Biological Activity of Quinazoline and Their Fused-Ring Systems

In the family of heterocyclic compounds, nitrogen-containing heterocycles are an important class of compounds in medicinal chemistry. There has been considerable interest in the development of preparative methods for the production of quinazolines [1]. This is because quinazolines and their ring-fused derivatives display a broad spectrum of biological activities [2] like anti- tubercular, analgesic, anti-inflammatory, and anti-bacterial. Adding to this class of heterocyclic compounds, we have reported earlier [3] the reaction of aromatic aldehyde, thiourea and cyclic ketone to synthesize quinazoline-2(1H)-thiones. Then, these were alkylated/aralkylated. The present paper describes the reaction of 2- [isothiocyanato (substituted phenyl)methyl]-3,4- dihydronaphthalene-1(2H)ones with primary aromatic amines to give another cyclized products viz. quinazoline-2-thiols. Our literature survey reveals that quinazoline-2-thiols are unknown in the literature except for a report mentioning the synthesis of similar compounds [4, 5] 1-(substituted phenyl)-4,4,6-trimethyl-1H,4H-pyrimidine-2-thiols. The later compounds have shown many biological activities [6-8] like anticonvulsive activity like a well-known drug phenobarbitone, as the structure of both of these, are somewhat chemically similar. Also, it has been mentioned in the literature that heterocyclic thiols can act as vulcanization accelerators [4]. Therefore, working on the similar guidelines and in continuation with our research program dealing with the synthesis of biologically active compounds, we report herein a general route to the title compounds.

Melting points were determined in open-end capillaries and are uncorrected. Compounds were checked for their purity by TLC on silica gel G plates and spots were located by iodine vapors. 1H NMR spectra were recorded on BRUKER ADVANCE II 400 NMR Spectrometer using TMS as internal standard. The mass spectra were obtained on a JEOL 5x102/DA-6000 mass spectrometer. The IR spectra were recorded on Perkin-Elmer spectrum RX IFT-IR System using KBr pellets. Elemental analyses of the newly synthesized compounds were carried out on Perkin Elmer model 2400 C H N analyzer. All the compounds gave satisfactory elemental analysis within ±0.4% of theoretical values. The microwave-irradiated reactions were performed in domestic household microwave oven Samsung M177N.

A mixture of α-tetralone and substituted aromatic aldehydes were subjected to microwave heating for 2-5 minutes using absolute alcohol (5 ml) as energy transfer medium and conc. HCl (0.5 ml) as a catalyst. The reaction mixture was cooled to room temperature. The solid, so obtained, was filtered, washed with ethanol and finally crystallized from ethanol to give 1a-1i. Table 1: Synthesis of 2-arylidenetetralin-1-one (1a-1i) Product R Time (min) Yield

(%)

(0C)

IR (KBr, cm-1)

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1a H 4.30 50 104-105 105,102-103 1661.2 (C=O), 1589.6(C=C), 1491.1 ( C --- C ) 1b 2,4(Cl) 2.30 35 54-56 ---- ---- 1c 4-NO2 4.00 42 182-183 184,185 ---- 1d 3-NO2 4.00 38 142-143 ---- ---- 1e 4-OCH3 4.15 40 109-110 110,109 ---- 1f 2,3(O-CH2- O)

4.30 75 133-139 ---- ----

1g 4-Br 4.00 47 158-159 ---- ----- 1h 3-OH 4.00 37 135-139 ---- ----- 1i 4-CH3 3.30 36 125-126 124 ----- The PMR spectra of compound 1e shows a multiplet due to aromatic protons at 7.89--3.07 &  2.94- 2.93 were assigned to C5CH2 & C6CH2. A -OCH3. Also, a General procedure for the synthesis of 2-[isothiocyanato(substituted phenyl)methyl]-3,4-dihydronaphthalene-1(2H)-one (2a- 2i): The mixture of compound 1a-1i (1 mole) and potassium isothiocyanate (1 mole) was taken in a conical flask. To it few pieces of ice were added and then H2SO4 (9.8 ml, 1 mole) was added drop wise. It was stirred for 15-20 minutes. The solid product, so obtained, was washed with sodium carbonate and then with distilled water. The IR spectral values of some of the representative members are given below: Table 2: Synthesis of 2-[isothiocyanato(substituted phenyl)methyl]-3,4-dihydronaphthalene-1(2H)-one (2a-2i). Product R IR (KBr, cm-1); PMR (ppm, ) 2a H 2056.1 (NCS); 1664.8 (C=O); 1454.7( C --- C ); 1223.7 (C-N) 2d 3-NO2 2050.3 (NCS); 1664.2 (C=O), 1529.3 (NO2); 1224.4 (C-N) 2e 4-

OCH3 2055.8 (NCS); 1645 (C=O); 1510 ( C --- C ); 1178.4 (C-N):

7.99-6.97 (m, 8H, Ar-H), 3.85 (s, 3H,4- OCH3), 3.09-3.07 (t, 2H, C5CH2 or C6CH2), 2.94-2.93 (t, 2H, C5CH2 or C6CH2), 1.81-1.80 (d, 1H, C2H), 1.42-1.35 (d, 1H, C1H) 2i 4-CH3 2057.9 (NCS); 1654.1 (C=O); 1516.4 ( C --- C ); 1313 (C-N) Synthesis of 1-(substitutedphenyl)-4-aryl-1,4,5,6-terahydrobenzo[h]quinazoline-2-thiol (3-9): A mixture of 2a-2i (0.01 mole), substituted anilines (0.01 mole) and ethanol (2-3 ml) was taken in a flask. To it, few drops (4-5) of H2SO4 was added and stirred for 5-10

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Product Z R Yield; IR (KBr, cm-1); Mass(m/z); Elemental analysis, 1H (, ppm) 3a 2-CH3 H 76%; 217-219; 2850.4 (arom. C-H str.), 2604.7 (S-H), 1637 (C=N), 1560 (C=C), 1498.4( C --- C ); 1313.9 (C-N) 382.10 M+ (60.79%), 218.15 (97.04%), 128.05 (3.07%), 105.90 (100%), 90.15 (4.36%), 77 (28.65%), 65.05 (6.61%), 50.05 (5.55%) Anal. Calcd. For C25H22N2S: C78.53; H 5.76; N 7.33. Found: C 78.45; H 5.62; N

7.21%

3b 2-CH3 2,4(Cl) 40%; 215-217; Anal. Calcd. For C25H20N2S: C66.66; H 4.44; N 6.22. Found: C 66.56;

H 4.38; N 6.15%

3c 2-CH3 4-NO2 77%; 223-225; Anal. Calcd. For C25H21N3SO2: C70.26; H 4.92; N 9.84. Found: C 70.19; H 4.88; N 9.76% 3d 2-CH3 3-NO2 44%; 218-220; 2909.4 (arom. C-H str.), 2654.6 (S-H), 1616.9 (C=N),

1544.5 (C=C), 1495.2( C --- C ); 1394.4 (C-N)

Anal. Calcd. For C25H21N3SO2: C70.26; H 4.92; N 9.84. Found: C 70.22; H

4.86; N 9.80%

3e 2-CH3 4-OCH3 13%; 222-224; 2870.2 (arom. C-H str.), 2604.6 (S-H), 1640.4 (C=N), 1590

(C=C), 1461.9 ( C --- C ); 1302 (C-N)

7.95 (s, 1H, SH), 7.66-6.78 (m, 12H, Ar-H), 4.80 (s, 1H, C4H), 3.74 (s, 3H, 4- OCH3), 3.09-3.07 (t, 2H,C5CH2 or C6CH2), 2.94-2.93 (t, 2H, C5CH2 or C6CH2), 2.54-2.53 (s, 3H, 4-OCH3), 2.21 (s, 3H, CH3) Anal. Calcd. For C26H24N2SO: C75.72; H 5.82; N 6.79. Found: C 75.65; H

5.78; N 6.65%

3f 2-CH3 2,3(O-CH2- O) 85%; 215-219; 276 (1.75%), 122 (4.58%), 65 (5.88%), 63.95 (100%), 58.10 (0.60%), 52.10 (6.85%), 40.10 (2.54%) Anal. Calcd. For C26H22N2SO2: C73.24; H 5.16; N 6.57. Found: C 73.16; H 5.20; N 6.42% 3g 2-CH3 4-Br 224-225; 2820 (arom. C-H str.), 2589 (S-H), 1601.9 (C=N), 1485.2 (C=N),

1400.2( C --- C ); 1317.5 (C-N)

Anal. Calcd. For C25H21N2S: C 64.93; H 4.54; N 6.06. Found: C 64.99; H

4.42; N 6.01%

3h 2-CH3 3-OH 38%; 228-230; Anal. Calcd. For C25H22N2SO: C 75.38; H 5.53; N 7.03. Found: C 75.29; H 5.47; N 6.95% 3i 2-CH3 4-CH3 38%; 222-224; 2910.4 (arom. C-H str.), 2655.3 (S-H), 1586.8 (C=N), 1544.8 (C=C), 1495( C --- C ); 1316.4 (C-N) Anal. Calcd. For C26H24N2S: C 78.78; H 6.06; N 7.07. Found: C 78.69; H 5.99; N 7.01% 4a 4-CH3 H 69%; 239-241; Anal. Calcd. For C25H22N2S: C78.53; H 5.76; N 7.33. Found: C 78.49; H 5.66; N 7.25%

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4b 4-CH3 2,4(Cl) 38%; 232-234; Anal. Calcd. For C25H20N2S: C66.66; H 4.44; N 6.22. Found:

C 66.59; H 4.37; N 6.17%

4c 4-CH3 4-NO2 69%; 216-218; Anal. Calcd. For C25H21N3SO2: C 70.26; H 4.92; N 9.84. Found: C 70.21; H 4.86; N 9.78 % 4d 4-CH3 3-NO2 36%; 237-239; Anal. Calcd. For C25H21N3SO2: C70.26; H 4.92; N 9.84. Found: C 70.20; H 4.95; N 9.78% 4e 4-CH3 4-OCH3 07%; 220-222; Anal. Calcd. For C26H24N2SO: C 75.72; H 5.82; N 6.79. Found: C 75.68; H 5.75; N 6.83% 4f 4-CH3 2,3(O-CH2- O) 77%; 221-223; Anal. Calcd. For C26H22N2SO2: C73.24; H 5.16; N 6.57. Found: C 73.29; H 5.11; N 6.49% 4g 4-CH3 4-Br 31%; 246-248; 2874.8 (arom. C-H str.), 2596.4 (S-H), 1592.2 (C=N), 1485.5 (C=C), 1400.1( C --- C ); 1297.9 (C-N) Anal. Calcd. For C25H21N2S: C 64.93; H 4.54; N 6.06. Found: C 64.89; H 4.46; N 5.97% 4h 4-CH3 3-OH 38%; 253-255; Anal. Calcd. For C25H22N2SO: C 75.38; H 5.53; N 7.03. Found: C 75.43; H 5.48; N 6.99% 4i 4-CH3 4-CH3 38%; 235-237; 2924 and 2849 (arom. (C-H), 2590.9 (S-H), 1617.8 (C=N), 1559.8 (C=C), 1458.2( C --- C ); 1320.9 (C-N) 396, 277, 276, 128, 105, 103, 65, 58, 40 Anal. Calcd. For C26H24N2S: C 78.78; H 6.06; N 7.07. Found:

C 78.71; H

6.12; N 7.13% 5a 4-OCH3 H 71%; 246-249; 2918 (arom. C-H str.), 2603.4 (S-H), 1618.1 (C=N), 1513.5 (C=C), 1458.1( C --- C ); 1303 (C-N) Anal. Calcd. For C25H22N2SO: C 75.37; H 5.53; N 7.03. Found: C 75.29; H 5.44; N 7.11% 5b 4-OCH3 2,4(Cl) 77%; 240-242; Anal. Calcd. For C25H20N2SO: C 64.38; H 4.29; N 6.01. Found: C 64.29; H 4.21; N 5.92 % 5c 4-OCH3 4-NO2 90%; 241-243; Anal. Calcd. For C25H21N3SO2: C 67.72; H 4.74; N 9.48. Found: C 67.68; H 4.63; N 9.40 % 5d 4-OCH3 3-NO2 34%; 238-240; Anal. Calcd. For C25H21N3SO2: C 67.72; H 4.74; N 9.48. Found: C 67.66; H 4.67; N 9.42 % 5e 4-OCH3 4-OCH3 65%; 253-255; Anal. Calcd. For C26H24N2SO2: C 72.89; H 5.61; N 6.54. Found: C 72.76; H 5.57; N 6.49 % 5f 4-OCH3 2,3(O-CH2- O) 78%; 247-249; Anal. Calcd. For C26H22N2SO3: C 70.59; H 4.98; N 6.33. Found: C 70.48; H 4.89; N 6.39 % 5g 4-OCH3 4-Br 254-255; Anal. Calcd. For C25H21N2SO: C 62.76; H 4.39; N 5.86. Found: C 62.69; H 4.30; N 5.74 % 5h 4-OCH3 3-OH 269-271; Anal. Calcd. For C25H22N2SO2: C 72.46; H 5.31; N 6.76. Found: C 72.52; H 5.39; N 6.82 % 5i 4-OCH3 4-CH3 74%; 245-247; 2919.6 (arom. C-H str.), 2596.4 (S-H), 1600 (C=N), 1586.6 (C=C), 1453.6( C --- C ); 1317.6 (C-N) Anal. Calcd. For C26H24N2SO: C 75.73; H 5.82; N 6.79. Found: C 75.68; H 5.77; N 6.69 % 6a 4-Cl H 71%; 242-244; Anal. Calcd. For C24H19N2S: C 71.64; H 4.73; N 6.96. Found: C 71.52; H 4.79; N 6.88 % 6b 4-Cl 2,4(Cl) 58%; 254-256; Anal. Calcd. For C24H17N2S: C 61.28; H 3.62; N 5.95. Found: C 61.23; H 3.68; N 5.89 % 6c 4-Cl 4-NO2 33%; 229-231; Anal. Calcd. For C24H18N3SO2: C 64.43; H 4.03; N 9.39. Found: C 64.47; H 4.09; N 9.25 %

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6d 4-Cl 3-NO2 37%; 244-246; Anal. Calcd. For C24H18N3SO2: C 64.43; H 4.03; N 9.39. Found: C 64.39; H 4.11; N 9.29 % 6e 4-Cl 4-OCH3 10%; 235-237; Anal. Calcd. For C25H21N2SO: C 69.44; H 4.86; N 6.48. Found: C 69.47; H 4.78; N 6.32% 6f 4-Cl 2,3(O-CH2- O) 79%; 240-242; Anal. Calcd. For C25H19N2SO2: C 67.26; H 4.26; N 6.28. Found: C 67.19; H 4.23; N 6.24 % 6g 4-Cl 4-Br 31%; 253-255; Anal. Calcd. For C24H18N2S: C 59.75; H 3.73; N 5.81. Found: C 59.67; H 3.65; N 5.72 % 6h 4-Cl 3-OH 37%; 264-266; Anal. Calcd. For C24H19N2SO: C 68.89; H 4.54; N 6.69. Found: C 68.80; H 4.42; N 6.58 % 6i 4-Cl 4-CH3 74%; 255-256; 2925.9 (arom. C-H str.), 2590 (S-H), 1617.2 (C=N), 1559.8 (C=C), 1494.2( C --- C ); 1289.2 (C-N) 357, 229,129, 128, 127, 125, 92, 65, 26 Anal. Calcd. For C25H21N2S: C 72.11; H 5.05; N 6.73. Found: C 72.02; H 5.12; N 6.65 % 7a 4-COOH H 71%; 2911.7 (arom. C-H), 2596 (S-H), 1613.8 (C=N), 1513.8 (C=C), 1431.7( C --- C ); 1394.5 (C-N) Anal. Calcd. For C25H20N2SO2: C 72.81; H 4.85; N 6.79. Found: C 72.72; H 4.93; N 6.68 % 7i 4-COOH 4-CH3 46%; 2919.5 (arom. C-H), 2603.9 (S-H), 1601.2 (C=N), 1586.6 (C=C), 1455.3 ( C --- C ); 1317.7 (C-N) Anal. Calcd. For C26H22N2S: C 73.23; H 5.16; N 6.57. Found: C 73.15; H 5.12; N 6.65 % 7f 4-COOH 2,3(O-CH2- O) 71%; 230-232(d); 91 (2.01%), 65.05 (1.88%), 52.40 (1.50%), 43.90 (100%) Anal. Calcd. For C26H20N2SO4: C 68.42; H 4.38; N 6.14. Found: C 68.32; H 4.29; N 6.09 % 8a H H 2874.1 (arom. C-H), 2588.9 (S-H), 1600 (C=N), 1557.8 (C=C), 1494.3( C --- C ); 1328.7 (C-N) Anal. Calcd. For C24H20N2S: C 78.26; H 5.55; N 7.61. Found: C 78.35; H 5.48; N 7.72 % 8e H 4-OCH3 2871.6 (arom. C-H), 2589 (S-H), 1600.1 (C=N), 1494.6 (C=C), 1328.7 (C-N) Anal. Calcd. For C25H22N2S: C 75.37; H 5.53; N 7.03. Found: C 75.28; H 5.43; N 7.24 % 8i H 4-CH3 2590 (S-H), 1654.1 (C=N), 1508.3 (C=C) Anal. Calcd. For C25H22N2S: C 78.53; H 5.76; N 7.33. Found: C 78.46; H 5.82; N 7.21 % 9i 2-NH2 4-CH3 3334 & 3412 (N-H), 2924 (arom. C-H), 2596.4 (S-H), 1577 (C=N), 1540.9 (C=C), 1463.8 (C --- C ); 1316.7 (C-N) 269, 176, 128, 127, 106, 92, 65, 59, 41 Anal. Calcd. For C25H23N3S: C 75.56; H 5.79; N 10.57. Found: C 75.67; H 5.70; N 10.46 % 3. Results and Discussion 2-Arylidenetetraline-1-one (1), obtained by the reaction of -tetralone and substituted aromatic aldehyde, when treated with potassium isothiocyanate gave 2-[isothiocyanato (substituted phenyl) methyl]-3,4-dihydronaphthalene-1(2H)-one (2). Infrared absorption spectra measurements of compounds 2a-2i showed a band at about 2040 cm-1, the characteristic broad band attributed to the isothiocyano group. This compound on further reaction with primary aromatic amine gave 1-(substituted phenyl)-4-aryl-1,4,5,6- terahydrobenzo [h] quinazoline-2-thiol (3-9) (Scheme 1). The IR spectra of the prepared compounds displayed the characteristic S-H stretching vibration at 2550-2600 cm-1. In addition, the Mass Spectra (MS) of the compound 3a showed the molecular ion peak at 382 while the MS of maximum compounds did not show any molecular ion peak but showed the peaks due to fragments that supported the expected structure.

Z = (3) 2-CH3 (4) 4-CH3 (5) 4-OCH3 (6) 4-Cl (7) 4-COOH (8) H (9) 2-NH2 R = (a) H (b) 2,4(Cl) (c) 4-NO2 (d) 3-NO2 (e) 4-OCH3 (f) 2,3(O-CH2-O) (g) 4-Br (h) 3-OH (i) 4-CH3

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As an example, the disappearance of IR band for isothiocyano group at 2055.8cm-1 and appearance of S-H band at 2604.6 cm-1 clearly proves the formation of 3e from 2e. Therefore, the spectroscopic data along with the literature survey [4-5], helped in proposing the following mechanism for the above-mentioned reaction:

Keeping in view the biological potential of Quinazoline derivatives, a methodology has been developed to synthesize new derivatives of Quinazolines viz. Quinazoline-2-thiols. For this, 2-[isothiocyanato (substituted phenyl)methyl]-3,4- dihydronaphthalene-1(2H)-ones were treated with primary aromatic amines. Also, Guassian-03 studies of the prepared compounds have been carried out.

As shown by the Gaussian 03 studies through the instrument, the stereochemistry of the synthesized compounds seems to be like the reported compounds (I) in the literature [9-13].

Solid-state conformation of I as hydrochloride salt. Hydrogen bond distances: N1 – Cl = 3.088 A0, N3 – Cl = 3.075 A0 The stereochemistry of the prepared compounds is given below showing that phenyl ring is not in the same plane as the rest of the molecule:

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[1] (a) Kidwai M, Kukreja S, Rastogi S, Singhal K, 2007. Microwave-accelerated multicomponent synthesis for a novel scaffold of monastrol analogues. Letters in Organic Chemistry, 4(5): 357-361. (b) Barluenga J, Tomas M, Ballesteros A, Lopez LA, 1994. A simple approach to pyrimidine and quinazoline derivatives by [4+2] cycloaddition of 1,3-diazadienes and enamines. Heterocycles, 37(2): 1109-20. [2] (a) Kunes J, Bazant J, Pour M, Waisser K, Slosarek M, Janota J, 2000. Quinazoline derivatives with antitubercular activity. IL Farmaco, 55: 725-729. (b) Alagarsamy V, Salomon VR, Vanikavitha G, Paluchamy V, Chandran MR, Sujin AA, Thangathiruppathy A, Amuthalakshmi S, Revathi R, 2002. Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-phenyl- 3- substituted quinazolin-4(3h) ones. Biological and Pharmaceutical Bulletin, 25(11): 1432-1435. [3] Kaur B, Kaur R, 2007. Synthesis of fused quinazolinethiones and their S-alkyl/aryl derivatives. ARKIVOC, (xv): 315-323. [4] Mathes RA, Stewart FD, Swedish F, 1948. A synthesis of 2-pyrimidinethiols. Journal of American Chemical Society, 70: 1452-1453. [5] Mathes RA, 1953. 2-Pyrimidinethiols. Journal of American Chemical Society, 75: 1747-1748. [6] Koppel HC, Springer RH, Robins RK, Cheng CC, 1961. Pyrimidines. I. Synthesis of pyrimidinethiols. Journal of Medicinal Chemistry, 26: 792-803. [7] Alagarsamy V, Shankar D, Solomon VR, 2006. Synthesis of some novel 2-mercapto-3-(substituted amino)-5,6.7,8-tetrahydro- 3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-ones as analgesic and anti-inflammatory agents. ARKIVOC, xvi: 149-159.