*Corresponding Author:
S. Patil
Organic Research Laboratory, Department of Chemistry, P. D. V. P. College, Tasgaon, Sangli 416312, India.
E-mail: [email protected]
Date of Submission 28 October 2009
Date of Decision 2 March 2010
Date of Acceptance 1 August 2010
Indian J Pharm Sci, 2010, 72 (4): 500-504  

Abstract

2-thio-3-aryl quinazolin-4(3H)one (1) was synthesized by reacting anthranilic acid with thiocarbamate salts of substituted aniline and carbon disulphide, which on refl ux with excess of hydrazine hydrate to form 2-hydrazino quinazolin-4(3H)one derivatives (2). The reaction of (2) with variously substituted aryl aldehydes gave the corresponding hydrazones (3). Further, the cyclization of compound (3) in acetic anhydride gave tricyclic pyrazoloquinazolinones (4). All newly synthesized compounds have been tested for their antibacterial activity against gram +ve bacteria B. substilis, S. aureus and gram –ve bacteria E. coli, P. vulgaris. The species used for antifungal activity are Aspergillus niger and Phytophora. Introduction of -OCH3, -OH and -Cl groups to the heterocyclic frame work enhanced antibacterial and antifungal activities.

Keywords

Acetic anhydride, hydrazino, hydrazones, pyrazolo-quinazolinones, quinazolinones

Derivatives quinazolines are of special importance because of their versatile biological activities [1,2], especially antihistaminic [3], antiinflammatory [4], antihypertensive [5], antiHIV [6], antifungal [6,7], antimicrobial [8,9], anticonvulsant [10], antithrombotic [11], antitubercular [12,13], antitumor [14], analgesic [15], antibacterial [6,15] and insecticidal [16]. In this paper, a new route for the synthesis of pyrazolo quinazolinones is reported.

reported. The strategy employed for the synthesis of desired compounds involved the sequential treatment of anthranilic acid with thiocarbamate salts of substituted aniline and carbon disulphide to give substituted 2-thio-3-aryl quinazol-4(3H)ones (1). The appearance of broad band at 3330-3110 cm-1 in IR spectrum and a singlet displayed at δ, 10-13 ppm in the PMR spectrum due to –SH supports their formation. Compound (1) were refluxed with excess hydrazine hydrate to form 2-hydrazino derivative (2), the formation witch has been explained by the appearance of IR band at 3390-3100 cm-1 due to -NHNH2 and disappearance of signal observed at δ, 10-13 ppm due to -SH and the appearance of two additional singlet between δ, 9-11 and δ, 2-7 ppm due to -NH and -NH2 protons, respectively in their PMR spectra. The condensation of (2) with variously substituted aryl aldehydes gave the corresponding hydrazones (3). The appearance -NH and =CH protons at δ, 5.1 and δ, 8.2 in PMR spectrum and also disappearance of -NH2 band 3390-3200 cm-1 in IR spectrum indicated their formation. Further, the cyclization of compound (3) in acetic anhydride gave tricyclic triazolo quinazolones (4). The formation of these compounds have been established by the disappearance of the PMR singlet due to –NH and =CH displayed at δ, 5.1 and δ, 8.2, respectively in the PMR spectrum of (3). (Scheme 1)

Figure

Scheme 1: Synthetic route for synthesis of Quinazolin-4(3H)One derivatives

All chemicals used were of AR grade and are used without further purification. Melting points were determined by open capillary method and are uncorrected. 1H NMR spectra in DMSO-d6 were scanned on a Bruker A-300 F-NMR spectrometer. IR spectra were recorded on a Perkin-Elmer 783 (FTIR) spectrophotometer. Purity of the products in addition to the elemental analysis was checked by TLC.

The starting compound (1) was prepared by reported method [17]. 2-Hydrazino 3-p-methoxy phenyl quinazolin-4(3H)one (2a) was synthesized as follows; The compound (la) (5.0 g, 0.018 mole) was refluxed with excess of hydrazine hydrate (15 ml) with constant stirring at 100oC for about 1 ½ h, cooled and the solid obtained was filtered and recrystallized from ethanol to furnish (2a), IR(KBr); 3386-3328 (-HNNH2), 1664 (cyclic amido C=O) cm-1; 1H NMR (DMSO-d6): δ, 3.81(3H,s,Ar-OCH3), 6.25(2H,s,-NH2), 6.9-7.8(8H,m, Ar-H), 10.9(1H,s, br, -NH).

2-(p-Methoxybenzylidene)hydrazine-3-(p methoxyphenyl) quinazolin-4-(3H)one (3a-1) was synthesized using following procedure; the mixture of compound (2a) (0.2 g, 0.0007 mole) and p-methoxy benzaldehyde (0.1 g, 0.0007 mole) in ethanol (10 ml) to which two drops of acetic acid were added and the reaction mixture heated on oil bath for 5 h. The separated solid was filtered under vacuum and further recrystallized from DMF, IR(KBr); 3100-3350(-NH), 1665 cm-1 (cyclic amido >C=O), 1600 cm-1 (-C=N); 1H NMR (DMSO-d2): 3.82 (3H, s, Ar-OCH3), 3.84 (3H, s, another Ar-OCH3), 6.00 (1H, s, br, -NH), 8.21 (1H, s, =CH), 6.8-8.1 (12H, m, Ar-H), 8.20 (=CH) ppm.

3,5’-(p-Dimethoxyphenyl) pyrazolo- [3’,4’-a] quinazolin-4(3H)one (4a-1) was synthesized as follows; To a solution of compound (3a-1) (0.1 g, 0.00025 mole) in acetic anhydride (10 ml) was refluxed for about 2 h then poured in ice-cold water and separated solid was filtered, recrystallized from DMF to get desired tricyclic pyrazolo quinazolinones, IR (KBr): 1665 cm-1 (cyclic amido > C=O) and 1620 cm-1 (C=N); 1H NMR: (DMSO-d6): 3.79 (3H, s, Ar-OCH3) 3.95(3H, s, another Ar-OCH3), 6.8-8.2(12H, m, Ar-H) ppm. (Table 1)

S. No. R Groups M.P.(o) Yield(%) Mol. Formula % C % H % N
Cal. Found Cal. Found Cal. Found
2a p-OCH3 205 76 C15H14O2N4 63.82 63.76 5.00 5.10 19.85 19.90
2b p-CH3 215 86 C15H14ON4 67.65 67.59 5.30 5.38 21.04 21.10
2c p-Cl 218 82 C14H11ON4Cl 58.65 58.58 3.87 4.95 19.54 19.47
2d p-Br 196 83 C14H11ON4Br 50.78 50.62 3.35 3.40 16.92 16.86
  R’ groups                  
4a-1 p-OCH3C6H4 230 83 C23H18O3N4 69.34 69.45 4.55 4.41 14.06 13.86
4a-2 o-NO2C6H4 193 78 C22H15O4N5 63.92 63.85 3.66 3.70 16.94 16.82
4a-3 3,4,5(OCH3)3-C6H2 211 68 C25H22O5N4 65.49 67.00 4.84 4.89 12.22 12.18
4a-4 o-OHC6H4 216 77 C22H16O3N4 68.74 68.80 4.20 4.16 14.58 14.49
4a-5 p-OHC6H4 239 71 C22H16O3N4 68.74 68.65 4.20 4.18 14.58 14.50
4a-6 o-ClC6H4 241 70 C22H15O2N4Cl 65.60 65.60 3.75 3.68 13.91 14.00
4a-7 p- ClC6H4 235 72 C22H15ON4Cl 65.60 65.58 3.75 3.81 13.91 13.86
4a-8 p-OH,m-OCH3 -C6H3 243 78 C23H18O4N4 66.66 66.70 4.38 4.40 13.52 13.60
4b-1 p-OCH3C6H4 198 86 C23H18O2N4 72.24 72.30 4.74 4.81 14.65 14.72
4b-2 o-NO2C6H4 175 81 C22H15O3N5 66.49 66.40 3.80 3.75 17.62 17.70
4b-3 3,4,5(OCH3)3-C6H2 203 78 C25H22O4N4 67.86 67.70 5.01 5.11 12.66 12.73
4b-4 o-OHC6H4 218 68 C22H16O2N4 71.73 71.62 4.38 4.29 15.21 15.30
4b-5 p-OHC6H4 221 62 C22H16O2N4 71.73 71.66 4.38 4.30 15.21 15.16
4b-6 o-ClC6H4 216 72 C22H15ON4Cl 68.31 68.40 3.91 3.83 14.48 14.53
4b-7 p-ClC6H4 235 72 C22H15ON4Cl 68.31 68.39 3.91 4.00 14.48 14.51
4b-8 p-OH,m-OCH3 -C6H3 235 81 C23H18O3N4 69.34 69.28 4.55 4.49 14.06 14.10
4c-1 p-OCH3C6H4 246 86 C22H15O2N4Cl 65.60 64.30 3.75 3.81 13.91 13.84
4c-2 o-NO2C6H4 198 82 C21H12O3N5Cl 60.37 60.45 2.89 2.81 16.76 16.68
4c-3 3,4,5(OCH3)3-C6H2 261 79 C24H24O4N4Cl 62.27 62.32 4.14 4.21 12.10 12.05
4c-4 o-OHC6H4 232 71 C21H13O2N4Cl 64.87 64.91 3.37 3.42 14.41 14.35
4c-5 p-OHC6H4 222 69 C21H13O2N4Cl 64.87 65.00 3.37 3.40 14.41 14.50
4c-6 o-ClC6H4 248 65 C21H12ON4Cl2 61.93 61.85 2.97 3.05 13.76 13.81
4c-7 p-ClC6H4 242 80 C21H12ON4Cl2 61.93 61.86 2.97 3.10 13.76 13.82
4c-8 p-OH,m-OCH3 -C6H3 243 65 C22H15O3N4Cl 63.09 63.13 3.61 3.53 13.38 13.31
4d-1 p-OCH3C6H4 246 86 C21H15O2N4Br 59.08 59.10 3.38 3.42 12.53 12.60
4d-2 o-NO2C6H4 198 82 C21H12O3N5Br 54.56 54.50 2.62 2.56 15.15 15.10
4d-3 3,4,5(OCH3)3 -C6H2 261 79 C24H19O4N4Br 56.82 56.89 3.77 3.68 11.04 11.12
4d-4 o-OHC6H4 232 71 C21H13O2N4Br 58.22 58.16 3.02 3.11 12.93 12.84
4d-5 p-OHC6H4 222 69 C21H13O2N4Br 58.22 58.31 3.02 3.12 12.93 12.86
4d-6 o-ClC6H4 248 65 C21H12ON4ClBr 55.84 55.91 2.68 2.61 12.40 12.32
4d-7 p-ClC6H4 218 73 C21H12ON4ClBr 55.84 55.80 2.68 2.73 12.40 12.46
4d-8 p-OH,m-OCH3 C6H3 226 78 C23H18O4N4Br 57.04 57.12 3.26 3.20 12.09 12.11

Table 1: Characterization Data of Compounds 2, 3 and 4

The antimicrobial screening of synthesized compounds was carried out by paper disc diffusion method [18] at 100 ppm against Gram +ve bacteria B. substilis, S. aureus and Gram –ve bacteria like E. coli, P. vulgaris. The antifungal activity of the compounds was assayed using fungal species Aspergillus niger and Phytophora. Standard antibacterial streptomycin and antifungal griseofulvin were also screened under similar condition for comparison. (Table 2)

Comp  Bacteria Fungi
E. coli P. valgaris B. subtilis S. aureus Aspergillusniger Phytophora spp.
4a-1 17 16 12 17 17 15
4a-2 5 7 15 14 5 11
4a-3 20 14 19 14 16 12
4a-4 7 10 7 4 8 1
4a-5 14 5 9 11 13 8
4a-6 16 20 17 15 17 20
4a-7 18 18 17 12 19 18
4a-8 12 15 11 12 12 14
4b-1 20 19 11 16 19 12
4b-2 4 8 9 7 4 8
4b-3 25 20 16 17 20 16
4b-4 9 4 14 4 9 7
4b-5 5 9 12 8 7 9
4b-6 17 11 16 11 19 19
4b-7 16 20 16 13 18 11
4b-8 11 12 14 11 12 12
4c-1 16 20 13 16 20 15
4c-2 9 4 8 4 8 10
4c-3 20 18 17 20 18 20
4c-4 8 6 12 6 8 5
4c-5 5 5 11 7 6 8
4c-6 22 19 18 17 23 16
4c-7 19 22 17 16 24 17
4c-8 11 11 7 12 9 12
4d-1 20 20 11 19 18 11
4d-2 14 14 6 8 12 7
4d-3 22 24 18 25 20 18
4d-4 7 8 11 5 7 7
4d-5 12 12 14 9 13 10
4d-6 25 23 20 16 24 20
4d-7 20 21 25 20 22 24
4d-8 15 12 14 11 15 11

Table 2: Antimicrobial Screening Data of the Derivatives of 4

The result indicated that some compounds exhibit good antimicrobial activity against the above mentioned bacterial and fungal species, while some compounds have moderate antimicrobial activity against both Gram +ve and Gram –ve bacterial and fungal species. It was absovered that introduction of OCH3 and Cl groups to the heterocyclic frame work enhanced antibacterial and antifungal activities.

References