Synthesis of novel 3-[(dialkyl/aryl amino) methyl]-2-substituted-4(3H)-Quinazolinones and evaluation of their Anti-inflammatory activity

 

Ganesh Akula¹*, Rangu Nirmala², CH. Shanthipriya², S. Rohini Reddy², Dr. A. Jaswanth²

¹Department of Pharmaceutical Chemistry, Surabhi Dayakar Rao College of Pharmacy, Rimmanaguda (V), Gajwel (M), Siddipet (D), Telangana-502312

²Surabhi Dayakar Rao College of Pharmacy, Rimmanaguda (V), Gajwel (M), Siddipet (D), Telangana-502312

 

ABSTRACT:

Literature survey reveals that in recent years several Quinazolinone derivatives have been synthesized and reported to possess varied biological and pharmacological properties. They are found to be useful as antibacterial, analgesic, anti-inflammatory, antifungal, anticonvulsant and anticancer agents. A new series of 3-[(di alkyl amino) methyl]-2-substituted-4(3H)-Quinazolinones were synthesized by the reaction of a mixture of 2-substituted-4(3H)-Quinazolinone, formaldehyde and dialkyl or diaryl amine by mannich reaction. The chemical structures of the synthesized compounds were confirmed by IR, mass spectral and C, H, N analysis techniques. The synthesized compounds were screened for anti-inflammatory activity by the carrageenan induced rat hind paw edema method. The synthesized compounds were significantly showed their anti-inflammatory activity that of standard.

 

 

 

1. INTRODUCTION:

Quinazoline^1,2 is a bicyclic compound prepared by fusing  of six-membered simple aromatic rings consisting of pyrimidine system with benzene, viewing array of  applications. The many derivatives of quinazoline system known so far, keto-quinazolines also called as Quinazolinone³, are the most important compounds. Literature survey reveals that in recent years several Quinazolinone derivatives^4,5,6 have been synthesized and reported to possess varied biological and pharmacological properties.  They are found to be useful as antibacterial^7,8, analgesic⁹, anti-inflammatory¹⁰, antifungal^11-14, anticonvulsant¹⁵ and anticancer agents^16,17.

 

In the present investigation, synthesis of Quinazolinone derivatives were carried out according to scheme-1 and these compounds were evaluated for their pharmacological activities especially antimicrobial activity. These compounds showed pharmacological activity in comparison with the standard compounds.

 

2. MATERIALS AND METHODS:

All chemicals are of analytical grade and are brought from Sd. fine Chem. Ltd. The melting points were recorded on technico apparatus and were uncorrected.

 

 

Scheme-1

 

Compounds: a₁– c₂

Compound a: R= C₆H_5,                  a₁: R₁= R₂= CH₃, a_2: R₁= R₂= C₆H₅

Compound b: R= CH_3,                      b₁: R₁= R₂= CH₃, b2_: R₁= R₂= C₆H₅

Compound c: R= H,                       c₁: R₁= R₂= CH₃, c2_: R₁= R₂= C₆H₅

 

Step-I: Synthesis of 2-substituted-4(3H)-Quinazolinone (compound a-c): Ortho amino benzoic acid (0.1mole) was dissolved in 100ml of methanolic potassium hydroxide. Then gradually added alkyl or aryl amide (0.1 moles), the contents were refluxed for 3-4 hours and were cooled at room temperature. The reaction mixture was filtered and washed with methanol and dry the product. The dried crude product was recrystallized from methanol to get the compound.

 

Step-II: Synthesis of 3-[(dialkyl/aryl amino) methyl]-2-substituted-4(3H)-Quinazolinones (compound a₁-c₁ and a₂-c₂):  2-substituted-4(3H)-Quinazolinone (0.01 mole) was taken in 5 ml of 95% Ethanol and slurry was formed. To this 37% formaldehyde (0.02mole) and dialkyl or diaryl amine (0.01 moles) gradually added then a clear solution was obtained. To this solution 95% ethyl alcohol was added and it was concentrated by evaporation on a hot plate until a semisolid was formed and re-crystallized with ethanol.

Anti-inflammatory Activity¹⁸: The anti-inflammatory activity of the test compound was determined by rabbit hind paw edema method. A 1% W/V solution of carrageenan (0.1ml) as the phlogistic agent was used to induce inflammation. By measuring the change in paw volume of mercury displaced by the inflamed paw in plethysmograph, the extent of reduction was determined for each compound which in turn reflects directly on the anti-inflammatory activity of compounds. Control drug at a dose of 100mg/kg was employed as the standard drug. The control group was maintained with normal saline. Albino rats were divided into six groups of four animals each. Initial paw volume (both left and right) of each rat was recorded using plethysmograph. Test compounds were prepared in a 0.3% suspension of Carboxy Methyl Cellulose and given by oral route at a dose of 100mg/kg subcutaneously. After 30min of administration of test and standard compounds, 0.1ml of 1% carrageenan in 0.9% saline was injected subcutaneously in the sub plantar region of left hind paw of each animal. After the lapse of 3 hours following the injection of carrageenan, the change in the paw volume of each animal was measured by using plethysmograph. Control groups received 0.3ml of normal saline sub cutaneous. Paw volumes of control group were compared with the standard and test. The paw volume of albino rats was measured and shown in table-1.

 

3. RESULTS AND DISCUSSION:

Various novel Derivatives of 3-[(dialkyl/aryl amino) methyl]-2-substituted-4(3H)-Quinazolinone were synthesized from Quinazolinone by Mannich reaction with 37% Formaldehyde, dimethyl amine or diphenyl amine and Ethanol.  For the synthesis of Quinazolinone, Anthranilic acid was taken as a starting material by condensing with the amide and Methanolic Potassium hydroxide.

 

Anti-inflammatory Activity: Table-1 showing the data on anti-inflammatory activity of the compounds could reveal that all the six compounds could exhibit a moderate to potent activity. Compounds a₂, b₂, and c₂ showed potent anti-inflammatory activity and its activity were found to be comparable to that of the standard drug Indomethacin.

 

 

TABLE-1:Results of Anti-inflammatory activity in Albino Rats

*Oral Dose: 100mg/kg

 

4. CONCLUSION:

In present work we have synthesized some of the derivatives of Quinazolinone by different substitutions like dimethyl and diphenyl. It is interesting that new three (a₂, b₂, c₂) Quinazolinone derivatives possess significant anti-inflammatory activity comparable with the standard employed (Indomethacin). It is desirable to determine their toxicity to decide on whether to go for further screening or not.

 

5. ACKNOWLEDGEMENT:

I am very much thank full to the management of Surabhi Dayakar Rao College of Pharmacy for providing necessary facilities. I am also grateful to my colleagues and my friends for their kind help from time to time at each and every step of this work.

 

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Received on 13.03.2017       Accepted on 28.05.2017     

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