Quinazolone: A Molecule of Significant Pharmacological and Biological Activity

 

Sunakar Panda*,  Upendra Prasad Tripathy

Department of Chemistry, Berhampur University, Bhanjabihar, Berhampur-7, Ganjam, Odisha, INDIA

*Corresponding Author E-mail:- sunakar_panda@yahoo.com

 

Quinazolones are nitrogen containing heterocyclic compounds exhibiting a wide spectrum of pharmacological activities like hypotensive, CNS depressant, anticonvulsant, antiparkinsonian, antibacterial, anti-inflammatory, anti-HIV, anti-viral, antimicrobial, antifungal, antitumor and anticancer etc.  The diverse pharmacological and biological properties of these compounds have received much importance in the recent years. The present paper covers a brief review on the synthesis, reactivity and biological activities of some quinazolin 4(3H) ones and their derivatives reported during the last decade.

 

 

INTRODUCTION:

Quinazolone and its derivatives have been demonstrated to exhibit a wide range of pharmacological and biological properties . Quinazolone is a bicyclic system consisting of a pyrimidine ring system fused with benzene ring and containing a ketonic group at position-4 shown in structures -I. The I.U.P.A.C name of quinazolone is 4-keto 3, 4-dihydro quinazoline^1-2. The compound and its derivatives are exclusively synthetic and forms the following tautomeric structures with its enol form (shown in Scheme-1 having structures II, III and IV)

 

Quinazolone

(I)

 

(Scheme-1)

 

The diverse pharmacological properties exhibited by quinazolone and its derivatives have relieved much significance in recent years. 2, 3-Disubstituted quinazolones have been demonstrated to be associated with their reposed and antifungal activities³. Some quinazolone derivatives containing sulphonamide group cause antihypertensive effect² probably due to the initial reduction of blood volume because of Na⁺ depletion and subsequently on account of direct relaxation of arteriolar smooth muscles. Some other quinazolone derivatives are generally effective in lowering blood pressure³ in the spontaneous hypertensive rats’ model and show  a-adrenergic blocking activity. Quinazolone bearing imidazoline, thiourea and amide at position-3 exhibit anticancer and anti-AIDS (H.I.V) activity ⁴.

 

Synthesis of Quinazolone

The general synthesis of quinazolone started from anthranilic acid or its derivatives. The most common employed route for the synthesis of quinazolone is the condensation of anthranilic acid with amides. The synthesis of 4-quinazolone may be classified into the following headings⁵.

(i)      Reaction of anthranilic acids with amides, thioamides, amines

(ii)    Reaction of N-acyl anthranilic acid with amines

(iii)   Reaction of isatoic anhydride with primary amines

(iv)   Reaction of acyl anthranils with amines

(v)    Pyrolysis of o-acyl amin benzene

(vi)   Cyclization of urea derivatives of anthranilic acid.

 

Methods of Synthesis

The extent of the pharmacological and biological effects of quinazolone derivatives depend on the active groups to which it is attached. A number of methods for the synthesis of different quinazolone derivatives have been published. Rahimizadeh et.al.⁶ have reported the synthesis of 2-alkyl 4-(3H) quinazolin ones starting from 2-aminobenzamide and carboxylic acid shown in Scheme-2.

 

(Scheme-2)

 

The 2-chloromethyl -3-heterocycle substituted quinazolones have been synthesised successfully from anthranilic acid by Thirugnanasambanthan et.al.⁷ with good yield and their structures have been confirmed through the spectral data (shown in Scheme-3). The synthesized compounds show moderate analgesic and antimicrobial activity.

 

(Scheme-3)

Kidwai et al ⁸ have reported the synthesis of quinazolone derivative i.e., quinazolin 4-(3H)-one starting from 2-Aryl-3, 1-benzoxazin-4-ones given in Scheme-4. In the presence of D.D.C. the product was obtained in poor yield.

 

(Scheme-4)  

 

Reddy et al ⁹ have also synthesized 2-(2-aminophenyl) –3- hydroxy quinazolin –4-(3H)-one from 2-nitro benzoyl chloride (Scheme-5).

 

(Scheme-5)

 

In view of the broad spectrum biological activities of quinazolinone and pyrazolinone, a series of new class of compounds have been prepared as reported by. Panda et al.¹⁰ containing both the ring system. (Scheme-6)

(Scheme-6)

 

Pattan et. al.¹¹ (2009) synthesize N-3-(5 Substituted-1,3,4-thiadiazol-2-yl-(2-amino methyl)quinazolin 4(3H)-one derivatives. They synthesize around 30 new derivitives of this group and study their antimicrobial, antifungal, antitubercular and anti-inflammatory activities with the standard drugs in a well equipped microbiology and pharmacology laboratory standard methods. These compounds show more effective toward antimicrobial, antifungal, antitubercular and anti-inflammatory activities. A possible synthesis is shown in scheme-7.

 

(Scheme-7)

 

CHEMICAL REACTIONS:

Reactivity of 4-(3H) Quinazolone:

The compounds like 4-(3H)-quinazolones are generally high melting water soluble compounds unlike 2-subsituted 4-(3H) quinazolones which are soluble in alkalies. The 4-(3H) quinazolone ring system is quite stable to oxidation, hydrolysis and other treatments. The chemical attack generally takes place at the carbonyl group or at the hetero atom or at the substituted alkyl group at position-2.Both electrophilic and nucleophlic substitution reactions take place on quinazolone ring systems. Simple and 2-substituted 4- (3H) quinazolones when heated with PCl_5­­ and PCl₃ give the corresponding 4-chloroquinazolines¹² (Scheme-8)

(Scheme-8)

 

When the simple 2-substituted 4-(3H) quinazolone is treated with    C₆H₅ COCl, it forms the N-substituted product with the simple replacement of H-atom (Scheme-9).

 

(Scheme-9)

 

The Quinazoline 4-(3H) one, on boiling with concentrated nitric acid undergoes nitration giving    6-nitro-4-quinazolinone ¹³. On further nitration, another nitro group enters into the 8-position of the benzene ring system. (Scheme-10)

 

(Scheme-10)

 

When 2-chloromethyl quinazolin 4-(3H) one is treated with K₂CO₃ salt in presence of methyl cyanide CH₃CN­, condensation of two quinazolone rings take place forming pyrazin diquinazolone(Scheme-11).

 

(Scheme-11)

 

 

 

BIOLOGICAL ACTIVITIES:

Quinazolones are versatile nitrogen heterocyclic compounds displaying a broad spectrum of biological and pharmacological activities like hypertensive, CNS depressant, anticonvulsant, antiparkinsonian, antibacterial, anti-inflammatory anti-HIV, anti-viral anthelmintic, antimicrobial, antifungal, antitumor and anticancer. The diverse pharmacological and biological properties exhibited by quinazolones and its derivatives have received much importance in recent years. A novel 3-amino-4(3H)-Quinazolinone is synthesized by Ammar et. al.(2011) showing antimicrobial activities¹³. Fathalla et.al¹⁴(2008) synthesize new series of some 2[(E)-2-furan-2-yl-vinyl]-Quinazolin-4(3H)-ones incorporated into pyrazolin, isoxazoline,pyramidine or pyrimidine-thione ring system at position-3 of qunazololine ring these compounds shows significant antimicrobial activity & anti inflammatory activity. Substituted 6-Bromo quinazolones are developed by Rajveer et.al.¹⁵(2010) shows anti-inflammatory, analgestic and anti bacterial activity. Pandey et.al.¹⁶(2008)  synthesized 4-arylkyl-7-arylamido/imido alkyl-6-hydroxy-2-oxo 1,2,3,4-tetra hydroquinazolin 3 which shows effect on central nervous system(CNS) and cardiovascular system(CVS).Wasfy ¹⁷ have  synthesized some 2,2-disubstituted-3,3-biquinazolin-4-(3H)-ones which show antimicrobial activity. Girija et al.(2011)¹⁸synthesized some 2, 3-disubstituted quinazoline-4-(3H)-one derivatives which possesses a wide range of biological activities such as sedative, anticonvulsant, anti-inflammatory, analgesic, antifungal, antibacterial etc. A series of 3-(substituted arylidene) hydrazinoacetylamino 2-methyl-6-bromo-quinazolin-4(3H) ones have been prepared by Kumar et.al.¹⁹(IV) possessing hypertensive activity. The 5-substituted aryl-3-[3'-amino-2'-methyl-6'-monosubsitutted quinazoline-4-(H)-one]-isoxazolines (V) which exhibit good anticonvulsant activity. Tyagi et.al(2002).²⁰ have prepared a series of substituted quinazolones (VI),(VII) and (VIII) which possess blood pressure lowering activity. The compounds tested 2-phenyl-3-{[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl4-(3H) quinazolinone and 6-bromo-2-phenyl-3-{[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl sulfonyl 4-(3H) quinazolinone  synthesized by Venkataraman et. al.²¹ (2010) shown better anti-inflammatory activity. Some new 2-[(E)-2-(substituted phenyl) ethenyl]-3-(2/4methyl phenyl) quinazolin-4(3H)-ones have been synthesized by Sathish et. al.²² (2012)  from 3-(methyl phenyl) quinazolin-4(3H)-one and 3-(4-methyl phenyl) quinazolin-4(3H)-one by introducing different aromatic aldehydes. The  synthesized compounds shown anti-inflammatory activity. The aryl furyl vinyl quinazolinones (IX) and (X) as shows significant antibacterial agents. The compounds 1-acetyl-5-aryl-3-(m-2' methyl-4' (3H) quinazolone -3'-yl-phenyl) pyrazoline (XI) which show very good antimicrobial activity. The compound, 2-Hydrazinomethylene-3-aryl-6-bromo-4(3H) quinazolinones  (XII) have been synthesized. This pyrido derivaties of qunazolone show anti bacterial and antifungal activities²³. Srivastava K²⁴(2009) synthesize 2-Phenyl-3,1-benzoxazine-4one(XIII) from anthranilic acid by stirring pyridine at room temperature shows antiviral activity against Japanse ence phalitis virus(JEV) a RNA virous of high pathogenicity.

 

(IV)

 

(V)

 

(VI)

 

(VII)

 

(VIII)

 

(IX)

 

(X)

 

(XI)

 

(XII)

 

(XIII)

 

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Accepted on 22.06.2013                © RJPT All right reserved