INTRODUCTION

Cancer is a multifaceted disease that represents one of the leading causes of mortality in developed countries. Worldwide, one in eight deaths is due to cancer, and it is the second most common cause of death in the US, exceeded by heart diseases [1]. Chemotherapy is the mainstay for cancer treatment; however, the use of available chemotherapeutics is often limited due to undesirable side effects. It is important to identify new agents and new targets for the treatment of cancer.

Nitrogen-containing heterocyclic compounds featured prominently in early studies of chemistry, and they have received a great deal of attention in the literature due to their role as active pharmacophores of historical significance. Especially, pyrimidines have a long and distinguished history extending from the days of their discovery as important constituents of nucleic acids to their current use in the chemotherapy of AIDS. For instance, pyrimethamine [2], and tri­metho­prim [3] are powerful antimalarial drugs, minoxidil [4] is used as antihypertensive, and sulfa­diazine [5] is one of the chemotherapeutics containing a pyrimidine moiety.

The imidazo[1,2-a]pyrimidine nucleus is present in many biologically active compounds, and derivatives based thereon have been found to possess anxiolytic (Fig. 1) [6], cardiovascular [7], analgesic [8], antihyper­tensive [9], and neuroleptic [10, 11] activities. The structure of imidazo[1,2-a]pyrimidine is related to the purine ring system, and anti-inflammatory [12], insec­ticidal, acaricidal, and nematocidal activities [13] of imidazo[1,2-a]pyrimidine derivatives have been reported. Based on the importance of these moieties, herein we describe the synthesis of amide-functional­ized imidazo[1,2-a]pyrimidines and their anticancer activity against four human cancer cell lines.

Fig. 1.
figure 1

Imidazo[1,2-a]pyrimidine-based bioactive compounds.

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RESULTS AND DISCUSSION

2-Amino-6-(trifluoromethyl)pyrimidin-4(3H)-one (1) was synthesized by well known method [14, 15] from ethyl 4,4,4-trifluoro-3-oxobutanoate and guani­dine hydrochloride. Compound 1 reacted with pro­pargyl bromide in the presence of a base, resulting in the formation of two regioisomers, i.e., N-propargyl derivative 2 (60%) and O-propargyl analog 3 (10%) (Scheme 1). Both regioisomers were isolated in the pure state by column chromatography and were iden­tified on the basis of their 1H NMR spectra, which showed a singlet at δ 4.83 ppm due to NCH2 group of 2 or at δ 5.01 ppm for OCH2 group of 3. Compound 2 underwent cyclization in acetonitrile in the presence of potassium carbonate to give imidazo[1,2-a]­pyrimidine 4.

Scheme
scheme 1

1.

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Compound 4 was used as a precursor to obtain final compounds functionalized with an acetamide moiety. For this purpose, it was reacted with ethyl bromoacetate in DMF using potassium carbonate as a base to produce exclusively ester 5. Compound 5 was then reacted with various primary aliphatic amines and cyclic secondary amines under different conditions to afford acetamide derivatives 6 and 7, respectively. N-Aryl acetamides 8a–8d were synthesized as follows. Initially, we pre­pared the corresponding 2-chloro-N-arylacetamides by reacting chloroacetyl chloride with substituted anilines in dimethylformamide. Finally, the alkylation of com­pound 4 with these 2-chloro-N-arylacetamides in DMF in the presence of potassium carbonate as a base at room temperature gave target imidazopyrimidinylacet­amides 8a–8d. The synthetic sequence is outlined in Scheme 2.

Scheme
scheme 2

2.

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Biological activity. The anticancer activity of com­pounds 6a–6j, 7a–7d, and 8a–8d was evaluated against four human cancer cell lines, namely MCF7 human breast cancer (ATCC no. HTB-22), A549 human pancreatic cancer (ATCC no. CRL-1469), HeLa human cervical cancer (ATCC no. CCL-2), and MDA-MB-231 human breast cancer (ATCC no. HTB-26). 5-Fluoro­uracil and dimethyl sulfoxide were used as positive and negative controls, respectively. All tested compounds showed a good activity against the selected cancer cell lines, and their IC50 values are collected in Table 1. Most of the synthesized compounds exhibited prom­ising anticancer activity with IC50 values ranging between 2.6 and 25.1 μg/mL. Compounds 7a and 8b turned out to be potent against human cervical cancer cell line (HeLa) and human pancreatic cancer cell line (A549) with IC50 values of 2.3 and 2.6 µg/mL. Com­pounds 6c, 6e, and 7c exhibited promising activity against human pancreatic cancer cell line (A549) with IC50 values of 4.8, 4.8, and 4.3 µg/mL, respectively. Compounds 6c–6f and 6i were active against human breast cancer cell line MCF7 with IC50 values of 5.4, 5.1, 5.5, 5.1, and 5.7 µg/mL, respectively. Compounds 6d, 6g, and 8c showed good activity against human cervical cancer cell line. Compounds 6a, 6h, 6i, and 7b showed good activity against MDA-MB-231 with IC50 values of 5.3, 6.0, 6.1, and 6.6 µg/mL, respectively.

Table 1. Anticancer activity of compounds 6a–6j, 7a–7d, and 8a–8da
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The structure–activity relationship analysis revealed that compound 6c with a propyl group in the acetamide moiety showed promising anticancer activity; the activity of N-ethyl analog 6b was lower, and it further decreased in going to N-methyl derivative 6a. Amides 6d and 6e bearing a polar group on the amide nitrogen atom were more active than simple N-alkyl amides 6a–6c. The presence of a pyrrolidine group in 7a and methoxy group on the phenyl ring in 8b favored their enhanced activity against human cervical cancer cell line (HeLa) and human pancreatic cancer cell line (A549) with IC50 values of 2.3 and 2.6 µg/mL, respec­tively. Compounds 7a and 8b are thus considered to be most potent among the other tested compounds.

EXPERIMENTAL

The melting points were measured in open glass capillaries on a Casia-Siamia (VMP-AM) melting point apparatus and are uncorrected. The IR spectra were recorded in KBr on a Perkin Elmer FTIR 240C spectrophotometer using KBr optics. The 1H and 13C NMR spectra were recorded on a Bruker AV 300 spectrometer at 300 and 75 MHz, respectively, using DMSO-d6 as solvent and tetramethylsilane as internal standard. The high-resolution mass spectra (electro­spray ionization) were run on a determined by using a Bruker microTOF-Q II HRMS/MS instrument. The progress of reactions was monitored by thin-layer chromatography (TLC) on precoated silica gel 60 F254 plates; spots were visualized with UV light. Merck silica gel (60–120 mesh) was used for column chro­matography.

Ethyl 2-[2-methyl-5-oxo-7-(trifluoromethyl)­imid­azo[1,2-a]pyrimidin-1(5H)-yl]acetate (5). 2-Methyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5(1H)-one (4), 100 mg, 0.46 mmol) was dissolved in DMF (5 mL), potassium carbonate (0.28 mmol) was added, and ethyl 2-bromoacetate (0.51 mmol) was then slowly added. The mixture was stirred at room tem­pera­ture for 4 h. After completion of the reaction, the mixture was poured onto crushed ice, and the precip­itate was filtered off and dried. Yield 89%, white powder, mp 110–114°C. IR spectrum, ν, cm–1: 1656 (C=O), 1589 (C=N), 1287 (C–F). 1H NMR spectrum, δ, ppm: 1.28 t (3H, J = 7.17 Hz, Me), 2.39 s (3H, CH3), 4.24 q (2H, J = 7.17 Hz, OCH2), 4.99 s (2H, NCH2), 6.34 s (1H, Harom), 7.45 s (1H, Harom). 13C NMR spec­trum, δC, ppm: 9.3, 13.5, 42.8, 61.9, 97.4, 103.7, 117.5 q (J = 274.1 Hz), 128.9, 146.4, 151.1 q (J = 34.3 Hz), 156.4, 166.1. Mass spectrum: m/z 304.0909 [M + H]+. Calculated for C12H12F3N3O3: M + H 304.0903.

Amide-functionalized imidazo[1,2-a]pyrimidine derivatives 6a–6j and 7a–7d (general procedure). A mixture of ethyl 2-[2-methyl-5-oxo-7-(trifluoro­methyl)­imidazo[1,2-a]pyrimidin-1(5H)-yl]acetate (4, 0.33 mmol) and excess amine (1.6 mmol) was heated at 50–100°C in a sealed tube for 10–12 h. After com­pletion of the reaction (TLC), the tube was cooled to room temperature and opened, the mixture was quenched with crushed ice, and the solid product was filtered off, washed with excess water, and dried.

N-Methyl-2-[2-methyl-5-oxo-7-(trifluoromethyl)­imidazo[1,2-a]pyrimidin-1(5H)-yl]acetamide (6a). Yield 89%, white powder, mp >250°C. IR spectrum, ν, cm–1: 3437 (N–H), 1656 (C=O), 1588 (C=N), 1287 (C–F). 1H NMR spectrum, δ, ppm: 2.27 s (3H, CH3), 2.70 d (3H, NCH3), 4.72 s (2H, NCH2), 6.21 s (1H, Harom), 7.34 s (1H, Harom), 7.93 s (1H, NH). 13C NMR spectrum, δC, ppm: 9.3, 25.6, 44.2, 96.2, 103.7, 121.2 q (J = 274.4 Hz), 130.7, 146.4, 149.6 q (J = 35.1 Hz), 156, 165.8. Mass spectrum: m/z 289.0908 [M + H]+. Calculated for C11H11F3N4O2: M + H 289.0907.

N-Ethyl-2-[2-methyl-5-oxo-7-(trifluoromethyl)­imidazo[1,2-a]pyrimidin-1(5H)-yl]acetamide (6b). Yield 86%, white powder, mp 242–246°C. IR spec­trum, ν, cm–1: 3292 (N–H), 1655 (C=O), 1593 (C=N), 1284 (C–F). 1H NMR spectrum, δ, ppm: 1.15 t (3H, J = 7.5 4 Hz, CH2CH3), 2.38 s (3H, CH3), 3.01 q (2H, NCH2), 4.81 s (2H, NCH2), 6.30 s (1H, Harom), 7.65 s (1H, Harom), 8.11 s (1H, NH). 13C NMR spectrum, δC, ppm: 8.5, 13.2, 32.9, 43.2, 95.4, 102.4, 129.1, 145.5, 155.2, 163.9. Mass spectrum: m/z 303.1072 [M + H]+. Calculated for C12H13F3N4O2: M + H 303.1069.

2-[2-Methyl-5-oxo-7-(trifluoromethyl)imidazo­[1,2-a]pyrimidin-1(5H)-yl]-N-propylacetamide (6c). Yield 79%, white powder, mp 230–234°C. IR spec­trum, ν, cm–1: 3289 (N–H), 1658 (C=O), 1590 (C=N), 1284 (C–F). 1H NMR spectrum, δ, ppm: 0.92 t (3H, J = 7.41 Hz, CH2CH3), 1.50–1.58 m (2H, CH2), 2.38 s (3H, CH3), 3.18 q (2H, J = 6.35 Hz, NCH2), 4.82 s (2H, NCH2), 6.31 s (1H, Harom), 7.57 s (1H, Harom), 8.01 s (1H, NH). 13C NMR spectrum, δC, ppm: 9.2, 10.6, 21.7, 40.5, 43.9, 96.4, 103.08, 129.6, 146.1, 150.5, 156.1, 164.7. Mass spectrum: m/z 317.1226 [M + H]+. Calculated for C13H15F3N4O2: M + H 317.1225.

N-(2-Aminoethyl)-2-[2-methyl-5-oxo-7-(tri­fluoro­methyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]­acetamide (6d). Yield 73%, white powder, mp 222–226°C. IR spectrum, ν, cm–1: 3382, 3361 (NH2), 3289 (N–H), 1661 (C=O), 1591 (C=N), 1285 (C–F). 1H NMR spectrum, δ, ppm: 2.37 s (3H, CH3), 3.35–3.40 m (2H, CH2), 3.62–3.67 m (2H, CH2), 4.87 s (2H, NCH2), 6.33 s (1H, Harom), 7.33 s (1H, Harom), 7.43 s (2H, NH2), 8.08 s (1H, NH). 13C NMR spectrum, δC, ppm: 8.02, 40.3, 42.7, 58.2, 94.8, 102.02, 118.5, 128.1, 128.9, 163.9. Mass spectrum: m/z 319.1015 [M + H]+. Calculated for C12H13F3N4O3: M + H 319.1018.

N-(2-Hydroxyethyl)-2-[2-methyl-5-oxo-7-(tri­fluoro­methyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]­acetamide (6e). Yield 68%, white powder, mp 160–164°C. IR spectrum, ν, cm–1: 3440 (O–H), 3290 (N–H), 1664 (C=O), 1585 (C=N), 1286 (C–F). 1H NMR spectrum, δ, ppm: 2.38 s (3H, CH3), 2.87 t (2H, J = 5.85 Hz, NH2), 3.33–3.40 m (2H, CH2), 4.86 s (2H, NCH2), 6.33 s (1H, Harom), 7.43 s (1H, Harom), 8.35 s (1H, NH). Mass spectrum: m/z 318.1175 [M + H]+. Calculated for C12H14F3N5O2: M + H 318.1178.

N-Cyclopropyl-2-[2-methyl-5-oxo-7-(trifluoro­methyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]acet­amide (6f). Yield 83%, white powder, mp >250°C. IR spectrum, ν, cm–1: 3288 (N–H), 1661 (C=O), 1589 (C=N), 1287 (C–F). 1H NMR spectrum, δ, ppm: 0.53 m (2H, CH2), 0.70–0.75 m (2H, CH2), 2.37 s (3H, CH3), 2.69–2.76 m (1H, CH), 4.77 s (2H, NCH2), 6.31 s (1H, Harom), 7.41 s (1H, Harom), 7.55 s (1H, NH). 13C NMR spectrum, δC, ppm: 5.5, 9.3, 22.3, 44.3, 96.1, 103.7, 121.4 q (J = 274.1 Hz), 130.9, 146.4, 149.8 q (J = 33.7 Hz), 155.9, 166.4. Mass spectrum: m/z 315.1075 [M + H]+. Calculated for C13H13F3N4O2: M + H 315.1069.

N-Cyclopentyl-2-[2-methyl-5-oxo-7-(trifluoro­methyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]acet­amide (6g). Yield 82%, white powder, mp >250°C. IR spectrum, ν, cm–1: 3289 (N–H), 1659 (C=O), 1586 (C=N), 1286 (C–F). 1H NMR spectrum, δ, ppm: 0.38 m (2H, CH2), 0.61 m (2H, CH2), 2.13 s (3H, CH3), 2.27–2.44 m (4H, CH2), 3.63–3.77 m (1H, CH), 4.60 s (2H, NCH2), 6.20 s (1H, Harom), 7.47 s (1H, Harom), 8.37 br.s (1H, NH). 13C NMR spectrum, δC, ppm: 5.7, 9.5, 22.5, 44.4, 96.4, 103.9, 121.4 q (J = 272.2 Hz), 131.2, 146.6, 150.05 q (J = 34.1 Hz), 156.3, 166.8. Mass spectrum: m/z 343.1384 [M + H]+. Calculated for C15H17F3N4O2: M + H 343.1382.

N-Cyclohexyl-2-[2-methyl-5-oxo-7-(trifluoro­methyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]acet­amide (6h). Yield 78%, white powder, mp 225–229°C. IR spectrum, ν, cm–1: 3287 (N–H), 1657 (C=O), 1588 (C=N), 1285 (C–F). 1H NMR spectrum, δ, ppm: 1.13–1.42 m (6H, CH2), 1.69–1.79 m (2H, CH2), 1.82– 1.91 m (2H, CH2), 2.37 s (3H, CH3), 3.62–3.75 m (1H, CH), 4.80 s (2H, NCH2), 6.30 s (1H, Harom), 7.42 s (1H, Harom), 7.97 br.s (1H, NH). 13C NMR spectrum, δC, ppm: 9.07, 23.8, 24.5, 31.7, 43.8, 47.7, 96.1, 102.8, 129.5, 142.9, 145.9, 155.9, 163.5. Mass spectrum: m/z 357.1543 [M + H]+. Calculated for C16H19F3N4O2: M + H 357.1538.

2-[2-Methyl-5-oxo-7-(trifluoromethyl)imidazo­[1,2-a]pyrimidin-1(5H)-yl]-N-[2-(morpholin-4-yl)­ethyl]acetamide (6i). Yield 72%, white powder, mp 181–185°C. IR spectrum, ν, cm–1: 3303 (N–H), 1677 (C=O), 1589 (C=N), 1284 (C–F). 1H NMR spec­trum, δ, ppm: 2.16 s (3H, CH3), 2.35–2.41 m (4H, NCH2), 2.43–2.49 m (4H, OCH2), 3.32–3.39 m (2H, CH2), 3.66 t (2H, J = 4.53 Hz, CH2), 4.85 s (2H, NCH2), 6.30 s (1H, Harom), 7.45 s (1H, Harom), 8.02–8.09 br.s (1H, NH). Mass spectrum: m/z 388.1597 [M + H]+. Calculated for C16H20F3N5O3: M + H 388.1596.

N-Benzyl-2-[2-methyl-5-oxo-7-(trifluoromethyl)­imidazo[1,2-a]pyrimidin-1(5H)-yl]acetamide (6j). Yield 65%, white powder, mp 145–149°C. IR spec­trum, ν, cm–1: 3278 (N–H), 1670 (C=O), 1583 (C=N), 1283 (C–F). 1H NMR spectrum, δ, ppm: 2.39 s (3H, CH3), 4.44 d (2H, J = 5.47 Hz, CH2), 4.87 s (2H, NCH2), 6.34 s (1H, Harom), 7.24–7.37 m (5H, Harom), 7.42 s (1H, Harom), 8.55–8.62 br.s (1H, NH). Mass spectrum: m/z 365 365.1229 [M + H]+. Calculated for C17H15F3N4O2: M + H 365.1225.

2-Methyl-1-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5(1H)-one (7a). Yield 58%, white powder, mp 204–206°C. IR spectrum, ν, cm–1: 1655 (C=O), 1589 (C=N), 1278 (C–F). 1H NMR spectrum, δ, ppm: 1.87–1.98 m (2H, CH2), 2.03–2.14 m (2H, CH2), 2.37 s (3H, CH3), 3.48 t (2H, J = 6.60 Hz, CH2), 3.69 t (2H, J = 6.60 Hz, CH2), 4.97 s (2H, NCH2), 6.28 s (1H, Harom), 7.45 s (1H, Harom). Mass spectrum: m/z 329.1220 [M + H]+. Calculated for C14H15F3N4O2: M + H 329.1225.

2-Methyl-1-[2-oxo-2-(piperidin-1-yl)ethyl]-7-(tri­fluoromethyl)imidazo[1,2-a]pyrimidin-5(1H)-one (7b). Yield 55%, white powder, mp 183–187°C. IR spectrum, ν, cm–1: 1657 (C=O), 1591 (C=N), 1281 (C–F). 1H NMR spectrum, δ, ppm: 1.59–1.75 m (6H, CH2), 2.35 s (3H, CH3), 3.54–3.61 m (4H, CH), 4.92 s (2H, NCH2), 6.39 s (1H, Harom), 7.41 s (1H, Harom). 13C NMR spectrum, δC, ppm: 8.6, 22.6, 24.7, 42.8, 44.5, 44.9, 95.6, 102.4, 120.2 q (J = 273.5 Hz), 129.4, 145.5, 149.6 q (J = 32.9), 155.4, 162.1. Mass spectrum: m/z 343.1385 [M + H]+. Calculated for C15H17F3N4O2: M + H 343.1382.

2-Methyl-1-[2-(morpholin-4-yl)-2-oxoethyl]-7-(tri­fluoromethyl)imidazo[1,2-a]pyrimidin-5(1H)-one (7c). Yield 84%, white powder, mp 246–250°C. IR spectrum, ν, cm–1: 1657 (C=O), 1591 (C=N), 1281 (C–F). 1H NMR spectrum, δ, ppm: 2.28 s (3H, CH3), 3.25–3.30 m (4H, NCH2), 3.52–3.57 m (4H, OCH2), 4.82 s (2H, NCH2), 6.21 s (1H, Harom), 7.37 s (1H, Harom). Mass spectrum: m/z 345.1181 [M + H]+. Calculated for C14H15F3N4O3: M + H 345.1175.

2-Methyl-1-[2-(4-methylpiperazin-1-yl)-2-oxo­ethyl]-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5(1H)-one (7d). Yield 60%, white powder, mp 120–124°C. IR spectrum, ν, cm–1: 1664 (C=O), 1586 (C=N), 1281 (C–F). 1H NMR spectrum, δ, ppm: 2.35 s (3H, CH3), 2.36 s (3H, NCH3), 2.43 t (2H, J = 4.91 Hz, NCH2), 2.54 t (2H, J = 4.91 Hz, NCH2), 3.62–3.71 m (4H, NCH2), 5.02 s (2H, NCH2), 6.33 s (1H, Harom), 7.51 s (1H, Harom). 13C NMR spectrum, δC, ppm: 8.4, 40.7, 41.9, 43.4, 44.4, 52.9, 53.4, 95.5, 102.3, 129.4, 145.4, 149.6, 155.2, 162.4. Mass spectrum: m/z 358.1497 [M + H]+. Calculated for C15H18F3N5O2: M + H.

N-Aryl-2-[2-methyl-5-oxo-7-(trifluoromethyl)­imidazo[1,2-a]pyrimidin-1(5H)-yl]acetamides 8a–8d (general procedure). Potassium carbonate (0.28 mmol) was added to a solution of 2-methyl-7-(trifluoro­methyl)­imidazo[1,2-a]pyrimidin-5(1H)-one (4, 100 mg, 0.461 mmol) in DMF (5 mL), and the corre­sponding N-arylchloroacetamide (0.51 mmol) was then slowly added. The mixture was stirred at room tem­perature for 4 h and poured onto crushed ice, and the precipitate was filtered and dried.

N-(3-Chlorophenyl)-2-[2-methyl-5-oxo-7-(tri­fluoro­methyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]­acetamide (8a). Yield 89%, white powder, mp 168–172°C. IR spectrum, ν, cm–1: 1664 (C=O), 1586 (C=N), 1281 (C–F). 1H NMR spectrum, δ, ppm: 2.35 s (3H, CH3), 5.07 s (2H, NCH2), 6.35 s (1H, Harom), 7.15 d (1H, J = 7.74 Hz, Harom), 7.33–7.46 m (2H, Harom), 7.68 s (1H, Harom), 7.77 s (1H, Harom), 10.72 s (1H, NH). Mass spectrum: m/z 385.0677 [M + H]+. Calculated for C16H12ClF3N4O2: M + H 385.0679.

N-(3-Methoxyphenyl)-2-[2-methyl-5-oxo-7-(tri­fluoromethyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]­acetamide (8b). Yield 86%, white powder, mp 151–155°C. IR spectrum, ν, cm–1: 1664 (C=O), 1586 (C=N), 1281 (C–F). 1H NMR spectrum, δ, ppm: 2.35 s (3H, CH3), 3.71 s (3H, OCH3), 5.04 s (2H, NCH2), 6.27 s (1H, Harom), 6.62 d (1H, J = 8.49 Hz, Harom), 7.06–7.10 m (2H, Harom), 7.18 t (1H, J = 8.49 Hz, Harom), 7.27 s (1H, Harom), 10.46 s (1H, NH). 13C NMR spectrum, δC, ppm: 7.5, 42.9, 52.8, 94.4, 101.7, 103.1, 107.3, 109.4, 118.8 q (J = 274.5 Hz), 127.4, 128.8, 137.3, 144.6, 147.7 q (J = 34.6 Hz), 153.9, 157.5, 162.1. Mass spectrum: m/z 381.1177 [M + H]+. Cal­culated for C17H15F3N4O3: M + H 381.1175.

N-(3-Fluorophenyl)-2-[2-methyl-5-oxo-7-(tri­fluoromethyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]­acetamide (8c). Yield 85%, white powder, mp 156–160°C. IR spectrum, ν, cm–1: 1664 (C=O), 1586 (C=N), 1281 (C–F). 1H NMR spectrum, δ, ppm: 2.33 s (3H, CH3), 5.06 s (2H, NCH2), 6.35 s (1H, Harom), 6.93 t (1H, J = 8.49 Hz, Harom), 7.25–7.44 m (2H, Harom), 7.54 m (1H, Harom), 7.68 s (1H, Harom), 10.76 s (1H, NH). 13C NMR spectrum, δC, ppm: 9.4, 44.9, 96.4, 103.8, 106.1 d (J = 26.40 Hz), 110.3 d (J = 20.35 Hz), 115.0, 120.09 q (J = 275.09 Hz), 130.5, 131.1, 139.7, 146.5, 149.6 q (J = 34.11 Hz), 155.9, 161.8, 164.6. Mass spectrum: m/z 369.0976 [M + H]+. Calculated for C16H12F4N4O2: M + H 369.0975.

N-(4-Fluorophenyl)-2-[2-methyl-5-oxo-7-(tri­fluoromethyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]­acetamide (8d). Yield 88%, white powder, mp 145–149°C. IR spectrum, ν, cm–1: 1664 (C=O), 1586 (C=N), 1281 (C–F). 1H NMR spectrum, δ, ppm: 2.33 s (3H, CH3), 5.01 s (2H, NCH2), 6.21 s (1H, Harom), 6.90–7.01 m (2H, Harom), 7.48–7.58 m (2H, Harom), 7.89 s (1H, Harom), 10.41 s (1H, NH). Mass spectrum: m/z 369.0976 [M + H]+. Calculated for C16H12F4N4O2: M + H 369.0975.

CONCLUSIONS

A series of new N-substituted 2-[2-methyl-5-oxo-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-1(5H)-yl]­acetamides have been synthesized, and their in vitro anticancer activity against some human cancer cell lines has been evaluated. Among the synthesized compounds, N-(2-hydroxyethyl), N-[2-(morpholin-4-yl)ethyl], and N,N-pentamethylene derivatives showed potent anticancer activities in comparison with standard drugs, and the other compounds showed good activity against four tumor cell lines. Studies aimed at improving the biological activity of the imidazo­[1,2-a]­pyrimidine scaffold are underway