INTRODUCTION:

BACKGROUND:

A Brief Survey on Biologically Active Quinazolin-4(3h)-Ones: Quinazoline (1) is a bicyclic compound earlier known as benzo-1, 3-diazine was first prepared in the laboratory by Gabriel¹ in 1903 although one of its derivatives was known much earlier.²

The name quinazolinone (German: Chinazolin) was first proposed for its compound by Weddige³, on observing that this was isomeric with the then compounds cinoline (2) and quinaoxaline (3).

The numbering of the quinazoline ring system, which is currently used, was suggested by Paal and Busch⁴. The other less commonly used names for this ring system are ‘phenmiazine’ and 5, 6-benzopyrimidine. However, the name ‘quinazoline’ is now universally accepted. The ‘oxo’ derivative is suffixed by ‘one’, that is ‘quinazolinone’.

Quinazolinones and several of their derivatives have been found to be of greater interest in view of their varied biological and pharmacological properties. The prominence enthused several chemists and medicinal chemists to prepare newer and newer quinazolinones by different synthetic routes while incorporating a variety of known phrmacophores into their molecular systems and evaluating them for their possible biological and pharmacological properties.

The present survey aims to bring out the various routes that are intended to achieve the synthesis of quinazolinones and their derivatives of specific biological and pharmacological importance.

2-Cyanoquinazolin-4(3H)-one was the first quinazoline derivative prepared by Griess⁵.

Dave et al.⁶ reported the synthesis of some 2-mercapto-3-arylquinazolin-4-ones (I) by two general methods from anthranilic acid.

Later Bhargava and Chaurasia⁷ reported the synthesis of some 3-aryl-6,8-dibromo-2-mercapto-4-quinazolines (II) from 3,5-dibromo anthranilic acids and corresponding aryl isothiocyanate in absolute ethanol.

Pathak et al.⁸ reported the synthesis of 3-amino-2-mercaptoquinazolin-

4(3H)-ones (III) by an alternative route starting from methyl anthranilate.

From the same laboratory Alagarsamy and Pathak⁹ have reported a novel and innovative route for the synthesis of 3-amino-2-mercapto-quinazolin-4(3H)-ones (IV) starting from anthranilic acid.

Several 1,3,4-thiadiazolo [2,3-b] quinazolin-5-ones were synthesized and characterized by spectral data. Making use of amino and mercapto group by Pathak et al.⁸

Alagarsamy and Pathak⁹ in continuation of their work on 3-amino- 2-mercapto-4(3H)-quinazolinones reported the synthesis of 2-mercapto-3-(substituted methyl amino) quinazolin-4(3H)-ones (V) as analgesic, anti-inflammatory and antibacterial agents.

Further, in continuation of their work on 3-amino-2-mercapto-quinazolin- 4(3H)-ones reported^10,11 the synthesis of 3-amino-2-benzyl-aminoquinolin-4(3H)-ones (VI) and 2-substituted [1,3,4]-thiadiazolo [2,3-b] quinazolin-5(4H)-ones (VII). They were evaluated for their antiviral, antibacterial and antihypertensive agents respectively.

Brief Account of Literature on Fused 1, 3, 4-Thiadiazoloquinazolinones: Radha Vakula et al.¹² during their studies on reactive 1,3,4-thiadiazoles reported the synthesis of some fused 1,3,4-thiadiazoloquinazolinones (VIII) as potential mefenamic acid analogues.

Pathak et al.^13,14 reported the synthesis of 1,3,4-thiadiazolo [2,3-b]-quinazolin-5-ones (IX) starting from 3-amino-2-mercapto-4(3H)-quinazolinones. In the latter communication¹⁵, they reported antibacterial activity with the standard amoxycillin.

Pathak and Alagarsamy reported¹⁵ further, synthesis of some 2-substituted [1,3,4]-thiadiazolo [2,3-b] quinazolin-5(4H)-ones and found them to possess antihypertensive activity.

R.L. Sharma et al.¹⁶ have reported a variety of tetracyclic linearly fused benzothiazoloquinazolones i.e. benzothiazolo [2,3-b] quinazolin-12(H)-ones (XI) by the condensation of substituted o-chloro benzoic acids with substituted 2-aminobenzothiazoles. All the benzothiazolo quinazolinones have been characterized by their elemental analysis and spectral studies.

V. Alagarsamy et al.¹⁷ have reported the synthesis of a series of 2-substituted [1,3,4] thiadiazolines (XII) were synthesized by the cyclocondensation of 3-amino-2-CNS depressants activity (analgesic, anti-inflammatory, sedative-hypnotic and anticonvulsant).

Azza R. Maaroufa, Eman R. El-Bendarya et al.¹⁸ have reported the synthesis of a new series of quinazolin-4(3H)-one derivatives containing either a thiazole or a 1,3,4-thiadiazole moiety were prepared (XIII, XIV, XV and XVI). Biological evaluation of some of the target compounds as diuretic agents was carried out. The detailed synthesis, spectroscopic and biological data are reported.

METHODS:

I. Synthesis of 3-Amino-6-Substituted-2-Mercapto-Quinazolin-4(3h)-Ones (II) –General Procedure¹⁹:

The compound 3-amino-2-mercaptoquinazolin-4(3H)-ones (II) was synthesized by adding carbon disulphide (1.6ml, 0.026mol) and aqueous sodium hydroxide (1.2 ml, 20M) drop wise to a vigorously stirred solution of anthranillic acid (2.74g, 0.02mol) in dimethylsulfoxide (10ml) at room temperature. After thirty min dimethylsulphate (1.89ml, 0.02mol) was added drop wise under cooling with an ice bath. Stirring was continued for 3hrs; the reaction mixture was then poured into ice water and extracted with chloroform. The solvent was removed by distillation under reduced pressure. Thus the obtained methyl-N-(2-carboxyphenyl) dithiocarbamate was used for further reaction without purification. Hydrazine hydrate (9.80ml, 0.2mol, 80%) was added drop wise with stirring to methyl-N-(2-carboxyphenyl) dithiocarbamate in cold condition. After complete addition, stirring was continued for 1½ hrs at 50⁰C and then it was poured into ice water, the solid obtained was filtered, washed with water dried and recrystallized from dimethylformamide-ethanol mixture to yield (II) as a white crystalline product.

The following 3-amino-6-substituted-2-mercaptoquinazolin-4(3H)-ones were synthesized adopting the above procedure.

1)3-Amino-2-mercaptoquinazolin-4(3H)-ones (II; X=H)

The product was purified by recrystallization from mixture of ethanol and dimethylformamide to get a colorless crystalline product, yield: 85.49%, m.p. 236-237⁰C (lit. 236-237)³⁰ [Found: C, 49.68; H, 3.54; N, 21.62; C₈H₇N₃OS requires C: 49.74; H, 3.62; N, 21.75].

2)3-Amino-6-iodo-2-mercaptoquinazolin-4(3H)-ones (II; X=I)

Recrystallized from a mixture of ethanol and dimethylformamide to get a crystalline product, yield: 80.25%; m.p. 228^oC [Found: C, 30.14; H, 1.75; N, 13.06; C8H6IN3OS requires C, 30.11; H, 1.88; N, 13.16].

II. Synthesis Of 2,7- Disubstituted [1,3,4]- Thiadiazolo [2,3-B] Quinazolin 5(4h)-Ones (IV):

General Procedure: A mixture of compound (II) (1.93g, 0.01mole) acetyl chloride/benzoyl chloride/ chloro acetyl chloride/p-chloro benzoyl chloride/3-nitro benzoyl chloride (0.01mole) and POCl₃ (15ml) was heated and reflux for 2-4 hrs while monitoring by TLC. Phosphorous oxychloride was removed after ensuring the completion of the reaction under reduced pressure and cooled. The residue pour on to the crushed ice (100g), while stirring the resultant solution was neutralized with sodium bicarbonate while cooling in ice bath. The precipitated solid was filterer, washed with cold water and dried. The crude product was recrystalize from ethanol.

Each of these two 3-amino-2-mercaptoquinazolinones, has been subjected to the following two sets of cyclocondensation reactions, as depicted in Scheme-I.

Table No. 1 Physical and Analytical Data of 2,7-Disubstituted [1,3,4]- Thiadiazolo [2,3-b] Quinazolin-5(4H)-oneS

Sl. No.	Comp. Code	R	X	Melting Point	% Yield	Molecular Formula	Mol. weight	C %	H %	N%
01	DB-1		H	161°C	59.90	C₁₀H₇N₃OS	217	55.29	3.25	19.34
02	DB-2		H	142°C	73.11	C₁₅H₉N₃OS	279	64.50	3.25	15.04
03	DB-3		H	96°C	79.76	C₁₀H₆ClN₃OS	252	47.72	2.40	16.70
04	DB-4		H	108°C	84.07	C₁₅H₈N₃OSCl	314	57.42	2.57	13.39
05	DB-5		H	244°C	87.65	C₁₅H₈N₄O₃S	324	55.55	2.49	17.28
06	DB-6		I	208°C	78.42	C₁₀H₆IN₃OS	343	35.00	1.76	12.25
07	DB-7		I	190°C	76.04	C₁₅H₈N₃OSI	405	44.46	1.99	10.37
08	DB-8		I	100°C	74.60	C₁₀H₅ClIN₃OS	378	31.81	1.33	11.13
09	DB-9		I	180°C	89.29	C₁₅H₇IClN₃OS	439	40.98	1.60	9.56
10	DB-10		I	158°C	86.44	C₁₅H₇N₄O₃SI	450	40.02	1.57	12.44

^*DB-stands for Compound code, R-stand for Alkyl or Aryl group, X-stand for Halide

Table No. 2(a): IR, ¹H NMR and Mass Spectral data of substituted new 2,7-disubstituted [1,3,4]-thiadiazolo [2,3-b] quinazolin-5(4H)-ones

Comd code.	Molecular weight	I.R. Spectral Data (in cm^-1)					¹H NMR (in d ppm) and Mass Spectral data
Comd code.	Molecular weight	X	C-H	C=O	C=C	C=N	¹H NMR (in d ppm) and Mass Spectral data
DB-1	217	–H	3063 and 2980	1690	1568	1460	NMR: 2.76 ( s, 3H, CH₃), 7.21-7.96 ( m, 3H, Ar-H) and 8.45 (d, 1H, Ar-H at 6-position, periproton). MS: m/z: 217 (M⁺): 176 (02%), 162 (46%), 130 (08%), 102 (14%).
DB-5	324	–H	2928 and 2856	1680	1516	1469	NMR: 7.24-8.41 ( m, 7H, Ar-H), 8.46 ( d, 1H, 6-position, periproton). MS: m/z: 322 (M^-2): 309 (29%), 190 (06%), 175 (07%), 145 (44%), 133 (15%), 119 (08%), 104 (23%), 90 (22%), 78 (80%), 63 (100%), 45 (28%).

Table No. 2(b): IR, ¹H NMR and Mass Spectral data of substituted new 2,7-disubstituted [1,3,4]-thiadiazolo [2,3-b] quinazolin-5(4H)-ones

Comd code.	Molecular weight	I.R. Spectral Data (in cm^-1)					¹H NMR (in d ppm) and Mass Spectral data
Comd code.	Molecular weight	X	C-H	C=O	C=C	C=N	¹H NMR (in d ppm) and Mass Spectral data
DB-9	439	–I	3040 and 2920	1660	1560	1464	NMR: 7.57-8.52 ( m, 7H, Ar-H). MS: m/z: 439 (M⁺): 423 (21%), 288 (18%), 272 (09%), 245 (05%), 228 (03%), 216 (06%), 155 (11%), 141 (32%), 139 (100%), 101 (12%), 75 (16%).
DB-10	450	–I	2920 and 2854	1656	1570	1467	NMR: 7.11-8.51 ( m, 7H, Ar-H). MS: m/z: 450 (M⁺): 435 (04%), 434 (07%), 150 (100%), 78 (32%), 63 (44%).

Anti-inflammatory activity (in vitro model)^20-24,30,33

Table No. 3

Sl. No.	Compound code	Absorbance value (Mean ± SE)	Inhibition of denaturation (in %)
01	Control	0.048 ± 0.00056	--
02	Standard (Ibuprofen)	0.08430 ± 0.00030	75.00%
03	DB-1	0.06246 ± 0.00046	29.16%
04	DB-2	0.07613 ± 0.00013	58.33%
05	DB-3	0.06620 ± 0.0020	37.50%
06	DB-4	0.08310± 0.0010	72.91%
07	DB-5	0.06460 ± 0.00068	33.33%
08	DB-6	0.05366 ± 0.00066	10.41%
09	DB-7	0.08133 ± 0.00046	68.75%
10	DB-8	0.07523± 0.00020	56.25%
11	DB-9	0.07166 ± 0.00066	47.91%
12	DB-10	0.05733 ± 0.00033	18.75%

Anti-inflammatory activity (in vivo model)^{25-29,34,35-42.}

Anti-inflammatory activity by carrageenan induced rat hind paw oedema method:

Table No. 4

SI. No.	Compound code	Dose Mg/ kg	Mean difference in Paw volume ± SE after 3 hrs. (ml)	Percentage of inhibition
01	Control	--	5.45±0.039	--
02	Standard (Ibuprofen)	50	1.53±0.050^***	72.92%
03	DB-2	50	1.83±0.0792^**	66.42%
04	DB-4	50	1.60±0.049***	70.64%
05	DB-7	50	1.73±0.0723***	68.26%
06	DB-8	50	1.93±0.0533**	64.58%
07	DB-9	50	2.26±0.1532**	58.53%

^*P<0.05, **P<0.01, ***P<0.001 when compared to control group

RESULTS:

Anti-inflammatory activity (in vitro model):

The five out of ten compounds having more than 40% inhibition of albumin denaturation. Out of that DB-2, DB-4, DB-7, DB-8 and DB-9 showed 58.33%, 72.91%, 68.75%, 56.25% and 47.91% inhibition of albumin denaturation respectively.

Anti-inflammatory activity (in vivo model):

The tested compounds DB-2 (66.42%), DB-4 (70.64%), DB-7 (68.26%), DB-8 (64.58%) and DB-9 (58.53%) showed significant anti-inflammatory activity, compare to standard ibuprofen (72.92%).

From this it is concluded that one of the tested compounds have shown anti-inflammatory activity close to standard ibuprofen.

DISCUSSION:

Anti-inflammatory activity (in vitro model):

Synthesized compounds of 2,7-disubstituted [1,3,4]-thiadiazolo [2,3-b]-quinazolin-5(4H)-ones have been evaluated for anti-inflammatory activity (in vitro). The results are presented in Table No. 3. reveals that some of compounds promisingly inhibit albumin denaturation in comparison with standard drugs, ibuprofen exhibited 75.00% inhibition of albumin denaturation.

Anti-inflammatory activity (in vivo model):

The selected compounds have been evaluated for anti-inflammatory activity by carrgeenan induced rat hind paw oedema method compounds, which have been found more significant anti-inflammatory activity by in vivo model. The results are presented in Table No. 4. Compared with standard drug ibuprofen showed significant anti-inflammatory activity.

CONCLUSION:

Ten different new compounds of 2, 7-disubstituted [1, 3, 4]-thiadiazolo [2, 3-b] quinazolin-5(4H)-ones were synthesized. All the synthesized compounds were characterized by IR, ¹HNMR and Mass spectral properties. The synthesized compounds were screened for anti-inflammatory (Invitro-invivo) activities. Most of these compounds showed significant anti-inflammatory activity on both in vitro and in vivo models, comparing to standard. The compounds, which have been found to be more active, a detail further investigation required for exploitation.

ABBREVIATIONS:

CS-Carbon Disulphide, DMSO-Dimethyl sulfoxide, HH-Hydrazine hydrate, Ar-Aryl group, R-Alkyl group, X-Halide, TLC-Thin layer chromatography.

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Received on 22.04.2021 Modified on 26.05.2021

Asian J. Res. Pharm. Sci. 2021; 11(3):213-218.

DOI: 10.52711/2231-5659.2021.00034