Synthesis and Antimicrobial Activity of Some Novel Hydrazinyl Quinazoline Amine Derivatives

 

Amarish B. Samel and Nandini R. Pai*

Department of Chemistry, D.G. Ruparel College, Senapati Bapat Marg, Mahim, Mumbai-400 016, India

*Corresponding Author E-mail: nandini_pai@hotmail.com

 

ABSTRACT:

2-chloro-4-aminoquinazolines 3a-b were synthesized by intramolecular cyclization of substituted formamide 2a-b in presence of phosphorus oxychloride in one pot. These were further condensed with 5-aryl/alkyl- 2-hydrazino-1,3,4-thiadiazoles 8a-e. synthesized by condensation of hydrazine hydrate with 2-chloro-5-aryl/alkyl-1,3,4-thiadiazoles 7a-e which in turn were obtained by copper mediated diazotization of 2-amino-5-aryl/alkyl-1,3,4-thiadiazoles 6a-e in acetic acid to give various 2-[2-(1,3,4-thiadiazol-2-yl)hydrazinyl] quinazolin-4-amines 9a-l. The structures of the compounds have been confirmed by elemental analysis and spectral analysis. Newly synthesized compounds were screened for their antimicrobial activities.

 

KEYWORDS: Antimicrobial activity, Quinazoline-4- amine, aryl/alkyl-1,3,4-thiadiazoles.

 


 

INTRODUCTION:

Medicinally quinazoline has been used in various areas especially as an anti-malarial agent and in cancer treatment. Quinazoline and its derivatives are a class of hetero aromatic compounds that have drawn much attention because of their biological and pharmaceutical activities including a wide range of antitumor activity1–4. Among other pharmacological activities, quinazoline derivatives show remarkable antimicrobial properties5.

 

1,3,4-Thiadiazole, is a versatile pharmacophore which exhibits a wide variety of biological activities. A few of them which are worthy of mention are diuretic6,7 CNS depressants8,9, hypoglycemic10,11, anti-inflammatory12, and anti-microbial activities13.

 

Hence it was planned to suitably incorporate the 4-amino quinazoline moiety into the 1,3,4-thiadiazole ring system and to explore the possibilities of some altered biological action. So, the following Hydrazinyl Quinazoline amine derivatives were synthesized and tested for antimicrobial activity.

 

EXPERIMENTAL SECTION:

Melting points were determined in open capillaries on a Thomas Hoover apparatus and are uncorrected. 1H-NMR and 13C-NMR spectra were recorded on a Bruker AM 300 (300 MHz) instrument using tetramethylsilane (TMS) as an internal standard. Chemical shifts are given in parts per million (ppm). Splitting patterns are designated as follows: s- singlet, d- doublet, t- triplet, q- quartet and m- multiplet. Mass spectra (MS) were recorded on Shimadzu LC-MS. The reactions were followed up on pre-coated TLC plates (Silica gel 60 F254, Merck), visualizing the spots in ultraviolet light.

 

Preparation of 6-cyanoaniline-1-yl formamide (2a-b) 14:

2-amino benzonitrile (56 mmol) is taken in 50 ml glacial acetic acid and cooled to 10-15 C. To this solution is added a suspension of sodium cyanate (84 mmol) in 25ml water over a period of one hour and stirred further for one hour. The solid is filtered and washed with water and acetone to get 6-cyanoaniline-1-yl formamides.

 

Preparation o f 2-Chloro-quinazolin-4-yl amine (3a-b)14:

A round bottom flask was charged with 6-cyanoaniline-1-yl formamides (32 mmol) and phosphorus oxychloride (50 ml) in one lot at 25-30 C. Then the reaction mixture is heated to 65- 70 C for one hour, cooled to 25-30 C and poured in ice water. The solid precipitates out which is filtered and suck dried. The wet cake is then taken in 50 ml water and pH is adjusted to 7.5 with saturated solution of sodium hydroxide. The solid is filtered and washed with water and acetone to get 2-Chloro-quinazolin-4-yl amines 3a-b

 

3a Yield (82%), mp. 237-240 ºC15; 1H-NMR (300 MHz;DMSO-d6): 7.50 (t, 1H), 7.59 (d, 1H), 7.79 (t, 1H) ), 8.21 (d, 1H), 8.33 (s, 2H) 13C-NMR (75.5 MHz; DMSO-d6) 112.9, 123.8, 125.8, 126.4, 133.8, 150.7, 156.9, 163.6. MS m/z: 179

3b Yield (79%); 1H-NMR (300 MHz; DMSO-d6): 7.61 (d, 1H), 7.81 (d, 1H), 8.38 (s, 1H), 8.44 (s, 2H) 13C-NMR (75.5 MHz; DMSO-d6) 114.9, 124.2, 129.6, 130.8, 135.2, 150.5, 158.3, 163.8. MS m/z: 213

 

Preparation of 2-Amino-(5-aryl/alkyl)-1,3,4-thiadiazoles (6a-e)16:

To a round bottom flask (r.b.f.) was added carboxylic acid 1 (0.01 mol), thiosemicarbazide 2 (0.012 mol) and conc. H2SO4 (15 mL) slowly under cooling. The resultant reaction mixture was heated on a water bath for 3 h, then poured into crushed ice and neutralized with ammonia solution cautiously. A yellow coloured solid separates out. It was filtered off, washed with saturated sodium bicarbonate solution and water. Then dried under suction and crystallized from ethanol to get 6a-e.

 

Preparation of 2-chloro-(5-aryl/alkyl)-1,3,4-thiadiazoles (7a-e)17:

The round bottom  flask was charged with a stirred suspension of 6a-e (50 mmol) in a mixture of glacial acetic acid (150 mL) and concentrated HCl (30 mL) with copper turnings (0.1 times the weight of 6a-e) was cooled to 15 C , and a solution of sodium nitrite (51.5 mmol) in water (10 mL) was added over 0.5 h. The mixture was kept at 10-15 C for a further 2-4 h, poured into water, and extracted with CHC13 (three times). The combined extracts were washed with NaHC03 solution, dried (Na2S04), and evaporated to give crude 7a-e. If necessary, purification was by passage through a short silica gel column with CHCl3 eluent.

 

Preparation of 5-(aryl/alkyl)-2-hydrazino-1,3,4-thiadiazoles (8a-e)17:

In a slight modification to the procedure of Potts and Wuseby18, a solution of a 2-chlorothiadiazole 7a-e (0.025 mol) and hydrazine hydrate (0.075 mol) in EtOH (50 mL) was heated at reflux for 2 -4 h. The solvent was evaporated, water was added, and the product was isolated by filtration to get 8a-e.

 

8a. Yield (82%), mp. 158 C19; 1H-NMR (300 MHz; DMSO-d6): 2.49 (t, 3H, -CH3), 4.95 (s, 2H,-NH-NH2), 8.68 (s, 1H, NH-NH2); 13C-NMR (75.5 MHz; DMSO-d6) 15.6, 154.0, 177.4.

 

8b. Yield (79%), mp. 113-114ºC20; 1H-NMR (300 MHz; DMSO-d6): 1.20 (t, 3H, CH2-CH3), 2.78 (q, 2H, CH2-CH3), 5.01 (s, 2H,-NH-NH2), 8.68 (s, 1H, NH-NH2); 13C-NMR (75.5 MHz; DMSO-d6) 13.8, 23.0, 159.9, 176.5

 

8c .Yield (85%), mp. 184-186 C21; 1H-NMR (300 MHz; DMSO-d6): 5.25 (s, 2H,-NH-NH2), 7.40-7.48 (m, 3H, Ar), 7.75-7.78 (m, 2H, Ar) ), 9.00 (s, 1H, NH-NH2); 13C-NMR (75.5 MHz; DMSO-d6) 126.0, 129.0, 129.3, 131.7, 156.3, 177.1.

8d. Yield (90%), mp. 208-210ºC 21;1H-NMR (300 MHz; DMSO-d6): 5.20 (s, 2H,-NH-NH2), 7.23 (d, 2H, Ar), 7.62 (d, 2H, Ar) ), 8.94 (s, 1H, NH-NH2), 13C-NMR (75.5 MHz; DMSO-d6) 125.9, 128.4, 129.5, 139.0, 156.5, 176.8.

 

8e. Yield (71%), mp. 162-163ºC 21;1H-NMR (300 MHz; DMSO-d6): 5.20 (s, 2H,-NH-NH2), 7.24-7.33 (m, 3H, Ar), 7.52 (d, 1H, Ar) ), 8.92 (s, 1H, NH-NH2); 13C-NMR (75.5 MHz; DMSO-d6) 126.2, 128.9, 130.1, 131.3, 125.7, 155.8, 177.2.

 

8f. Yield (92%), mp. 308-310ºC 21;1H-NMR (300 MHz; DMSO-d6): 5.25 (s, 2H,-NH-NH2), 7.49 (d, 2H, Ar), 7.65 (d, 2H, Ar) ), 9.05 (s, 1H, NH-NH2); 13C-NMR (75.5 MHz; DMSO-d6) 127.6, 129.1, 130.0, 133.7, 155.1, 177.4.

 

Preparation of 2-[2-(1,3,4-thiadiazol-2-yl)hydrazinyl] quinazolin-4-amines 9a-l :

The round bottom  flask was charged with 5-(aryl/alkyl)-2-hydrazino-1,3,4-thiadiazoles 8a-e (0.001mole) and 2-Chloro-quinazolin-4-yl amine 3a-b (0.001mol) in ethanol and heated for reflux for 2 to 4 hours, cooled to room temperature solid precipitates out which is filtered and washed with ethanol to give 9a-l.

 

9a. IR: 3394 (NH2str.), 1635 (pri- NH bending.), 1527(sec- NH bending.), 1365 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 2.52 (s, 3H, -CH3), 7.24-7.76 (m, 4H,Ar-H), 8.12 (d, 2H, D2O exchangeable), 9.00 (s, 1H, D2O exchangeable), 9.48 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 15.1, 111.6, 121.5, 123.0, 123.6, 123.9, 125.3, 132.7, 154.0, 162.5, 175.8; MS m/z: 274 (M+1).

 

9b. IR: 3332 (NH2str.), 1627 (pri- NH bending.), 1550(sec- NH bending.), 1326 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 2.63 (s, 3H, -CH3), 7.60-7.88 (m, 3H,Ar-H), 9.43 (d, 2H, D2O exchangeable), 11.56 (s, 1H, D2O exchangeable), 12.48 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 14.6, 111.5, 121.5, 123.0, 123.6, 123.9, 125.3, 137.6, 155.0, 162.5, 175.8; MS m/z: 308 (M+1).

 

9c. IR: 3350 (NH2str.), 1612 (pri- NH bending.), 1527(sec- NH bending.), 1365 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 1.30 (t, 3H, -CH2-CH3), 2.87 (q, 2H, -CH2-CH3)7.43-8.42 (m, 4H,Ar-H), 9.13 (s, 1H, D2O exchangeable), 9.43 (s, 1H, D2O exchangeable), 10.99 (s, 1H, D2O exchangeable), 12.48 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 13.7, 23.2, 110.2, 117.6, 125.0, 135.4, 138.8, 155.0, 162.8, 170.4.; MS m/z: 288 (M+1).

 

9d. IR: 3312 (NH2str.), 1605 (pri- NH bending.), 1537(sec- NH bending.), 1335 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 1.22 (t, 3H, -CH2-CH3), 2.95 (q, 2H, -CH2-CH3)7.43-8.42 (m, 3H,Ar-H), 9.13 (s, 1H, D2O exchangeable), 9.43 (s, 1H, D2O exchangeable), 10.99 (s, 1H, D2O exchangeable), 12.48 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 13.6, 23.1, 111.2, 117.2, 125.0, 136.4, 137.8, 155.1, 162.6, 171.4.; MS m/z: 322 (M+1).

 

9e. IR: 3386 (NH2str.), 1638 (pri- NH bending.), 1512 (sec- NH bending.), 1373 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 7.49-8.39 (m, 9H,Ar-H), 9.18 (s, 1H, D2O exchangeable), 9.39 (s, 1H, D2O exchangeable), 11.11 (s, 1H, D2O exchangeable), 12.64 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 110.2, 117.7, 125.1, 126.5, 129.2, 130.0, 130.4, 135.4, 135.9, 138.8, 155.0, 161.7, 171.4.; MS m/z: 336 (M+1).

 

9f. IR: 3392 (NH2str.), 1645 (pri- NH bending.), 1525(sec- NH bending.), 1345 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 7.25-8.35 (m, 8H,Ar-H), 9.04 (s, 1H, D2O exchangeable), 9.24 (s, 1H, D2O exchangeable), 10.98 (s, 1H, D2O exchangeable), 12.50 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 111.6, 119.9, 124.4, 126.5,126.7, 129.0, 129.2, 129.9, 130.4, 130.8, 135.3, 137.8, 155.2, 161.9, 174.1.; MS m/z: 370 (M+1).

 

9g. IR: 3400 (NH2str.), 1635 (pri- NH bending.), 1527(sec- NH bending.), 1373 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 2.34 (s, 3H,Ar-CH3) 7.28-8.40 (m, 8H,Ar-H), 9.18 (s, 1H, D2O exchangeable), 9.42 (s, 1H, D2O exchangeable), 11.09 (s, 1H, D2O exchangeable), 12.64 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 20.9, 110.2, 117.8, 124.9, 125.7, 126.5, 126.6, 127.3, 129.8, 135.4, 140.3, 140.8, 155.1, 161.9, 174.1.; MS m/z: 350 (M+1).

 

9h. IR: 3317 (NH2str.), 1627 (pri- NH bending.), 1521(sec- NH bending.), 1350 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 2.34 (s, 3H,Ar-CH3) 7.28-8.55 (m, 7H,Ar-H), 9.25 (s, 1H, D2O exchangeable), 9.42 (s, 1H, D2O exchangeable), 11.19 (s, 1H, D2O exchangeable), 12.66 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 20.8, 111.6, 117.1,119.9, 124.4, 126.4, 127.2, 129.0, 129.8, 135.3, 137.8, 140.4, 155.0, 161.9, 174.3.; MS m/z: 384 (M+1).

 

9i. IR: 3311 (NH2str.), 1604 (pri- NH bending.), 1527(sec- NH bending.), 1357 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 2.55 (s, 3H,Ar-CH3) 7.29-8.37 (m, 8H,Ar-H), 9.16 (s, 1H, D2O exchangeable), 9.36 (s, 1H, D2O exchangeable), 11.06 (s, 1H, D2O exchangeable), 12.60 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 21.1, 110.3, 117.7, 124.9, 125.1, 126.4, 129.0, 129.9, 130.2, 131.5, 135.5, 136.1, 157.8, 162.9, 170.3.; MS m/z: 350 (M+1).

 

9j. IR: 3301 (NH2str.), 1596 (pri- NH bending.), 1550(sec- NH bending.), 1357 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 2.55 (s, 3H,Ar-CH3) 7.29-8.56 (m, 7H,Ar-H), 9.13 (s, 1H, D2O exchangeable), 9.33 (s, 1H, D2O exchangeable), 11.03 (s, 1H, D2O exchangeable), 12.24 (s, 1H, D2O exchangeable) 13; C-NMR (75.5 MHz; DMSO-d6): 21.1, 111.6, 120.5, 124.3, 126.4, 128.7, 129.0, 129.8, 130.1, 131.4, 135.1, 136.0, 136.4, 139.0, 155.5, 161.9, 171.1.; MS m/z: 384 (M+1).

 

9k. IR: 3394 (NH2str.), 1645 (pri- NH bending.), 1528(sec- NH bending.), 1345 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 7.54-8.51 (m, 8H, Ar-H), 9.18 (s, 1H, D2O exchangeable), 9.44 (s, 1H, D2O exchangeable), 11.13 (s, 1H, D2O exchangeable), 12.61 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 110.2, 117.7, 125.0, 125.1, 128.2, 128.8, 129.3, 134.9, 135.5, 138.8, 158.0, 162.8, 171.4.; MS m/z: 370 (M+1).

 

9l. IR: 3354 (NH2str.), 1635 (pri- NH bending.), 1537(sec- NH bending.), 1355 (C-N str.), cm-1;1H-NMR (300 MHz; DMSO-d6): 7.54-8.51 (m, 7H, Ar-H), 9.28 (s, 1H, D2O exchangeable), 9.49 (s, 1H, D2O exchangeable), 11.16 (s, 1H, D2O exchangeable), 12.64 (s, 1H, D2O exchangeable);13C-NMR (75.5 MHz; DMSO-d6): 111.2, 119.7, 124.9, 125.2, 127.9, 128.8, 129.3, 134.9, 135.7, 138.8, 157.9, 161.8, 172.1.; MS m/z: 404 (M+1).

 

RESULTS AND DISCUSSION:

The synthesis involves preparation of 2-chloro-4-aminoquinazolines 3a-b by one step process by intramolecular cyclization of appropriately substituted formamides derivatives 2a-b in presence of phosphorous oxychloride. The formamides 2a-b are prepared from substituted benzonitriles 1a-b and sodium cyanate. The advantage of one step intramolecular cyclization is that it avoids the use of hazardous phosphorous halides and reduces the number of steps required in preparation of 2-chloro-4-aminoquinazolines 3a-b, thereby increasing the overall yield14.

 

Further various aromatic /aliphatic acids on treatment with thiosemicarbazide in presence of sulfuric acid undergo dehydrative cyclization to produce 2-amino-5-aryl/alkyl-1,3,4-thiadiazoles16 6a-e. These undergo Sandmeyer reaction at 10-15oC in mixture of acetic acid and hydrochloric acid  under copper catalysis to give 2-chloro-5-aryl/alkyl-1,3,4-thiadiazoles17 7a-e which on further reaction with hydrazine hydrate afford 2-hydrazino-5-aryl/alkyl-1,3,4-thiadiazoles17 8a-e. These 2-hydrazino-5-aryl/alkyl-1,3,4-thiadiazoles on condensation with 2-chloroquinazolin-4-amine in ethanol give the various 2-[2-(1,3,4-thiadiazol-2-yl)hydrazinyl]quinazolin-4-amines 9a-l. Scheme 1 (Table-1).

 

Antimicrobial activity

The synthesized compounds 5a-r were screened for their antibacterial activity against E. Coli and S.Aureus and antifungal activity against S.Cerevisiae and C.albicans at a concentration of 100 μg/mL in DMF by cup-plate method22,23. Standard anti-bacterial and antifungal drug, gentamycin and miconazole respectively were also tested under similar conditions for comparison. Zone of inhibition in mm of synthesized compounds and standard drugs are shown in Table 2.

 

 


Scheme 1:

 

 


Table 1: Different 4-aminoquinazolines and R’ in 9a-l


Cpd

4-aminoquinazolines

R’

MP

% Yield

9a

 

 

245oC (dec)

73

9b

 

 

259oC (dec)

65

9c

 

 

256oC (dec)

75

9d

 

 

261oC (dec)

68

9e

 

 

258oC

71

9f

 

 

259oC (dec)

64

Cpd

4-aminoquinazolines

R’

MP

% Yield

9g

 

 

255oC

69

9h

 

 

264oC (dec)

65

9i

 

 

249oC

76

9j

 

 

247oC

64

9k

 

 

266oC (dec)

63

9l

 

 

269oC (dec)

59

 

 


Table 2: Antimicrobial activity of compounds [zones of inhibition in mm]

COMPOUNDS

E.COLI (-)

S.AUREUS(+)

C.ALBICANS

S.CEREVISIAE

9a

8.2

3.8

1.8

1.1

9b

8.0

4.8

0.8

1.8

9c

6.7

6.5

1.6

1.7

9d

6.1

6.3

0.7

1.6

9e

1.3

2.2

8.4

4.1

9f

1.2

2.8

8.3

4.2

9g

5.3

8.1

1.1

1.1

9h

4.7

8.2

0.8

0.8

9i

5.4

4.7

3.2

3.5

9j

5.6

5.1

2.8

3.1

9k

8.6

5.1

1.2

1.5

9l

7.6

6.8

0.8

0.8

GENTAMICIN

16.2

14.3

-

-

MICONAZOLE

-

-

11.5

13.2

 


 

CONCLUSION:

Most of the synthesized compounds have shown antibacterial activity to some extent. Among the synthesized compounds 9a, 9b and 9k show some activity against E. coli. Against S. Aureus the compounds 9g and 9h show some activity. The remaining compounds have been found to be less active against E. coli and S. Aureus. The compounds 9e and 9f show moderate activity against C. albicans. All the compounds are fairly inactive against S. Cerevisiae.

 

ACKNOWLEDGEMENTS:

The authors are thankful to BASF India Ltd. for providing analytical support.

 

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Received on 11.09.2010          Modified on 17.09.2010

Accepted on 30.09.2010         © RJPT All right reserved

Research J. Pharm. and Tech. 4(2): February 2011; Page 263-267