Active heterocyclic compounds are one of the main topics of interest for the medicinal chemists as they display a number of pharmacological activities. Nitrogen, sulfur, and oxygen containing five- and six-membered heterocyclic compounds have occupied enormous significance in the field of medicinal chemistry. The most important six-membered heterocyclic compounds are quinazoline and quinazolinone derivatives for their biological activities. The current chapter outlined the different methods for synthesis of quinazoline and quinazolinone derivatives that possess broad spectrum of biological activities.
- quinazolinone synthesis
- six-membered heterocycles
- biological activity
Quinazoline (1,3-diazanaphthalene or 5,6-benzopyrimidine) and 4(3H)-quinazolinone derivatives have a great interest in organic synthesis and medicinal chemistry fields as they possess a broad range of pharmacological activities. They exhibit antimicrobial , antimalarial , antioxidant , anti-inflammatory , anticonvulsant , antihypertensive , antidiabetic , and antitumor activities [8, 9, 10].
Many quinazolinone derivatives occurred naturally in various classes of the plant kingdom, microorganisms, and different animals (
). The first discovery of quinazolinone alkaloid is
Quinazoline is a heterocyclic compound of two fused six-membered simple aromatic rings—benzene and pyrimidine ring. It is a yellow-colored compound, found usually in crystalline form. Its oxo-derivative (quinazolinone) is classified into three types according to the position and number of carbonyl group: 2(1H)quinazolinones, 4(3H)quinazolinones, and 2,4(1H,3H)quinazolinedione ( Figure 2 ).
2. Chemistry of quinazoline
Quinazoline is a compound made up of two fused six-membered simple aromatic rings—benzene and pyrimidine ring. The properties of the pyrimidine ring were affected by the presence of fused benzene ring. The two nitrogen atoms are not equivalent, and the marked polarization of the 3,4-double bond is reflected in the reactions of quinazoline. The properties of quinazoline derivatives depend on the following three factors:
The nature of the substituents
The presence of substituent whether they are in the pyrimidine ring or in the benzene ring
The presence of conjugation in the pyrimidine ring
The first synthesized quinazoline in laboratory was achieved by Gabriel in 1903 . Most of quinazoline derivatives are stable in cold acidic or basic medium but can be destroyed at high temperature and undergo ring opening reaction, affording O-aminobenzaldehyde, ammonia, and formic acid. Quinazoline derivative can be easily oxidized in acidic medium at room temperature to give 3,4-dihydro-4-oxo quinazoline, while in alkaline medium using potassium permanganate will afford 3,4-dihydro-6 4-oxo quinazoline (cf. Figure 3 ).
3. Spectral characterization of quinazoline and quinazolinone derivatives
The spectroscopic analysis of some synthesized quinazoline and quinazolinone derivatives was studied to investigate their structures including infrared, mass spectroscopy, 1HNMR, and elemental analysis. The resulted data could be taken as standard for the new synthesized quinazoline analogue .
3.1 Infrared spectra
Quinazoline derivatives found to give mainly three absorption bands in IR spectra: 1478–1517, 1566–1581, and 1612–1628 cm−1; these represented bands are correlated to C▬N, C=C, and C=N groups, while quinazolinone compounds showed 1680–1700 and 1640–1660 cm−1 corresponding to C=O and C=N groups [13, 14].
The 1HNMR spectra of quinazoline and quinazolinone derivatives are different from each other according to the presence of acidic proton and its position in the presented compound. In general the 1HNMR spectrum of the main quinazoline (I) represents multiple signals in the aromatic region δ 7–8 and two singlet signals for the two CH=N protons at δ 9–9.5 ppm, while quinazolinone (II) will show also signals of aromatic protons in the same region as well as one singlet signal for CH=N proton and one broad singlet signal at the down-field region for the NH proton at δ 12–13 ppm [13, 14].
On the other hand, the 13C NMR spectrum for quinazoline and quinazolinone derivatives is nearly the same, as it shows signals at δ 100–160 ppm region.
4. Synthesis of quinazoline and quinazolinone derivatives
The synthesis of various quinazoline compounds is largely based on the substitution patterns of the 1,3-diazine moiety of the system. The first quinazoline derivative (2-cyano-3,4-dihydro-4-oxoquinazoline) was synthesized in 1869 by the reaction of cyanogens with anthranilic acid . Many years later quinazoline was obtained by decarboxylation of the 2-carboxy derivative (quinazolinone) which can be synthesized more easily by a different method.
4.1 Synthesis of quinazolinone
4.1.1 Niementowski’s synthesis
From anthranilic acid and formamide.
4.1.2 Grimmel, Guinther, and Morgan’s synthesis
From the reaction of o-amino benzoic acid with amine in the presence of phosphorus trichloride in toluene.
4.1.3 From 3,1,4-benoxazones (acylanthranils) and amines
Various quinazoline and quinazolinone derivatives can be synthesized from the reaction of benzoxazinone and different amine compounds in different media.
220.127.116.11 Reaction with ammonium hydroxide
When ammonium hydroxide reacted with benzoxazinone (1) over 1–3 h, it produced anthranilamides (2) which cyclizes to 4-quinazolones (3) under thermal conditions (240–280°C) or on heating with acetic anhydride [16, 17].
18.104.22.168 Reaction with different aromatic amines
It was stated by several authors that 2-substituted benzoxazinone reacted easily with primary aromatic amines, giving the corresponding quinazolones (4) .
On the other hand, reaction of benzoxazinone (5) with o-phenylenediamine gave quinazolinone derivative (6) or the fused quinazoline derivative (7) according to the reaction medium .
22.214.171.124 Reaction with hydrazine hydrate
It was reported that benzoxazinone (8) reacted with hydrazine hydrate in ethanol and has the corresponding quinazolinone (9), while carrying out the same reaction in boiling acetic acid glacial afforded the fused quinazoline (10) .
126.96.36.199 Reaction with different carbohydrazide
Treatment of 2-substituted-3,1-benzoxazin-4-ones (11) with semicarbazide hydrochloride in dry pyridine is a good way to construct a third heterocyclic ring condensed with quinazoline (12) .
The reaction of benzooxazinone (8) with 2-benzamido-3-phenylacrylohydrazide (13) glacial acetic acid in the presence of fused sodium acetate gave quinazoline derivative (14). In contrast, their reaction in pyridine afforded pyrazoloquinazoline derivative (15) .
Reaction of benzoxazinone (8) with cyanoacetohydrazide gave the corresponding cyano quinazolinone (16) which was reacted with different nucleophiles to give fused quinazoline and annulated quinazolinone derivatives (17–19) .
It was also reported that refluxing an equimolar amount of the benzoxazinone (8) with thiocarbonohydrazide in ethanol and in the presence of few drops of glacial acetic acid furnished quinazolinone (20) in the two isomers of thione and thiol form .
4.1.4 Sen and Ray’s synthesis
Isobutyrylanilides with urethane and phosphorus pentoxide in xylene gave 2-propyl- and 2-isopropyl-3,4-dihydro-4-oxoquinazolines.
4.1.5 From 2-aminobenzylamine
Reaction of 2-aminobenzylamine with butyrolactone further condensed with benzaldehyde afforded 3-(2-chlorobenzylidene)-1,2,3,9-tetrahydropyrrolo-2-quinazoline.
5. Biological importance of quinazoline derivatives
As we mentioned above, the important biological activity of quinazoline and quinazolinone skeletons in various fields depends mainly on the substituents of quinazoline compounds. Different substituted quinazoline compounds are found to be active as antihypertensive, antineoplastic, antidepressant, and antipsychotic, and others are effective against analgesic, antipsychotic, antiarrhythmic, cancer, and other activities [20, 21, 22].
It was reported that 3-substituted quinazolin-4(3H)-ones and 3,4-dihydroquinazolin-2-(1H)-one derivatives possess broad spectrum antitumor activities toward different cell ( Figure 4 ) .
Also, different quinazoline derivatives containing thiosemicarbazide moiety possess antitumor activity ( Figure 5 ) .
5.2 Antibacterial activity
It was reported that some novel substituted iodoquinazoline derivatives possess remarkable activity toward Gram-negative bacteria
5.3 Antiviral agents
A series of Schiff bases of some 2-phenyl quinazoline-4(3)H-one derivatives have shown great activity as antiviral agents ( Figure 7 ) .
5.4 Antimutagenic activity
The (S)-4-aminoquinazoline alcohols performed great antimutagenic activity when tested by using
Quinazoline and quinazolinone compounds which have a lot of considerable pharmacological interests can be synthesized by different methods, and the most attractive method was carried out starting from benzoxazinone derivatives.
Grover G, Kini SG. Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents. European Journal of Medicinal Chemistry. 2006; 41:256-262
Verhaeghe P, Azas N, Gasquet M, Hutter S, Ducros C, Laget M, et al. Synthesis and antiplasmodial activity of new 4-aryl-2-trichloromethyl quinazolines. Bioorganic & Medicinal Chemistry Letters. 2008; 18:396-401
Roopan SM, Maiyalagan T, Khan FN. Solvent-free syntheses of some quinazolin-4(3H)-ones derivatives. Canadian Journal of Chemistry. 2008; 86:1019
Smits RA, Adami M, Istyastono EP, Zuiderveld OP, van Dam CME, de Kanter FJJ, et al. Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4receptor inverse agonists. Journal of Medicinal Chemistry. 2010; 53:2390-2400
Georgey H, Abdel Gawad N, Abbas S. Synthesis and anticonvulsant activity of some quinazolin-4-(3H)-one derivatives. Molecules. 2008; 13:2557-2569
Jain KS, Bariwal JB, Kathiravan MK, Phoujdar MS, Sahne RS, Chauhan AK, et al. Recent advances in selective alpha1-adrenoreceptor B.S. antagonists as antihypertensive agents. Bioorganic & Medicinal Chemistry. 2008; 16:4759-4800
Malamas MS, Millen J. Quinazoline acetic acids and related analogues as aldose reductase inhibitors. Journal of Medicinal Chemistry. 1991; 34:1492-1503
Shallal HM, Russu WA. Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives. European Journal of Medicinal Chemistry. 2011; 46:2043-2057
Chilin A, Conconi MT, Marzaro G, Guiotto A, Urbani L, Tonus F, et al. Exploring epidermal growth factor receptor (EGFR) inhibitor features: The role of fused dioxygenated rings on the quinazoline scaffold. Journal of Medicinal Chemistry. 2010; 53:1862-1866
Sagiv-Barfi I, Weiss E, Levitzki A. Design, synthesis, and evaluation of quinazoline T cell proliferation inhibitors. Bioorganic & Medicinal Chemistry. 2010; 18:6404-6413
Wattanapiromsakul C, Forster PI, Waterman PG. Alkaloids and limonoids from Bouchardatia neurococca: Systematic significance. Phytochemistry. 2003; 64:609-615
Gabriel S. Synthesis and pharmacological evaluation of 3-alkyl/aryl–2-methylquinazolin-4-one derivatives. Bernoulli Society. 1903; 36:800-845
Hemdan MM, Youssef ASA, El-Mariah FA, Hashem HE. Synthesis and antimicrobial assessments of some quinazolines and their annulated systems. Journal of Chemical Research. 2017; 41:106-111
Zeinab F, Nasrin R, Razieh S, Kamiar Z, Mohammad A, Soghra K. Synthesis of some novel dibromo-2-arylquinazolinone derivatives as cytotoxic agents. Research in Pharmaceutical Sciences. 2019; 14(2):115-121
Armarego WLF. A Text Book of Quinazolines. 1963. pp. 1-320
Essawy A, El-Hashash MA, El-Gendy AM, Hamed MMM. Synthesis and studies on heterocyclic compounds containing mixed and non-mixed systems. Indian Journal of Chemistry. 1982; 21B:593
Webber SE, Bleckman TM, Attard J, Deal JG, Kathardekar V, Welsh KM, et al. Design of thymidylate synthase inhibitors using protein crystal structures: The synthesis and biological evaluation of a novel class of 5-substituted quinazolinones. Journal of Medicinal Chemistry. 1993; 36:733-734
Madkour HMF. Reactivity of 4H-3,1-benzoxazin-4-ones towards nitrogen and carbon nucleophilic reagents: Applications to the synthesis of new heterocycles. ARKIVOC. 2004; 36
Ahmed MA, El-Azab AS, Mohamed MA, Bakhat MA, Abdel-Hamid SG. Synthesis of some new substituted iodo quinazoline derivatives and their antimicrobial screening. Journal of Saudi Chemical Society. 2011; 15:319-325
Rajput R, Mishra AP. A review on biological activity of quinazolinones. International Journal of Pharmacy and Pharmaceutical Sciences. 2012; 4(2):66-70
Pati B, Banerjee S. Quinazolines: An illustrated review. Journal of Advanced Pharmacy Education and Research. 2013; 3(3):136-151
Vijayakumar B, Prasanthi P, Teja KM. Quinazoline derivatives and pharmacological activities: A review. International Journal of Medicinal Chemistry & Analysis. 2013; 3(1):10-21
Abdel Gawad NM, Georgey HH, Youssef RM, El-Sayed NA. Synthesis and antitumor activity of some 2,3-disubstituted quinazolin-4(3H)-ones and 4,6-disubstituted-1,2, 3,4-tetrahydroquinazolin-2H-ones. European Journal of Medicinal Chemistry. 2010; 45(12):6058-6067
He J, Wang X, Zhao X, Liang Y, He H, Fu L. Synthesis and antitumor activity of novel quinazoline derivatives containing thiosemicarbazide moiety. European Journal of Medicinal Chemistry. 2012; 54:925-930
Alafeefy AM, El-Azab AS, Mohamed MA, Bakhat MA, Abdel-Hamid SG. Synthesis of some new substituted iodoquinazoline derivatives and their antimicrobial screening. Journal of Saudi Chemical Society. 2011; 15(4):319-325
Kumar KS, Ganguly S, Veerasamy R, DeClercq E. Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones. European Journal of Medicinal Chemistry. 2010; 45(11):5474-5479
Kohli D, Hashim SR, Vishal S, Sharma M, Singh AK. Synthesis and antibacterial activity of quinazolinone derivatives. International Journal of Pharmacy and Pharmaceutical Sciences. 2009; 1(1):163-169
Selvam TP, Kumar PV, Kumar AS. Synthesis and anti-oxidant activity of novel 6,7,8,9 tetra hydro-5H-5-(2'-hydroxy phenyl)-2-(4'-substituted benzylidine)- 3-(4-nitrophenyl amino) thiazolo quinazoline derivatives. Research in Biotechnology. 2010; 1(1):38-48