Home Physical Sciences 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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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

  • Nisheeth C. Desai EMAIL logo and Malay J. Bhatt
Published/Copyright: May 25, 2016
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 22 Issue 3

Abstract

In continuation of our work towards synthesizing bio-active molecules we developed and optimized the methodology for novel N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide analogues from readily available starting materials. We focused on the pressing demand to find eco-friendly pathways by means of catalytic optimization of the process. All synthesized compounds were screened for in vitro antibacterial and antifungal activities on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus pyogenes, Candida albicans, Aspergillus niger, and Aspergillus clavatus species.

Keywords: antimicrobial; 2-azetidinone; catalyst; indole; β-lactam; MIC; 1,2,3,4-tetrahydropyrimidine

Introduction

Recently our group has synthesized indole derivatives as antimicrobial agents [1]. The indole system is an important structural component of many pharmaceutical agents, such as antidepressant [2], anticonvulsant [3], antifungal [4], antiviral [5] and anti-inflammatory [6] drugs. Indole alkaloids also show antibacterial activity [7]. The C-3-substituted indoles are an important core moiety for the synthesis of many biologically active inhibitors of HIV-1 [8], antioxidant [9] and cytotoxic [10] agents. Another biologically important agents are tetrahydropyrimidines. Few efficient synthetic methods for synthesis of polysubstituted tetrahydropyrimidines have been reported [11]. Pyrimidine based analogous are widely known as, anti-inflammatory agents, COX inhibitors, anticancer, antiallergic, analgesic [12, 13], antiviral and antimicrobial agents [14, 15]. The β-lactams are the third biologically important class of compounds. The β-lactam skeleton is the key structural unit responsible for the antibacterial property of the most widely employed antibacterial agents [16]. 2-Azetidinones demonstrate numerous other interesting biological properties, and they are inhibitors of cholesterol absorption [17], human cytomegalovirus (HCMV), protease [18] and thrombin [19]. Several derivatives are antihyperglycemic [20], antitumor [21], anti-HIV [22], anti-inflammatory, analgesic [23], antimalarial [24], antifungal [25] and antiproliferative agents. Several selected bioactive derivatives of the three systems mentioned above are shown in Figure 1.

Figure 1 Marketed drugs having structural similarity with compounds 4a–o.
Figure 1

Marketed drugs having structural similarity with compounds 4a–o.

The first synthesis of 1,2,3,4-tetrahydropyrimidines has been reported by Biginelli [26]. In this paper we report synthesis of tetrahydropyrimidine derivatives 4a–o that are substituted with indole and β-lactam moieties. Only a single research paper has reported synthesis of a single member of this class of compounds [27].

Results and discussion

Chemistry

The indolylpyrimidine 1 was synthesized by one-pot three-component Biginelli reaction (Scheme 1). The preparation of 1 was optimized by using different solvents including acetonitrile, methanol, ethanol, DMF, THF, PPA and various catalysts including HCl, H2SO4, and a large number of inorganic salts. The best yield of 1 of 94% was obtained by reacting indole-3-carboxaldehyde (0.75 mol), ethyl acetoacetate (0.75 mol) and thiourea (0.50 mol) in ethanol in the presence of the catalyst SnCl2·2H2O (15 mmol). Ethanol was the standard azeotropic mixture containing 95% of EtOH. In the second step, a hydrazide 2 was prepared by treatment of compound 1 with hydrazine hydrate. Then, Schiff bases 3 were prepared by condensation of the hydrazide 2 with aromatic aldehydes. Cyclization of compounds 3 in the presence of triethylamine furnished the desired β-lactams 4a–o. The final products were thoroughly characterized by elemental analysis and spectral methods. These compounds were screened for antimicrobial activity.

Scheme 1 Synthesis route for preparation of compounds 4a–o.
Scheme 1

Synthesis route for preparation of compounds 4a–o.

Antimicrobial activity

The activity of compounds was determined as per the National Committee for Clinical Laboratory Standards (NCCLS) protocol using Mueller–Hinton Broth (t–Diackinss on, USA) [28–33]. All compounds were evaluated against Gram-positive bacteria (S. aureus, S. pyogenes), Gram-negative bacteria (E. coli, P. aeruginosa) and fungi (C. albicans, A. niger and A. clavatus) strains. Ciprofloxacin (for bacteria) and griseofulvin (for fungi) were used as the reference antibiotics. The results for the most active compounds are given in Table 1. As can be seen, compound 4e is the most promising antibacterial agent. Compound 4n exhibits excellent activity against A. clavatus with the MIC value that is several-fold higher (12.5–25 μg/mL) than the MIC value of the reference drug griseofulvin.

Table 1

Biological screening results of the most active compounds.

No.Minimum inhibitory concentration (MIC) for bacteria (μg/mL)Minimum inhibitory concentration (MIC) for fungi (μg/mL)
E. coli MTCC 443P. aeruginosa MTCC 1688S. aureus MTCC 96S. pyogenes MTCC 442C. albicans MTCC 227A. niger MTCC 282A. clavatus MTCC 1323
4a––––500––
4b––––500––
4e25–12.550100100–
4f––––500––
4k255050500–100
4l––––10050–
4n––––500–25
4o––50–250––
Ciprofloxacin25255050–––
Griseofulvin––––500100100

Bold values indicate the standard MIC of standard drugs.

Conclusion

SnCl2·2H2O is a highly active heterogeneous solid catalyst for the Biginelli reaction leading to the key substrate 1. The synthesized compounds 4a–o were screened for their in vitro antibacterial and antifungal activity. The new compounds 4a–o presented here clearly differ in their antimicrobial activity depending on the type of substituent in hybrid molecules. It can be seen from the activity results that halogen derivatives are as the most potent agents against bacterial strains and fungal strains. Compounds 4e, 4k and 4o exhibit outstanding antibacterial properties. Compounds 4l and 4n are antifungal agents.

Experimental

The progress of the reactions was monitored and purity of compounds 4a–o were checked on TLC [aluminum plates coated with silica gel 60, F245 (E. Merck)] eluting with chloroform/methanol (9:1). Elemental analysis was carried out on a Perkin-Elmer 2400 CHN analyzer. IR spectra were recorded on a Perkin-Elmer FT-IR spectrophotometer in KBr pellets. 1H NMR spectra (300 MHz) were recorded on a Varian Gemini 300, and 13C NMR spectra (100 MHz) were recorded on a Varian Mercury-400 spectrometer in DMSO-d6 with tetramethylsilane as the internal reference. Melting points are not corrected. Mass spectra were scanned on a Shimadzu LC-MS 2010 spectrometer.

Ethyl 4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1)

Compound 1 was synthesized according to the literature procedure [26] with the following modification. Thiourea (0.5 mol), ethyl acetoacetate (0.75 mol) and indole-3-carbaldehyde (0.75 mol) were dissolved in ethanol (95%) (35 mL). Amongst various catalysts tested for the reaction; SnCl2·2H2O was found to be highest yielding (96%) catalyst. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was cooled and red crystals were separated. The pure product obtained as red solid was filtered and dried. It was further crystallized from methanol: yield 94%; mp 247°C; IR: 3560, 3353, 3054, 2921, 2863, 1725, 1180 cm-1; 1H NMR: δ 11.52 (s, 1H), 10.8 (s, 1H), 7.86 (s, 1H), 6.9–7.6 (m, 5H), 4.05 (q, J = 7 Hz, 2H), 4.26 (s, 1H), 2.32 (s, 3H), 1.20 (t, J = 7 Hz, 3H); 13C NMR: δ 180.1, 168.6, 159.8, 135.6, 128.4, 122.7, 111.3, 104.6, 62.1, 57.2, 18.4, 14.6; LC-MS: m/z 315.10 (M+). Anal. Calcd for C16H17N3O2S: C, 61.32; H, 4.82; N, 13.41. Found: C, 61.28; H, 4.89; N, 13.32.

4-(1H-Indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (2)

A mixture of compound 1 (0.01 mol), hydrazine hydrate (0.01 mol) and SnCl2·2H2O (15 mmol) in 1,4-dioxane (20 mL) was heated under reflux for 8 h, then cooled and poured onto crushed ice. The resultant greenish precipitate was filtered, dried and crystallized from 95% ethanol: yield 80%; mp 208°C; IR: 3545, 3330, 2145, 3063, 2915, 2856, 1192 cm-1; 1H NMR: δ 11.52 (s, 1H), 10.8 (s, 1H), 9.42 (s, 1H), 7.86 (s, 1H), 6.9–7.6 (m, 5H), 4.55 (s, 2H), 4.18 (s, 1H), 2.3 (s, 3H); 13C NMR: δ 179.5, 165.3, 159.4, 137.2, 127.6, 123, 111.4, 59.4, 19.3; LC-MS: m/z 301.10 (M+). Anal. Calcd for C14H15N5OS: C, 55.80; H, 5.02; N, 23.24. Found: C, 55.72; H, 5.11; N, 23.32.

N′-Benzylidene-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazides 3a–o

The following procedure for 3a is representative. Other hydrazides were obtained in a similar way. A mixture of benzaldehyde (0.01 mol), 4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (2, 0.01 mol) and a catalytic amount of glacial acetic acid in ethanol (10 mL) was heated under reflux for 5–6 h. After cooling, the resulting crystals were filtered and crystallized from 95% ethanol to give 3a in a 78% yield; mp 190°C; IR: 3545, 3330, 2145, 3063, 2915, 2856, 1665, 1177 cm-1; 1H NMR: δ 11.47 (s, 1H), 10.86 (s, 1H), 9.42 (s, 1H), 8.16 (s, 1H), 6.95–7.88 (m, 10H), 4.10 (s, 1H), 2.25 (s, 3H); 13C NMR: δ 179.3, 167.9, 158.4, 146.4, 133.5, 128.6, 122.3, 119.1, 112.4, 58.5, 18.4; LC-MS: m/z 389.13 (M+). Anal. Calcd for C21H19N5OS: C, 64.76; H, 4.92; N, 17.98. Found: C, 64.76; H, 4.92; N, 17.98.

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 4a–o

A mixture of 2-chloroacetyl chloride (0.02 mol), N′-benzylidene-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbohydrazide (3a–o, 0.01 mol) and triethylamine (0.02 mol) was heated under reflux for 4 h, then cooled and poured into ice-cold water. The precipitate was filtered, washed with water, dried and crystallized from DMF/ethanol to give product 4a–o.

N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-4-(1H-indol-3-yl)- 6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4a)

Yield 80%; mp 172°C; IR: 3530, 3327, 3058, 2928, 2866, 2138, 1784, 1589, 1180, 762 cm-1; 1H NMR: δ 11.72 (s, 1H) 11.47 (s, 1H), 10.86 (s, 1H), 8.18 (s, 1H), 6.85–7.97 (m, 10H), 5.5 (s, 1H), 5.10 (s, 1H), 4.14 (s, 1H), 2.16 (s, 3H); 13C NMR: δ 180.2, 165.6, 163.2, 159.6, 135.6, 128.5, 124.1, 119.8, 111.1, 106.6, 67.5, 64.9, 59.5, 19.4; LC-MS: m/z 465.10 (M+). Anal. Calcd for C23H20ClN5O2S: C, 59.29; H, 4.33; N, 15.03. Found: C, 59.17; H, 4.40; N, 15.17.

N-(3-Chloro-2-(2-hydroxyphenyl)-4-oxoazetidin-1-yl)-4- (1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxamide (4b)

Yield 65%; mp 170°C; IR: 3545, 3335, 3280, 3053, 2932, 2858, 2147, 1793, 1648, 1161, 744 cm-1; 1H NMR: δ 11.78 (s, 1H), 11.55 (s, 1H), 10.89 (s, 1H), 9.62 (s, 1H), 8.15 (s, 1H), 6.80–7.91(m, 9H), 5.46 (s, 1H), 5.17 (s, 1H), 4.20 (s, 1H), 2.11 (s, 3H); 13C NMR: δ 180.2, 165.2, 163.4, 158.7, 154.4, 136.6, 127.7, 121.7, 115.8, 112.4, 106.9, 67.4, 64.9, 61.5, 59.3, 19.3; LC-MS: m/z 481.10 (M+). Anal. Calcd for C23H20ClN5O3S: C, 57.32; H, 4.18; N, 14.53. Found: C, 57.44; H, 4.25; N, 14.47.

N-(3-Chloro-2-(3-hydroxyphenyl)-4-oxoazetidin-1-yl)-4- (1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxamide (4c)

Yield 61%; mp 196°C; IR: 3538, 3338, 3295, 3061, 2942, 2849, 2137, 1798, 1648, 1168, 750 cm-1; 1H NMR: δ 11.75 (s, 1H), 11.51 (s, 1H), 10.83 (s, 1H), 9.57 (s, 1H), 8.19 (s, 1H), 6.85–7.97 (m, 9H), 5.52 (s, 1H), 5.25 (s, 1H), 4.24 (s, 1H), 2.13 (s, 3H); 13C NMR: δ 180.4, 165.7, 163.7, 158.4, 153.7, 135.6, 128.2, 122.1, 116.3, 111.1, 106.5, 67.1, 65.2, 59.8, 19.7; LC-MS: m/z 481.10 (M+). Anal. Calcd for C23H20ClN5O3S: C, 57.32; H, 4.18; N, 14.53. Found: C, 57.28; H, 4.30; N, 14.62.

N-(3-Chloro-2-(4-hydroxyphenyl)-4-oxoazetidin-1-yl)-4- (1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4d)

Yield 63%; mp 185°C; IR: 3526, 3318, 3278, 3061, 2934, 2844, 2126, 1785, 1646, 1156, 742 cm-1; 1H NMR: δ 11.78 (s, 1H), 11.55 (s, 1H), 10.78 (s, 1H), 9.53 (s, 1H), 8.15 (s, 1H), 6.79–7.87 (m, 9H), 5.46 (s, 1H), 5.20 (s, 1H), 4.27 (s, 1H), 2.17 (s, 3H); 13C NMR: δ 180.9, 164.8, 163.4, 158.6, 153.7, 135.2, 127.7, 121.9, 116.6, 111.5, 106.4, 67.9, 64.5, 58.9, 19.5; LC-MS: m/z 481.10 (M+). Anal. Calcd for C23H20ClN5O3S: C, 57.32; H, 4.18; N, 14.53. Found: C, 57.48; H, 4.25; N, 14.55.

N-(3-Chloro-2-(2-chlorophenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4e)

Yield 65%; mp 198°C; IR: 3545, 3324, 3066, 2928, 2852, 2135, 1778, 1630, 1172, 760, 605 cm-1; 1H NMR: δ 11.80 (s, 1H), 11.50 (s, 1H), 10.69 (s, 1H), 8.16 (s, 1H), 6.92–7.70 (m, 9H), 5.43 (s, 1H), 5.25 (s, 1H), 4.21 (s, 1H), 2.12 (s, 3H); 13C NMR: δ 180.3, 165.4, 163.8, 159.5, 143.6, 132.4, 127.5, 123.4, 119.5, 111.3, 106.7, 67.4, 64.1, 58.7, 18.7; LC-MS: m/z 499.06 (M+). Anal. Calcd for C23H19Cl2N5O2S: C, 55.21; H, 3.83; N, 14.00. Found: C, 55.38; H, 3.75; N, 13.92.

N-(3-Chloro-2-(3-chlorophenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4f)

Yield 64%; mp 176°C; IR: 3536, 3338, 3054, 2940, 2863, 2144, 1790, 1655, 1163, 778, 680; 1H NMR: δ 11.84 (s, 1H), 11.53 (s, 1H), 10.64 (s, 1H), 8.18 (s, 1H), 6.95–7.66 (m, 9H), 5.48 (s, 1H), 5.29 (s, 1H), 4.26 (s, 1H), 2.10 (s, 3H); 13C NMR: δ 180.5, 165.6, 163.4, 159.3, 143.2, 132.8, 128.2, 123, 119.8, 111.5, 106.6, 67.6, 64.7, 58.4, 18.6; LC-MS: m/z 499.06 (M+). Anal. Calcd for C23H19Cl2N5O2S: C, 55.21; H, 3.83; N, 14.00. Found: C, 55.35; H, 3.94; N, 13.79.

N-(3-Chloro-2-(4-chlorophenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4g)

Yield 67%; mp 224°C; IR: 3530, 3350, 3043, 2952, 2870, 2148, 1778, 1662, 1175, 765, 675 cm-1; 1H NMR: δ 11.81 (s, 1H), 11.49 (s, 1H), 10.67 (s, 1H), 8.21 (s, 1H), 6.90–7.68 (m, 9H), 5.51 (s, 1H), 5.31 (s, 1H), 4.28 (s, 1H), 2.13 (s, 3H); 13C NMR: δ 180.6, 165.7, 163.3, 158.9, 143.4, 133, 128.5, 123, 119.6, 111.1, 106.8, 67.8, 64.8, 58.3, 18.7; LC-MS: m/z 499.06 (M+). Anal. Calcd for C23H19Cl2N5O2S: C, 55.21; H, 3.83; N, 14.00. Found: C, 55.19; H, 3.80; N, 14.04.

N-(3-Chloro-2-(2-nitrophenyl)-4-oxoazetidin-1-yl)-4-(1H-indol- 3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4h)

Yield 58%; mp 210°C; IR: 3522, 3357, 3035, 2965, 2882, 2148, 1780, 1650, 1520, 1370, 1171, 759 cm-1; 1H NMR: δ 11.81 (s, 1H), 11.53 (s, 1H), 10.72 (s, 1H), 8.27 (s, 1H), 6.90–7.68 (m, 9H), 5.46 (s, 1H), 5.04 (s, 1H), 4.22 (s, 1H), 2.15 (s, 3H); 13C NMR: δ 180.7, 165.5, 163.2, 159.4, 147.6, 137.7, 136.4, 127.6, 122.8, 112.3, 106.8, 66.3, 64.7, 58.6, 19.2; LC-MS: m/z 510.95 (M+). Anal. Calcd for C23H19ClN6O4S: C, 54.07; H, 3.75; N, 16.45. Found: C, 54.19; H, 3.81; N, 16.37.

N-(3-Chloro-2-(3-nitrophenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4i)

Yield 62%; mp 234°C IR: 3538, 3368, 3024, 2955, 2890, 2155, 1775, 1639, 1532, 1357, 1149, 750 cm-1; 1H NMR: δ 11.78 (s, 1H), 11.55 (s, 1H), 10.69 (s, 1H), 8.22 (s, 1H), 6.82–7.56 (m, 9H), 5.51 (s, 1H), 5.08 (s, 1H), 4.25 (s, 1H), 2.10 (s, 3H); 13C NMR: δ 180.5, 165.3, 162.8, 159.7, 147.3, 137.2, 135.9, 127.8, 122.6, 112.1, 106.3, 66.5, 64.9, 58.3, 19.3; LC-MS: m/z 510.95 (M+). Anal. Calcd for C23H19ClN6O4S: C, 54.07; H, 3.75; N, 16.45. Found: C, 54.18; H, 3.83; N, 16.52.

N-(3-Chloro-2-(4-nitrophenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carboxamide (4j)

Yield 63%; mp 245°C; IR: 3545, 3376, 3030, 2968, 2878, 2145, 1785, 1645, 1526, 1368, 1158, 740 cm-1; 1H NMR: δ 11.74 (s, 1H), 11.57 (s, 1H), 10.73 (s, 1H), 8.28 (s, 1H), 6.87–7.62 (m, 9H), 5.55 (s, 1H), 5.05 (s, 1H), 4.28 (s, 1H), 2.11 (s, 3H); 13C NMR: δ 180.1, 165.2, 163.3, 160.4, 147.6, 137.5, 136.4, 127.5, 122.4, 112.3, 106.7, 66.7, 64.6, 58.5, 18.7; LC-MS: m/z 510.95 (M+). Anal. Calcd for C23H19ClN6O4S: C, 54.07; H, 3.75; N, 16.45. Found: C, 54.18; H, 3.69; N, 16.33.

N-(3-Chloro-2-(4-fluorophenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4k)

Yield 70%; mp 236°C; IR: 3525, 3335, 3052, 2924, 2875, 2140, 1780, 1668, 1155, 1125, 752 cm-1; 1H NMR: δ 11.79 (s, 1H), 11.45 (s, 1H), 10.67 (s, 1H), 8.19 (s, 1H), 6.98–7.48 (m, 9H), 5.47 (s, 1H), 5.12 (s, 1H), 4.20 (s, 1H), 2.15 (s, 3H); 13C NMR: δ 180.5, 165.7, 162.7, 158.5, 143.7, 132.8, 128.3, 123, 119.4, 112.3, 106.9, 67.6, 64.8, 58.1, 18.4; LC-MS: m/z 483.09 (M+). Anal. Calcd for C23H19ClFN5O2S: C, 57.08; H, 3.96; N, 14.47. Found: C, 57.21; H, 4.03; N, 14.59.

N-(3-Chloro-2-(3-methoxyphenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4l)

Yield 69%; mp 178°C; IR: 3540, 3336, 3280, 3062, 2934, 2852, 2156, 1770, 1666, 1168, 1110, 750 cm-1; 1H NMR: δ 11.87 (s, 1H), 11.47 (s, 1H), 10.61 (s, 1H), 6.95–7.60 (m, 9H), 8.24 (s, 1H), 5.57 (s, 1H), 5.36 (s, 1H), 4.28 (s, 1H), 3.75 (s, 3H), 2.13 (s, 3H); 13C NMR: δ 180.1, 165.4, 162.3, 159.4, 135.4, 128.2, 123.7, 119.5, 111.6, 106.3, 67.4, 64.7, 59.3, 55.4, 19.1; LC-MS: m/z 495.11 (M+). Anal. Calcd for C24H22ClN5O3S: C, 58.12; H, 4.47; N, 14.12. Found: C, 58.19; H, 4.44; N, 14.26.

N-(3-Chloro-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4m)

Yield 67%; mp 172°C; IR: 3325, 3266, 3074, 2940, 2865, 2165, 1762, 1655, 1173, 1122, 746 cm-1; 1H NMR: δ 11.84 (s, 1H), 11.53 (s, 1H), 10.64 (s, 1H), 8.26 (s, 1H), 6.98–7.65 (m, 9H), 5.53 (s, 1H), 5.31 (s, 1H), 4.24 (s, 1H), 3.72 (s, 3H), 2.15 (s, 3H); 13C NMR: δ 180.1, 165.4, 162.3, 159.4, 135.4, 128.2, 123.7, 119.5, 111.6, 106.3, 67.4, 64.5, 59.3, 55.4, 19.1; LC-MS: m/z 495.11 (M+). Anal. Calcd for C24H22ClN5O3S: C, 58.12; H, 4.47; N, 14.12. Found: C, 58.20; H, 4.60; N, 14.08.

N-(3-Chloro-2-oxo-4-(3,4,5-trimethoxyphenyl)azetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4n)

Yield 64%; mp 182°C; IR: 3555, 3358, 3062, 2942, 2866, 2145, 1765, 1666, 1154, 1110, 740 cm-1; 1H NMR: δ 11.83 (s, 1H), 11.44 (s, 1H), 10.57 (s, 1H), 8.22 (s, 1H), 6.91–7.50 (m, 7H), 5.48 (s, 1H), 5.26 (s, 1H), 4.24 (s, 1H), 3.75 (s, 9H), 2.13 (s, 3H); 13C NMR: δ 180.3, 165.6, 162.5, 159.1, 135.7, 127.8, 123.6, 119.6, 111.8, 106.5, 67.6, 64.6, 59.3, 55.2, 18.9; LCMS: m/z 555.13 (M+). Anal. Calcd for C26H26ClN5O5S: C, 56.16; H, 4.71; N, 12.60. Found: C, 56.28; H, 4.85; N, 12.51.

N-(2-(4-Bromophenyl)-3-chloro-4-oxoazetidin-1-yl)-4-(1H-indol-3-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4o)

Yield 62%; mp 209°C; IR: 3545, 3342, 3038, 2924, 2870, 2162, 1788, 1668, 1147, 1178, 735 cm-1; 1H NMR: δ 11.77 (s, 1H), 11.47 (s, 1H), 8.22 (s, 1H), 6.92–7.54 (m, 9H), 5.42 (s, 1H), 5.13 (s, 1H), 4.22 (s, 1H), 2.13 (s, 3H); 13C NMR: δ 180.2, 165.5, 162.5, 159.1, 143.6, 132.8, 127.9, 123, 119.2, 111.7, 106.2, 67.5, 64.7, 57.8, 18.6; LC-MS: m/z 543.01 (M+). Anal. Calcd for C23H19BrClN5O2S: C, 50.70; H, 3.52; N, 12.85. Found: C, 50.66; H, 3.48; N, 12.91.

Acknowledgments:

Authors are thankful to the University Grants Commission, New Delhi and Department of Science and Technology, New Delhi for financial support under the NON-SAP, UGC-BSR one-time grant and DST-FIST programs.

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Received: 2016-3-21
Accepted: 2016-4-30
Published Online: 2016-5-25
Published in Print: 2016-6-1

©2016 by De Gruyter

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

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
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  9. Synthesis of 6-alkylsulfanyl-1,4-dihydropyridines as potential multidrug resistance modulators
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https://doi.org/10.1515/hc-2016-0032
Keywords for this article
antimicrobial; 2-azetidinone; catalyst; indole; β-lactam; MIC; 1,2,3,4-tetrahydropyrimidine
Creative Commons
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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
  9. Synthesis of 6-alkylsulfanyl-1,4-dihydropyridines as potential multidrug resistance modulators
  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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