Synthesis, characterization and biological activity of 2-methyl-3-aminoquinazolin-4(3H)-ones Schiff bases

Abstracts

The 3-amino-2-methylquinazoline/6-bromo-2-methylquinazoline-4(3H)-ones, 2a,b, on treatment with 2,3-indolinedione in the presence of traces of glacial acetic acid yielded 3-{(2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methylquinazolin/6-bromo-2-methylquinazolin-4-(3H)-ones, 3a,b, which on condensation with various secondary amines and formaldehyde in ethanol afforded title compounds 3-{(1'-alkyl/arylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-ones, 4a1-6 and 4b1-6. C, H, N analysis, infrared spectroscopy, ¹H NMR, and mass spectroscopy allowed the identification of the synthesized compounds, which were investigated for their antimicrobial, analgesic, anti-inflammatory and antihelmintic activities. The results of the biological activities revealed that the compounds 4a3, 4a4 and 4b6 exhibited significant analgesic and anti-inflammatory activities. Compounds 4b5 and 4b6 showed antihelmintic activity when tested against Pheretima posthuma.

2-methylquinazolin-4(3H)-one; bromoderivative; 2,3-indolinedione; Mannich base; antimicrobial

O tratamento de 3-amino-2-metilquinazolina/6-bromo-2-metilquinazolina-4(3H)-onas, 2a,b, com 2,3-indolinediona na presença de traços de ácido acético glacial forneceu 3-{(2'-oxo-1',2'-di-hidroindol-3'-ilideno)amino} -2-metilquinazolina/6-bromo-2-metilquinazolina-4-(3H)-onas, 3a,b, as quais foram condensadas com várias aminas secundárias e formaldeído em etanol para originar compostos do tipo 3-{(1'-alquil/arilaminometil-2'-oxo-1',2'-di-hidroindol-3'-ilideno)amino} -2-metil-6-quinazolin-4-(3H)-onas, 4a1-6 e 4b1-6.Os compostos sintetizados foram caracterizados por análise elementar, espectroscopia no infravermelho, RMN ¹H e espectrometria de massas. Adicionalmente, foram investigadas suas atividades antimicrobiana, analgésica, anti-inflamatória e anti-helmíntica. Os resultados das atividades biológicas revelaram que os compostos 4a3, 4a4 e 4b6 exibiram atividades analgésica e anti-inflamatória significativas. Os compostos 4b5 e 4b6 apresentaram atividade anti-helmíntica, quando testados frente a Pheretima posthuma.

ARTICLE

Synthesis, characterization and biological activity of 2-methyl-3-aminoquinazolin-4(3H)-ones Schiff bases

S. K. Sahu^{I, *}; Md. Afzal Azam^II; M. Banerjee^I; S. Acharrya^IV; C. C. Behera^I; S. Si^III

^IUniversity Department of Pharmaceutical Sciences, Utkal University, Vani Vihar, Bhubaneswar-751004, Orissa, India

^IIDepartment of Pharmaceutical Chemistry, J. S. S., College of Pharmacy, Ootacamund-643001,Tamil Nadu, India

^IIISchool of Pharmaceutical Sciences, ITER, Bhubaneswar, Orissa, India

^IVInstitute of Pharmacy and Technology, Salipur, Orissa, India

ABSTRACT

The 3-amino-2-methylquinazoline/6-bromo-2-methylquinazoline-4(3H)-ones, 2a,b, on treatment with 2,3-indolinedione in the presence of traces of glacial acetic acid yielded 3-{(2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methylquinazolin/6-bromo-2-methylquinazolin-4-(3H)-ones, 3a,b, which on condensation with various secondary amines and formaldehyde in ethanol afforded title compounds 3-{(1'-alkyl/arylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-ones, 4a_1-6 and 4b_1-6. C, H, N analysis, infrared spectroscopy, ¹H NMR, and mass spectroscopy allowed the identification of the synthesized compounds, which were investigated for their antimicrobial, analgesic, anti-inflammatory and antihelmintic activities. The results of the biological activities revealed that the compounds 4a₃, 4a₄ and 4b₆ exhibited significant analgesic and anti-inflammatory activities. Compounds 4b₅ and 4b₆ showed antihelmintic activity when tested against Pheretima posthuma.

Keywords: 2-methylquinazolin-4(3H)-one, bromoderivative, 2,3-indolinedione, Mannich base, antimicrobial

RESUMO

O tratamento de 3-amino-2-metilquinazolina/6-bromo-2-metilquinazolina-4(3H)-onas, 2a,b, com 2,3-indolinediona na presença de traços de ácido acético glacial forneceu 3-{(2'-oxo-1',2'-di-hidroindol-3'-ilideno)amino} -2-metilquinazolina/6-bromo-2-metilquinazolina-4-(3H)-onas, 3a,b, as quais foram condensadas com várias aminas secundárias e formaldeído em etanol para originar compostos do tipo 3-{(1'-alquil/arilaminometil-2'-oxo-1',2'-di-hidroindol-3'-ilideno)amino} -2-metil-6-quinazolin-4-(3H)-onas, 4a_1-6 e 4b_1-6.Os compostos sintetizados foram caracterizados por análise elementar, espectroscopia no infravermelho, RMN ¹H e espectrometria de massas. Adicionalmente, foram investigadas suas atividades antimicrobiana, analgésica, anti-inflamatória e anti-helmíntica. Os resultados das atividades biológicas revelaram que os compostos 4a₃, 4a₄ e 4b₆ exibiram atividades analgésica e anti-inflamatória significativas. Os compostos 4b₅ e 4b₆ apresentaram atividade anti-helmíntica, quando testados frente a Pheretima posthuma.

Introduction

In recent years there has been an increased interest in the chemistry of quinazoline-4(3H)-ones because of their biological significance. Different types of quinazoline-4(3H)-ones exhibit a wide spectrum of biological activities including antihelmintic, antimicrobial and anti-inflammatory activity.^1-4 Certain Schiff and Mannich bases of 2,3-indolinedione derivatives have been reported to possess significant antimicrobial and anti-inflammatory activity.^5-9 In view of these findings it appeared of interest to synthesize a series of novel Schiff bases of 2-methylquinazoline/6-bromo-2-methylquinazoline-4(3H)-ones containing 2,3-indolinedione or Mannich bases of 2,3-indolinedione residues with the aim of obtaining some novel heterocyclic systems with potentially enhanced antimicrobial, analgesic, anti-inflammatory and antihelmintic activities. In the present investigation, a new series of novel 3-{(1^'-substituted aminomethyl-2^'-oxo-1^',2^'-dihydro-indole-3^'-yl-idene)amino} -2-methylquinazolin/6-bromo-2-methylquinazolin-4-(3H)-ones 4a_1-6and 4b_1-6 was prepared as per Scheme 1 and screened for their antimicrobial, analgesic, anti-inflammatory and antihelmintic activities.

Results and Discussion

Chemical synthesis

The starting material 3-amino-2-methylquinazolin-6-bromo-2-methylquinazolin-4(3H)-ones 2a,b were prepared according to literature methods,^10,11 from the corresponding anthranilic acid. 3-Aminoquinazolinone derivatives 2a,b were used as precursors for further reaction with the purpose of synthesizing several heterocyclic compounds attached to the 3-methylquinazolin-4(3H)-one moiety. Thus, condensation of 2a,b with 2,3-indolinedione in the presence of trace amount of glacial acetic acid, furnished the corresponding Schiff bases 3a,b. The Schiff bases thus obtained were treated in ethanol with formalin and various secondary amines to afford the corresponding Mannich bases 4a_1-6and 4b_1-6. Analytical data, FT-IR, ¹H NMR and mass spectra confirmed the structures of the new compounds 4a_1-6and 4b_1-6. Compounds 3a,b showed absorption bands at 3472 cm^-1 for NH group and at 1727 and 1670 cm^-1 due to C=O stretching vibrations. Also, the ¹H NMR spectra of compounds 3a and 3b showed a singlet at d 10.63 and 10.53 ppm, respectively for the NH hydrogens, confirming the formation of Schiff bases 3a,b.

The mass spectra of 3a showed molecular ion peak M⁺ at m/z 304 corresponding to the molecular formula C₁₇H₁₂N₄O₂. The infrared spectra of compounds 4a_1-6and 4b_1-6were characterized by the disappearance of the NH absorption band. Also, the ¹H NMR spectra of title compounds 4a_1-6and 4b_1-6 showed the presence of methylene group and the aromatic hydrogens all appeared at the expected chemical shifts (see Experimental). The mass spectra of 4a₁showed the molecular ion peak M⁺ at m/z 361 corresponding to the molecular formula C₂₀H₁₉N₅O₂.

Biological study

Antimicrobial activity

Compounds 4a_1-6and 4b_1-6 were assayed for their antibacterial activity against Staphylococcus aureus, Staphylococcus faecalis, Escherichia coli, and Salmonella typhi and for antifungal activities against Candida albicans and Aspergillus niger by cup plate method.¹² Further, their minimum inhibitory concentration values against these microorganisms were determined by serial dilution method.¹³ The test microorganisms were obtained from Department of Microbiology, OUAT, Orissa, India. Muller Hinton agar plates (37 ºC, 24 h) and Sabouraud's dextrose agar plates (26 ºC, 48-72 h) were used for the cultivation of bacteria and fungi, respectively. The results of antibacterial and antifungal activity tests are summarized in Tables 1 and 2 with standard drugs ciprofloxacin and clotrimazole for comparison. Most of the synthesized compounds were found to possess varied degrees of antibacterial activities as evident from their minimal inhibitory concentration (MIC). Compounds 4b₅ and 4b₆ were found to possess moderate activity against all the tested bacteria while all the tested compounds except 4b₅ and 4b₆ showed lower activity against Escherichia coli. Most of the synthesized compounds were found to possess moderate activity against tested fungi. However, no correlation was observed between different substituents at 1' position of 2,3-indolinedione ring and antifungal activity. It is noted that bromination at 6 position of 2-methylquinazolin-4(3H)-one ring does not have any significant effect on antimicrobial activity.

Analgesic and anti-inflammatory activity

The synthesized compounds 4a_1-6and 4b_1-6were evaluated for analgesic and anti-inflammatory activities. Students t-test were performed to ascertain the significance of the exhibited activities. The test compounds (100 mg kg^-1) and the standard drug indomethacin (10 mg kg^-1) were administered in the form of a suspension (1% carboxymethyl cellulose as vehicle) by oral route. The study of analgesic activity was done by tail immersion method,¹⁴ using wistar albino mice. The percent analgesic activity was calculated and listed in Table 3 with a standard drug indomethacin for comparison. Compounds 4a₂, a₄, and 4b₂, b₄having diethylaminomethyl and dihexylaminomethyl groups, respectively at 1' position of 2,3-indolinedione nucleus showed significant percent analgesic activity ranging from 50 to 54.96 after 1 h of administration. Moreover, diethylaminomethyl group was found to be optimum for analgesic activity in comparison to other groups. It was noted that bromination at 6 position of 3-methylquinoxaline-4(3H)-one ring decreases the analgesic activity. Remaining compounds showed less analgesic activity in comparison to standard drug indomethacin.

In the present investigation the anti-inflammatory activity of test compounds 4a_1-6and 4b_1-6 in acute conditions was evaluated using the carrageenan induced rat paw edema method of Winter et al.¹⁵ The carrageenan induced inflammation model is a cyclooxygenases(COX) dependent reaction and is used to determine COX inhibition. For anti-inflammatory evaluation, adult albino rats of either sex were divided in groups of 6. The percent anti-inflammatory activity with indomethacin as a standard drug is presented in Table 4. Compounds 4a_2-a₄ and 4a₆exhibited significant percent anti-inflammatory activity ranging from 43.14 to 46.85 after 1h of administration while remaining compounds showed lower activity in comparison to indomethacin. It was observed that compounds 4a₃ and 4a₄ having bulky diphenylaminomethyl and dihexylaminomethyl groups, respectively at 1' position of 2,3-indolinedione nucleus showed maximum activity. It is evident from Table 4 that bromination at 6 position of 3-methylquinoxalin-4(3H)-one nucleus decreases the anti-inflammatory activity.

Some of the compounds tested produced significant analgesic and anti-inflammatory effects. These compounds may exhibit both central and peripheral actions because analgesia and inflammation are central and peripheral processes, respectively. The compounds show suppressant activity on acute inflammation model of carrageenan induced inflammation in rats paw and produced significant analgesic activity. From these observations it can be indeed inferred that the endogenous chemical substances liberated during pain and inflammation like histamine, serotonin and arachidonic cascade metabolites are inhibited to produce analgesic and anti-inflammatory activities.

Antihelmintic activity

The antihelmintic activity of the synthesized compounds 4a_1-6 and 4b_1-6 were evaluated on adult Indian earthworm, Pheretima posthuma due to its anatomical and physiological resemblance with the intestinal roundworm parasites of human beings.^16-18 The method of Dash et al.¹⁹ was followed and the results are presented in Table 5. Piperazine citrate, which is used in the treatment of roundworm and threadworm (cestoda) infections was selected as a reference standard. The antihelmintic activity data revealed significant activity of all the test compounds against the tested Pheretima posthuma. In the present study compounds 4a_3-6 and 4b_5,6were found to be more potent than piperazine citrate. It is evident from results that compounds containing dihexylaminomethyl, piperazinylmethyl and morpholinomethyl groups at 1' position of 2,3-indolinedione ring are more active. It is also noted that bromination at 6 position of 2-methylquinazolin-4(3H)-one derivatives slightly increases the antihelmintic activity. The principal aim of the present study was to modify and optimize the structural features of 2, 3, 6-trisubstituted quinazolin-4(3H)-ones.

Conclusions

Generally, it can be concluded that 3-{(1'-aryl/alkylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6- quinazolin-4-(3H)-ones 4a_1-6and 4b_1-6 represent a new distinct classes of analgesic and anti-inflammatory agents with antimicrobial activity. The dibenzylaminomethyl 4a₃, dihexylaminomethyl 4a₄ and morpholinomethyl 4b₆ analogs appeared to be more active analgesic and anti-inflammatory agents in comparison to other synthesized Schiff bases. Compound 4b₆, which contain morpholinomethyl moiety at 1' position, was found to be the most active compound as analgesic, anti-inflammatory and antimicrobial agent. Antihelmintic study results revealed that the presence of piperazinylmethyl and morpholinomethyl groups at 1' position of 2,3-indolinedione nucleus and a bromine atom at 6 position of 2-quinazolin-4(3H)-one ring are optimum for the antihelmintic activity (4b₅ and 4b₆).

Experimental

Melting points were determined on a Tempstar apparatus and are uncorrected. Infrared spectra were recorded on a Jasco (410) FT-infrared spectrophotometer, measured as KBr disks.¹H NMR were recorded on a Bruker DPX-300 MHz spectrometer in deuteriochloroform with trimethylsilane as internal standard (chemical shift in δ ppm). The mass spectral data were obtained with a Perkin-Elmer Hitachi RMU-6L MS-30 spectrometer at 70 eV and a 90 ºC inlet temperature. Purity of all the compounds was checked on silica gel plates and spots were located in iodine vapours. Elemental analysis was performed on EURO EA (Italy) analyzer and the results were within ± 0.3% of calculated values.

General method for the preparation of Schiff bases (3a,b)

To a solution of 2,3-indolinedione (0.005 mol) in ethanol (50 mL) was added the appropriate 3-amino-2-methylquinazolin-4(3H)-one 2a,b (0.005 mol) and a few drops of acetic acid. The reaction mixture was refluxed for 17 h on a water bath and then allowed to cool. The solid thus separated was filtered, washed with aqueous ethanol and recrystallized from appropriate solvent. The following Schiff bases were prepared in this manner:

3-{(2'-Oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methylquinazolin-4-(3H)-one (3a)

Recryst. solvent: Benzene, Yield (1.110 g, 73%), mp 112 ºC. Elemental Analysis Calculated for C₁₇H₁₂N₄O₂ (304.30): 61.10% C; 3.97% H; 18.41% N. Found: 60.97% C; 4.22% H; 18.03% N. ¹H NMR δ 2.50 (s, 3H, CH₃), 6.21-8.57 (m, 8H, ArH), 10.63 (s, 1H, NH). MS m/z 304 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3472 (N-H), 3076(Ar-H), 1727 (C=O), 1670 (C=O), 1616 (C=N), 1588 (C=N), 1300 (C-N).

6-Bromo-3- {(2'-oxo-1', 2'-dihydroindole-3'-ylidene)amino} -2-methylquinazolin-4-(3H)-one (3b)

Recryst. solvent: Benzene, Yield (1.379 g, 72%), mp 121 ºC. Elemental Analysis Calculated for C₁₇H₁₁N₄O₂Br (383.19): 53.28% C; 2.89% H; 14.62% N. Found: 53.47% C; 3.09% H; 14.23% N. ¹H NMR δ 2.48 (s, 3H, CH₃), 6.38-8.49 (m, 7H, ArH), 10.53 (s, 1H, NH). MS (m/z) 383 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3472 (N-H), 3076(Ar-H), 1727 (C=O), 1670 (C=O), 1616 (C=N), 1588 (C=N), 1300 (C-N).

General method for the preparation of Mannich bases 4a_1-6and 4b_1-6

To a mixture of 3a,b (0.005 mol) and 37% formalin (1 mL) in ethanol (20 mL) was added drop wise appropriate secondary amines (0.005 mol) with stirring over 15 min. The stirring was continued for 1h at room temperature and the reaction mixture then warmed for 15 min on a water bath. The mixture was poured into ice-cold water and stored in a refrigerator. The solid thus separated was filtered, washed with water, dried and recrystallized from appropriate solvent. The following title compounds were prepared as just described:

3-{(1'-Dimethylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6- quinazolin-4-(3H)-one (4a₁)

Recryst. solvent: Ethanol, Yield (1.138 g, 63%), mp 150 ºC. Elemental Analysis Calculated for C₂₀H₁₉N₅O₂ (361.39): 66.47% C; 5.30% H; 19.38% N. Found: 66.32% C; 5.41% H; 19.31% N. ¹H NMR δ 1.12 , (s, 3H, CH₃), 2.5 (s, 6H, N (CH₃)₂), 4.43 (s, 2H, CH₂), 6.5-8.98 (m, 8H, ArH ). MS (m/z) 361.39 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3026 (Ar-H), 2816 (CH₂), 1733 (C=O), 1662 (C=O), 1570 (C=N), 1317 (C-N).

3-{(1'-Diethylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4a₂)

Recryst. solvent: Ethanol,Yield (1.479 g, 76%), mp 142 ºC. Elemental Analysis Calculated for C₂₂H₂₃N₅O₂ (389.45): 67.85% C; 5.95% H; 17.98% N. Found: 67.88% C; 5.87% H; 18.10% N. ¹H NMR δ 1.09 (s, 3H, CH₃), 2.55 (q, 10H, N(C₂H₅)₂), 2.88 (s, 3H, CH₃), ),4.32 (s, 2H, CH₂), 6.57-8.22 (m, 8H, ArH). MS (m/z) 389.40 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3030 (Ar-H), 2855 (CH₂), 1717 (C=O), 1661 (C=O), 1609 (C=N), 1350 (C-N).

3-{(1'-Diphenylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4a₃)

Recryst. solvent: Ethanol, Yield (10.769 g, 52%), mp 140 ºC. Elemental Analysis Calculated for C₃₀H₂₃N₅O₂ (485.53): 74.21% C; 4.77% H; 14.42% N. Found: 74.13% C; 4.74% H; 14.45% N. ¹H NMR δ 1.09 (s, 3H, CH₃), 5.10 (s, 2H, CH₂), 6.36-8.20 (m, 18H, ArH). Mass spectrum (m/z) 485.50 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3032 (Ar-H), 2841 (CH₂), 1742 (C=O), 1689 (C=O), 1636 (C=N), 1334 (C-N).

3-{(1'-Dihexylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4a₄)

Recryst. solvent: Ethanol, Yield (1.517 g, 61%), mp 152 ºC. Elemental Analysis Calculated for C₃₀H₃₅N₅O₂ (497.63): 72.41% C; 7.09% H; 14.07% N. Found: 72.49% C; 6.97% H; 14.21% N. ¹H NMR δ 1.59 (s, 3H, CH₃), 1.73 (t, 2H, CH₂), 3.91 (s, 22H, CH₂), 7.00-8.66 (m, 8H, ArH). MS (m/z) 497.63 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3076 (Ar-H), 2881 (CH₂), 1733 (C=O), 1670 (C=O), 1607 (C=N), 1307 (C-N).

3-{(1'-Piperazinylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4a₅)

Recryst. solvent: Ethanol, Yield (1.817 g, 59%), mp 154 ºC. Elemental Analysis Calculated for C₂₂H₂₂N₆O₂ (402.44): 65.66% C; 5.51% H; 20.88% N. Found 65.42% C; 5.80% H; 20.67% N. ¹H NMR δ 1.21 (s, 3H, CH₃), 2.63 (s, 2H, CH₂), 4.00 (t, 4H, CH₂), 4.49 (m, 4H, CH₂), 6.70-8.20 (m, 8H, ArH), 8.37(s, 1H, NH). MS (m/z) 402.39 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3361 (NH), 3013 (Ar-H), 2888 (CH₂), 1687 (C=O), 1652 (C=O), 1602 (C=N), 1325 (C-N).

3-{(1'-Morpholinoaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4a₆)

Recryst. solvent: Ethanol, Yield (1.35 g, 67%), mp 141 ºC. Elemental Analysis Calculated for C₂₂H₂₁N₅O₃Br (403.42): 65.50% C; 5.25% H; 17.36% N. Found 65.75% C; 5.55% H; 17.06% N. ¹H NMR δ 1.06 (s, 3H, CH₃), 2.37 (s, 2H, CH₂), 3.40 (t, 4H, CH₂), 5.75 (t, 4H, CH₂), 6.66-8.36 (m, 8H, ArH ), 8.58(s,1H, NH). MS (m/z) 403.42 (M⁺). FT-IR (KBr), </font><font size="2">&#957;</font><font face="verdana" size="2">_max/cm^-1: 3066 (Ar-H), 2818 (CH₂), 1726(C=O), 1675 (C=O), 1604 (C=N), 1314 (C-N) 1128 (COC), 632(C-Br).

6-Bromo-3- {(1'-dimethylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4b₁)

Recryst. solvent: Ethanol, Yield (1.089g, 69%), mp 165 ºC. Elemental Analysis Calculated for C₂₀H₁₈N₅O₂Br (440.29): 54.56% C; 4.12% H; 15.91% N. Found: 54.83% C; 4.10% H; 15.78% N. ¹H NMR δ 1.06 (s, 3H, CH₃), 2.37 (t, 3H, CH₃), 3.40 (t, 3H, CH₃), 5.57 (s, 2H, CH₂), 6.70-8.20 (m, 7H, ArH ), 8.37 (s,1H, NH). MS (m/z) 440.29 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3066 (Ar-H), 2818 (CH₂), 1726 (C=O), 1675 (C=O), 1604 (C=N), 1314 (C-N).

6-Bromo-3- {(1'-diethylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4b₂)

Recryst. solvent: Ethanol , Yield (1.428 g, 61%), mp 162 ºC. Elemental Analysis Calculated for C₂₂H₂₂N₅O₂Br (468.34): 56.42% C; 4.73% H; 14.95% N. Found: 56.47% C; 4.83% H; 15.17% N. ¹H NMR δ 1.11 (s, 3H, CH₃), 2.50-2.87 (q, 10H, N(C₂H₅)₂), 4.29 (s, 2H, CH₂), 6.65-8.34 (m, 7H, ArH). MS (m/z) 468.34 (M⁺). FT-IR (KBr, </font><font size="2">&#957;</font><font face="verdana" size="2">_max/cm^-1): 3032 (Ar-H), 2853 (CH₂), 1717 (C=O), 1663 (C=O), 1609 (C=N), 1353 (C-N).

6-Bromo-3- {(1'-diphenylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4b₃)

Recryst. solvent: Ethanol , Yield (1.777 g, 63%), mp 144 ºC. Elemental Analysis Calculated for C₃₀H₂₂N₅O₂Br (563.43): 63.84% C; 3.93% H; 12.41% N. Found 64.10% C; 4.22% H; 12.27% N. ¹H NMR δ 1.07 (s, 3H, CH₃), 4.98 (s, 2H, CH₂), 6.25-8.15 (m, 17H, ArH). MS (m/z) 563.43 (M⁺). FT-IR (KBr, ν_max/cm^-1): 3032 (Ar-H), 2845 (CH₂), 1745 (C=O), 1690 (C=O), 1636 (C=N), 1334 (C-N).

6-Bromo-3- {(1'-dihexylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4b₄)

Recryst. solvent: Ethanol, Yield (1.643 g, 57%), mp 168 ºC. Elemental Analysis Calculated for C₃₀H₃₄N₅O₂Br (576.52): 62.50% C; 5.94% H; 12.15% N. Found 62.41% C; 5.73% H; 12.37% N. ¹H NMR δ 1.06 (s, 3H, CH₃), 1.62 (t, 2H,CH₂), 3.84 (s, 22H, CH₂), 7.22-8.56 (m, 7H, ArH ). MS (m/z) 576.52 (M⁺). FT-IR (KBr, </font><font size="2">&#957;</font><font face="verdana" size="2">_max/cm^-1): 3078 (Ar-H), 2883 (CH₂), 1730 (C=O), 1665 (C=O), 1605 (C=N), 1307 (C-N).

6-Bromo-3- {(1'-piperazinylminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4b₅)

Recryst. solvent: Ethanol, Yield (1.492 g, 62%), mp 164 ºC. Elemental Analysis Calculated for C₂₂H₂₁N₆O₂Br (481.34): 54.90% C; 4.40% H; 17.46% N. Found: 54.83% C; 4.62% H; 17.16% N. ¹H NMR δ 1.17 (s, 3H, CH₃), 2.55 (s, 2H, CH₂), 4.12 (t, 4H, CH₂), 4.39 (t, 4H, CH₂), 6.71-8.24 (m, 7H, ArH), 8.58 (s, 1H, NH). MS (m/z) 481.34 (M⁺). FT-IR (KBr, </font><font size="2">&#957;</font><font face="verdana" size="2">_max/cm^-1): 3357 (NH), 3017 (Ar-H), 2876 (CH₂), 1687 (C=O), 1643 (C=O), 1600 (C=N), 1317 (C-N).

6-Bromo-3- {(1'-morpholinoaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4b₆)

Recryst. solvent: Ethanol, Yield (1.615 g, 67%), mp 160 ºC. Elemental Analysis Calculated for C₂₂H₂₀N₅O₃Br (482.32): 54.78% C; 4.18% H; 14.52% N. Found 54.53% C; 4.34% H; 14.29% N. ¹H NMR δ 1.06 (s, 3H, CH₃), 2.37 (s, 2H, CH₂), 3.40 (t, 4H, CH₂), 5.75 (t, 4H, CH₂), 6.66-8.36 (m, 7H, ArH), 8.58 (s, 1H, NH). MS (m/z) 482.32 (M⁺). FT-IR (KBr), ν_max/cm^-1: 3056 (Ar-H), 2822 (CH₂), 1720(C=O), 1666 (C=O), 1608 (C=N), 1321 (C-N),1124 (COC), 625 (C-Br).

Conclusions

Various 3-{(1'-aryl/alkylaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-ones 4a_1-6and 4b_1-6 were prepared with the objective of developing better anti-inflammatory compounds with antimicrobial activities. Among these, 6-Bromo-3- {(1'-morpholinoaminomethyl-2'-oxo-1',2'-dihydroindole-3'-ylidene)amino} -2-methyl-6-quinazolin-4-(3H)-one (4b₆) presented maximum activity. It also showed maximum antihelmintic activity. SAR studies and evaluation of more potent analogs are under way.

Acknowledgments

The authors are grateful to the authorities of University Department of Pharmaceutical Sciences, Utkal University, Bhubaneswar and Institute of Pharmacy and Technology, Salipur, Cuttack, Orissa, India for providing the necessary facility to carry out this research work. We are also thankful to Prof. A. C. Dash and Prof. C. S. Panda NISER, Bhubaneswar, India for valuable suggestions.

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Received: September 22, 2007

Web Release Date: May 9, 2008

Publication Dates

• Publication in this collection
  05 Aug 2008
• Date of issue
  2008

History

• Accepted
  09 May 2008
• Received
  22 Sept 2007