Inventi Rapid: Med Chem Vol. 2, Issue 1[ISSN 0976-3821]2011mc055, CCC: $10 © Inventi Journals (P) LtdPublished on Web 25/03/2011, www.inventi.in
Quinazoline 1 is a compound made up of twofused six-membered aromatic rings, abenzene ring and a pyrimidine ring.Quinazoline is a fused bicyclic compoundearlier known as benzo-1,3-diazine was first prepared in the laboratory by Gabriel
in1903, although one of its derivative wasknown much earlier.
Quinazolinones are theoxidized form of quinazoline and as such arealso part of the quinazoline alkaloids. Bothnaturally occurring and syntheticquinazolines and quinazolinones haveattracted widespread attention due to thediverse range of pharmacological activities.These structures are defined by the locationof the oxygen and the hydrogen on thenitrogen (NH). Of the many derivatives of quinazoline system known so far, keto-quinazolines also called as quinazolinones,are the most important compounds.
Depending upon the position of the keto oroxo group, these compounds may beclassified into three types
(Figure 1): 2(1H)quinazolinones 2, 4(3H)-quinazolinones 3and 2,4(1H,3H)-quinazolinedione 4 .Of the three quinazolinone structures4(3H)-quinazolinones are most prevalent,either as intermediates or as naturalproducts in many proposed biosyntheticpathways.
This is partly due to the structurebeing derived from the anthranilates(anthranilic acid or various esters, isatoicanhydride, anthranilamide andanthranilonitrile) while the 2(1H)-quinazolinone is predominantly a product of anthranilonitrile or benzamides withnitriles.
Although quinazolinone chemistry isconsidered to be an established area, newer
School of Pharmaceutical Sciences, JaipurNational University, Jagatpura, Jaipur- 302025,Rajasthan, India.E-mail: firstname.lastname@example.org*Correpsponing author
LBS College of Pharmacy, Udai Marg, Tilak Nagar, Jaipur- 302004, Rajasthan, India.
and more complex variants of thequinazolinone structures are still beingdiscovered.
The first reported synthesis of aquinazolinone occurred in 1869, which wasprepared from anthranilic acid and cyanidein ethanol creating 2-ethoxy-4(3H)-quina-zolinone
. These findings were confirmed bythe preparation of the derivatives of 2-amino-4(3H)-quinazolinone and 2,4(1H,3H)-quinazolinedione by reactions with ammoniaand water respectively (Scheme 1).Investigations of quinazolinones showthere is a strong lactam-lactim tautomericinteraction
(Figure 2). The significance of this tautomeric interaction can also be seenwhen a 4(3H)-quinazolinone containing amethyl in the 3-position is subjected tochlorination with POCl
, the methyl group islost and chlorination proceeds
; and whenthe methyl group is present in the 2-position,the tautomeric effect is extended generatingan exomethylene carbon, this compound canbe condensed with aldehydes producing 2-styryl-4(3H)-quinazolinones. The significanceof these extended tautomeric effects is that they enhance reactivity of the substituted4(3H)-quinazolinones.
The quinazolinone moiety is animportant pharmacophore showing manytypes of pharmacological activities.
Thequinazolinones are considered to be a“privileged structure” for drug development.
The chemistry of 4(3H)-quinazolinone hasreceived an increasing interest because of itsbiological significance. Many derivatives of this system showed antifungal
activities. Structureactivity relationship studies of quinazolinonering system revealed in various literatures
suggest position 2, 6 and 8 are very muchimportant for structure activity studies andposition 3 should be attached to different heterocyclic rings for betterchemotherapeutic activity.
In light of the growing number of applications in recent years there has beenan enormous increase in the interest amongbiologists and chemists in their synthesis andbioactivity of quinazoline derivatives.
Epilepsy is ubiquitous disease characterizedby recurrent seizures and inflicts more than60 million people worldwide according toepidemiological studies.
Every yearapproximately 250000 new cases are addedto this figure. It is roughly estimated that 28-30% of patients are resistant to the availablemedical therapies. Despite the development of several new anticonvulsants
, thetreatment of epilepsy remains stillinadequate, and the patients suffer from a lot of specific problems like neurotoxicity,depression and other CNS related diseases.Although several new anticonvulsants arealready in clinical use, some types of seizuresare still not adequately treated with current therapy and have limitations, intolerable sideeffects. In response to these limitations, thedevelopment of new drugs to optimallymanage seizures has been stronglyadvocated. Thus the search for newanticonvulsant drugs continues to be anactive area of investigation in medicinalchemistry.
A literature survey revealed that thepresence of aromatic or aliphatic group at position 2 and a substituted aromatic ring at position 3 are an essential requirement forCNS activities predominantly anticonvulsant properties. Various hypotheses wereanalyzed before the chemical synthesis of proposed compounds. First hypotheses wasinspired from the 4 (3
)-quinazolinonenucleus containing well known CNS activeMethaqualone (2-methyl-3-
. Modifications at the secondand third position of this agent have lead tothe generation of many CNS active agents.Second hypotheses explained, methyl groupat the second position is not necessary forthe CNS activity and other groups can alsolead to potent CNS active agents.
Aliterature survey exposed that replacement of the methyl group at the second position bysome other functionality such as alkyloxymethyl or alkylthiomethyl groups reportedlyyielded structural analogues which retainedthe anticonvulsant activity. Theanticonvulsant activity of quinazolinonederivatives was attributed to its ability to
bind the noncompetitive site of α
-amino-hydroxy-methyl-4-isoxazolepropionic acid(AMPA) receptors.
Since the discovery of methaqualone
(Figure 3) as a sedative hypnotic, the searchfor new anticonvulsant drugs with reducedtoxicity and fewer side effects has beencontinuous.
Our literature surveyrevealed that replacement of the methylgroup by some other functionality such asalkylthiomethyl or alkyloxymethyl groupsreportedly yielded structural analogueswhich retained the anticonvulsant activity.
In a previous report, compounds 6a, b
(Figure 3) were synthesized and tested for
Chemistry, Structure Activity Relationship andBiological Activity of Quinazolin -4 (3H)-OneDerivatives
Arun K Mahato
, Birendra Srivastava
, C Nithya Shanthi
Quinazolin-4-(3H)-one is a versatile lead molecule for the design of potentialbioactive agents. The molecular manipulation of a promising lead compound is still a majorline of approach for the discovery of new drugs. There has been considerable interest in thedevelopment of novel compounds with antibacterial, antifungal, anti-HIV, CNS depressant,antitubercular, anticancer, antioxidant, analgesic, anti-inflammatory, anticonvulsant andantiviral activities. SAR studies have indicated that substitution at position 2 and 3 canmodulate activities of the molecule. Therefore many researchers have synthesized thesecompounds as target structures and evaluated their biological activities. These observationshave been the guiding for the development for new quinazolinones that possesses variedbiological activities.
Quinazolinone, SAR, biological activity.