), and 8.719 (d, 1H, H3″); 13C NMR (δ, ppm, CDCl3): 27.356, 28.215, 30.223 (C4-6), 102.779 (C3), 114.814 (CN), 120.946 (C6″), 122.794 (C4″), 127.294, 129.869 (C2′-3′, C5′-6′), 135.404 (C3a), 136.906 (C1′), 137.887 (C5″), 142.809 (C6a), 144.787 (C4′), 149.884 (C3″), 156.185 (C1″), 157.236 (C2), and 164.986 (N=CH); and DART-TOF-MS (m/z): 330.11 [M + H]+; anal. calcd. for C20H15N3S (329.10): C, 72.92; H, 4.59; N, 12.76; and S, 9.73; found: C, 72.88; H, 4.55; N, 12.81; and S, 9.69.

2-((4-(Pyridin-2-yl)benzylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (7e). Yellow solid; yield: 83%; mp: 191–193°C; IR (KBr, υmax, cm−1): 2214.28 (CN), and 1582.55, 1552.3 (C=C); 1H NMR (δ, ppm, CDCl3): 1.853 (m, 4H, H5-6), 2.68 (d, 4H, H4, H7), 7.272 (m, 1H, H4″), 7.788 (s, 2H, H5″, H6″), 8.019 (d, 2H, J = 7.8 Hz, H2′, H6′), 8.094 (d, 2H, J = 7.8 Hz, H3′, H5′), 8.433 (s, 1H, N=CH), and 8.719 (s, 1H, H3″); 13C NMR (δ, ppm, CDCl3): 21.984, 23.05, 24.299, 25.25 (C4-5), 107.256 (C3), 114.538 (CN), 120.969 (C6″), 122.817 (C4″), 127.278 (C3′, C5′), 129.869 (C2′, C6′), 132.797 (C3a), 135.235 (C1′), 135.434 (C5″), 136.96 (C7a), 142.739 (C4′), 149.853 (C3″), 156.147 (C1″), 158.27 (C2), and 159.749 (N=CH); and DART-TOF-MS (m/z): 344.12 [M + H]+; anal. calcd. for C21H17N3S (343.11): C, 73.44; H, 4.99; N, 12.24; and S, 9.33; found: C, 73.48; H, 4.94; N, 12.31; and S, 9.27.

2-((4-(Pyridin-2-yl)benzylidene)amino)-5,6,7,8-tetrahydro-4H-cyclohepta [b]thiophene-3-carbonitrile (7f). Yellow solid; yield: 86%; mp: 199–200°C; IR (KBr, υmax, cm−1): 2218.75 (CN), and 1582.43, 1546.89 (C=C); 1H NMR (δ, ppm, CDCl3): 1.703 (m, 4H, H5, H7), 1.88 (s, 2H, H6), 2.801 (m, 4H, H4, H8), 7.275 (s, 1H, H4″), 7.795 (m, 2H, H5″, H6″), 8.026 (d, 2H, J = 7.8 Hz, H2′, H6′), 8.102 (d, 2H, J = 7.8 Hz, H3′, H5′), 8.463 (s, 1H, N=CH), and 8.722 (s, 1H, H3″); 13C NMR (δ, ppm, CDCl3): 27.126, 27.809, 29.15, 30.653, 31.994 (C4-8), 109.532 (C3), 115.036 (CN), 120.946 (C6″), 122.771 (C4″), 127.286 (C3′, C5′), 129.777 (C2′, C6′), 135.519 (C3a), 136.462 (C1′), 136.922 (C5″), 140.279 (C8a), 142.701 (C4′), 149.861 (C3″), 156.224 (C1″), 157.726 (C2), and 158.155 (N=CH); and DART-TOF-MS (m/z): 358.14 [M + H]+; anal. calcd. for C22H19N3S (357.13): C, 73.92; H, 5.36; N, 11.75; and S, 8.97; found: C, 73.97; H, 5.29; N, 11.81; and S, 9.02.

2.3. X-Ray Crystallographic Analysis

Compounds 4c and 7e were obtained as single crystals by slow evaporation of the ethanol solution of the pure compounds at room temperature. Crystallographic data were collected using a Bruker APEX-II D8 Venture area diffractometer, equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073, and Cu Kα radiation, λ = 1.54178 Å at 293 (2) K. Cell refinement and data reduction were carried out using Bruker SAINT. SheLXT was used to determine the structure [24, 25]. The final refinement was carried out by the full-matrix least-squares technique with anisotropic thermal data for -non-hydrogen atoms on F-CCDC 1823351 and 1534088 that contain the supplementary crystallographic data for these compounds obtained free of charge from the Cambridge Crystallographic Data Centre (http://www.ccdc.cam.ac.uk/data_request/cif).

2.4. Biology
2.4.1. Evaluation of Antimicrobial Activity

All selected organisms (0.5 McFarland standards) were thoroughly mixed with sterilized Mueller–Hinton agar (MHA). This suspension (25 mL) was placed into Petri dishes (90 mm diameter) and left to cool and solidify by placing the Petri dishes on a cool horizontal surface. A 10 mm diameter well was holed on both sides of the agar plate by using a sterilized hollow cylinder as a template. The formulations and control antibiotics (1 mg/mL) were placed into each well (50 μL) to permit diffusion. All plates were incubated at 37 ± 0.5°C for 24 h in aerobic conditions; the test was performed in triplicate. The antimicrobial activities of the selected formulations and control antibiotics against the tested microorganisms were compared. The diameter of the inhibition zone was measured with a gauge and expressed in mm (mean ± standard deviation (SD)).

2.4.2. Evaluation of Anti-Inflammatory Activity

Fresh whole human blood was collected and mixed with equal volumes of sterilized Alsever’s solution (2% dextrose, 0.8% sodium citrate, 0.05% citric acid, 0.42% sodium chloride, and 100 mL of distilled water). This blood solution was centrifuged at 3,000 rpm for 10 min and then washed three times with an equal volume of normal saline. The volume of blood was measured, and it was reconstituted with normal saline to prepare 10% v/v suspension. The reaction mixture consisted of 1 mL of the test sample in normal saline at different concentrations: 0.5 mL of 10% human red blood cell (HRBC) suspension, 1mL of 0.2 M phosphate buffer, and 1 mL of hypotonic saline. They were incubated at 37°C for 30 min and centrifuged at 3,000 rpm for 30 min. Hemoglobin content in the supernatant was determined spectrophotometrically at 560 nm. Each experiment was performed in triplicate. Diclofenac sodium was used as a standard, and distilled water was used as a control. The blood control represented 100% lysis or zero percent stability.

3. Results and Discussion

3.1. Chemistry

Using the Gewald method for thiophene synthesis, we synthesized the lead compounds (2a–f) (Scheme 1) [26, 27].

Scheme 1: Gewald thiophene synthesis.

A mixture of the appropriate compound (2b–f), 2-bromothiazole, and few drops of hydrochloric acid in ethanol was refluxed for 3–5 h to produce thieno[2,3-d]thiazolo[3,2-a]pyrimidine derivatives (Scheme 2).

Scheme 2: Synthesis of thieno[2,3-(d)]thiazolo[3,2-(a)]pyrimidine derivatives (3a–e).

This reaction involves nucleophilic substitution in bromothiazole followed by nucleophilic substitution on the ester group to form the pyrimidinone ring (compounds 3a–b). However, for compounds 3c–e, nucleophilic substitution was followed by nucleophilic addition of a cyanide group to the thiazole nitrogen to form the pyrimidinimine ring.

IR, 1H NMR, 13C NMR, and mass spectral data of the polycyclic compound 3a and new compounds 3b–e were consistent with the assigned structures. The IR spectrum of compound 3b showed an absorption band at 1674.41 cm−1 for the carbonyl group, whereas there was no amino group absorption band. The 1H NMR spectrum showed the presence of the cycloheptenyl protons and appearance of new signals: two doublet signals at δ = 6.855 and 7.984 ppm (each integrates for one proton corresponding to the two protons of the thiazole ring) with coupling constant (J) = 4.8 Hz, whereas there was no signal for the ethyl group linked to the ester group. In 13C NMR, the three carbons of the thiazole group appeared at δ = 109.494, 121.667, and 156.982 ppm, carbonyl peak appeared at δ = 162.317 ppm, and no peaks for the ethyl group. Finally, the direct analysis in real-time/time-of-flight mass spectrometry (DART-TOF-MS) spectrum showed a molecular ion peak [M + H]+ at m/z = 277.05.

The lead compounds (2b–f) were refluxed in bromoalkanoyl chloride derivatives (Scheme 3) to produce compounds (4a–e) by nucleophilic substitution reaction.

Scheme 3: Synthesis of compounds 4a–e.

However, the nucleophilic substitution reaction between compound 2e and 6-bromohexanoyl chloride was followed by nucleophilic addition of a cyanide group to the carbonyl oxygen to form the oxazinimine ring of the novel compound 5 (Scheme 4).

Scheme 4: Synthesis of thieno[2,3-(d)][1,3]oxazin-4-imine derivative (5).

The IR data of compound 4d showed the appearance of an NH absorption band at 3360.95 cm−1 and another absorption band with two heads at 1675.80 cm−1, which represents the two carbonyl groups. In 1H NMR, five new signals appeared: multiplet at δ = 1.508, 1.756, and 1.888 ppm and triplet at δ = 2.456 and 3.396 ppm (each signal integrates for two protons corresponding to the protons of the side chain). In addition, one proton singlet signal for NH appeared at δ = 11.2 ppm. The 13C NMR spectrum showed the appearance of the five carbons of the side chain in the aliphatic range; besides, it showed signals for the cycloheptenyl carbons in the range of δ = 24.442–36.564 ppm and a peak for the amide group at δ = 166.748 ppm. Finally, the DART-TOF-MS spectrum showed a molecular ion peak [M + H]+ at m/z = 416.09.

For compound 5, the disappearance of the cyanide absorption band in the IR spectrum, appearance of one proton signal for NH at δ = 12.177 ppm in the 1H NMR spectrum, and appearance of carbon peaks at δ = 159.013 and 163.559 ppm for C4 and C2, respectively, in the 13C NMR spectrum proved the formation of the oxazinimine ring. The six protons of the side chain appeared in the 1H NMR spectrum as multiplet signals at δ = 1.376 and 1.641–1.816 ppm for H2–H4′ and two triplet signals at δ = 2.533 and 3.508 ppm for H1′ and H5′, respectively (each signal integrates for two protons). Moreover, the 13C NMR spectrum showed the five carbons of the side chain in the aliphatic range. Finally, the molecular weight was confirmed by the appearance of a molecular ion peak [M + H]+ at m/z = 355.05 in the DART-TOF-MS spectrum.

A mixture of the appropriate lead compound (2d–f) and 4-(trifluoromethyl phenyl) isothiocyanate in absolute ethanol was stirred at 25°C for 2–7 h. The new thiophene-thiourea derivatives (6a–c) were obtained by nucleophilic addition (Scheme 5).

Scheme 5: Synthesis of thiophene-thiourea derivatives (6a–c).

Structures of compounds (6a–c) were confirmed by the presence of a cyanide group and appearance of (4-(trifluoromethyl)phenyl)thiourea bands and peaks in the IR, 1H NMR, and 13C NMR spectra. Herein, for compound 6b, the IR spectrum showed two absorption bands for the two NH groups at 3328.78 and 3235.86 cm−1 and an absorption band for cyanide at 2210.19 cm−1. The 1H NMR spectrum showed a doublet signal (2 H) with J = 7.8 Hz at δ = 7.715 ppm for H2′ and H6′, doublet signal (2 H) with J = 7.8 Hz at δ = 7.838 ppm for H3′ and H5′, and two singlet signals for NH at δ = 10.765 and 11.016 ppm (each integrates for one proton). The 13C NMR spectrum showed a peak for cyanide at δ = 114.791 ppm; additionally, the phenyl ring carbons appeared as follows: C3′ and C5′ at δ = 123.07 ppm, C2′ and C6′ at δ = 126.297 ppm, C4′ at δ = 130.988 ppm, and C1′ at δ = 142.862 ppm. CF3 appeared at δ = 123.77 ppm, whereas the thionyl group appeared at δ = 176.728 ppm. Finally, the molecular weight was confirmed by the appearance of a molecular ion peak [M + H]+ at m/z = 382.07 in the DART-TOF-MS spectrum.

Addition of few drops of sulfuric acid to a mixture of the appropriate lead compound (2d–f) and 4-(trifluoromethyl) benzaldehyde or 4-(2-pyridyl) benzaldehyde in absolute ethanol resulted in instant precipitation of the product (Scheme 6).

Scheme 6: Synthesis of thiophene-3-carbonitrile derivatives (7a–f).

All structures of the novel synthesized compounds (7a–f) were confirmed by the existence of a cyanide group, disappearance of NH2, and appearance of 4-(trifluoromethyl)benzylidene or 4-(pyridin-2-yl)benzylidene bands and peaks in the IR, 1H NMR, and 13C NMR spectra. For instance, compound 7d showed a cyanide absorption band at 2219.27 cm−1 and disappearance of the NH2 bands in the IR spectrum. The 1H NMR spectrum showed signals of the pyridyl ring protons as follows: a triplet signal (1 H) at δ = 7.273 ppm for H4″, multiplet signal (2 H) at δ = 7.794 ppm for H5″ and H6″, and doublet signal at δ = 8.719 ppm for H3″. In addition, the four protons of the benzene ring appeared as two doublet signals (each integrates for two protons) with J = 7.2 Hz at δ = 8.032 and 8.106 ppm. Moreover, an N=CH singlet signal (1 H) appeared at δ = 8.488 ppm. 13C NMR showed a cyanide peak (δ = 114.814 ppm), pyridyl ring peaks (C6″ at δ = 120.946 ppm, C4″ peak at δ = 122.794 ppm, C5″ peak at δ = 137.887 ppm, C3″ peak at δ = 149.884 ppm, and C1″ peak at δ = 156.185 ppm), benzene ring peaks (C2′ and C3′ at δ = 127.294, C5′ and C6′ at 129.869 ppm, C1′ at δ = 136.906 ppm, and C4′ at δ = 144.787 ppm), and N=CH peak at δ = 164.986 ppm. DART-TOF-MS confirmed the molecular weight of the expected structure, as evidenced by the appearance of a molecular ion peak [M + H]+ at m/z = 330.11.

3.2. X-Ray Crystallography

The structures of three of the synthesized compounds (4c, 7e) were examined by X-ray crystallography. The crystallographic data and refinement information are summarized in Table 1. As shown in Figure 2, the asymmetric units contained one independent molecule.

Table 1: Experimental detail of the crystalline structures of 4c and 7e.
Figure 2: ORTEP diagrams of the titled compounds 4c and 7e. Displacement ellipsoids are plotted at the 40% probability level for non-H atoms.
3.3. Biology
3.3.1. Evaluation of Antimicrobial Activity

An in vitro antimicrobial study was performed using the agar diffusion method to evaluate the ability of the synthesized compounds to inhibit microbial growth, as previously described by Bonev et al. [28]. The antimicrobial activities of the synthesized compounds (3a–c, 3e, 4e, 4b-c, 5, and 6a–c) were tested against some selected microorganisms, including Staphylococcus aureus, Bacillus species, Escherichia coli, Klebsiella species, Salmonella species, Pseudomonas species, and Candida albicans (Table 2).

Table 2: The zones of inhibition (mm) of the synthesized compounds and standard antimicrobial drugs.

As shown in Table 2, results of the antimicrobial activity studies revealed that the test compounds displayed variable inhibitory effects against the growth of the tested bacteria. Interestingly, compound 6a was equally potent to ampicillin against Bacillus species. The antimicrobial potencies of other derivatives, particularly compound 5 (against Klebsiella and Bacillus), were potentially comparable to those of ampicillin. The antifungal activity study revealed that the tested compounds exhibited no activity against Candida albicans.

3.3.2. Evaluation of Anti-Inflammatory Activity

Compounds 3a–c, 3e, 4a–e, 5, 6a–c, and 7a–f were screened in vitro for anti-inflammatory activity, using a method previously described by Mahajan et al. [29]. The anti-inflammatory activity of the thiazole and thiophene derivatives (Table 3) showed that compounds 3e, 4b, and 6a possessed more potent anti-inflammatory activity than that of diclofenac sodium. Compounds 4d and 7b showed good anti-inflammatory activity, whereas compounds 5, 7d, and 7f showed moderate activity.

Table 3: In vitro anti-inflammatory activity of the synthesized compounds and standard drug (diclofenac sodium).

4. Conclusions

In this study, we successfully synthesized some thiazole, pyrimidine, and thiophene derivatives. Among them, fifteen new target compounds were prepared. In addition, seven compounds (4c, 7e) were successfully obtained as pure crystals. Antimicrobial activity studies revealed that the test compounds displayed broad antibacterial spectrum and good potency. Interestingly, compound 6a was equally potent to ampicillin against Bacillus strains. According to the anti-inflammatory activity test, compounds 3e, 4b, and 6a possessed greater anti-inflammatory potency than that of the standard drug. Therefore, compound 6a was shown to exhibit both antibacterial and anti-inflammatory activities, which could be beneficial in the treatment of various diseases.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support.

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