Quinazoline PDF

Hindawi Publishing Corporation
International Journal of Medicinal Chemistry

Volume 2014, Article ID 395637, 27 pages
http://dx.doi.org/10.1155/2014/395637
Review Article
Chemical Characteristics, Synthetic Methods, and Biological
Potential of Quinazoline and Quinazolinone Derivatives
Mohammad Asif
Department of Pharmacy, GRD (PG) Institute of Management and Technology, Dehradun, Uttarakhand 248009, India
Correspondence should be addressed to Mohammad Asif; [email protected]
Received 15 August 2014; Revised 11 September 2014; Accepted 16 September 2014; Published 13 November 2014
Academic Editor: Giulio Rastelli
Copyright © 2014 Mohammad Asif. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The heterocyclic fused rings quinazoline and quinazolinone have drawn a huge consideration owing to their expanded applications
in the field of pharmaceutical chemistry. Quinazoline and quinazolinone are reported for their diversified biological activities
and compounds with different substitutions bring together to knowledge of a target with understanding of the molecule types
that might interact with the target receptors. Quinazolines and quinazolinones are considered as an important chemical for the
synthesis of various physiological significance and pharmacological utilized molecules. Quinazolines and quinazolinone are a
large class of biologically active compounds that exhibited broad spectrum of biological activities such as anti-HIV, anticancer,
antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant,
antileukemic, and antileishmanial activities and other activities. Being considered as advantaged scaffold, the alteration is made with
different substituent.
1. Introduction position of the keto or oxo group, these compounds may be

classified into three types [4]. Out of the three (2(1H)quina-
Quinazolines and quinazolinones are classes of fused het- zolinones, 4(3H)quinazolinones and 2,4(1H,3H)quinazoline-
erocycles that are of considerable interest because of the dione) quinazolinone structures, 4(3H)-quinazolinones are
diverse range of their biological properties [1]. Many sub- most prevalent, either as intermediates or as natural products
stituted quinazoline and quinazolinone derivatives possess in many proposed biosynthetic pathways (see Scheme 1).
a wide range of bioactivities such as antimalarial, anti- This is partly due to the structure being derived
cancer, antimicrobial, antifungal, antiviral, antiprotozoan, from the anthranilates (anthranilic acid or various esters,
anti-inflammatory, diuretic, muscle relaxant, antitubercular, isatoic anhydride, anthranilamide, and anthranilonitrile)
antidepressant, anticonvulsant, acaricidal, weedicide, and while the 2(1H)-quinazolinone is predominantly a product of
many other biological activities. Quinazoline and quinazoli- anthranilonitrile or benzamides with nitriles [4].
none compounds are also used in preparation of various
functional materials for synthetic chemistry and also present
in various drugs molecules (Figure 1). This review is an 2. History
attempt to expand the huge potentiality and focused on the
various biological activities of quinazolines and quinazoli- In 1869 Griess prepared the first quinazoline derivative,
nones [2]. 2-cyano-3,4-dihydro-4-oxoquinazoline, by the reaction of
Quinazolinones will be classified into the following five cyanogens with anthranilic acid. The bicyclic product was
categories, based on the substitution patterns of the ring called bicyanoamido benzoyl and used this name until
system [3]. These are 2-substituted-4(3H)-quinazolinones, 1885 [5]. The preparation of the quinazoline came many
3-substituted-4(3H)-quinazolinones, 4-substituted-quina- years later when Bischler and Lang obtained it by decar-
zolines, 2,3-disubstituted-4(3H)-quinazolinones, and 2,4- boxylation of the 2-carboxy derivative. A more satisfac-
disubstituted-4(3H)-quinazolinones. Depending upon the tory synthesis of quinazoline was subsequently devised by
2 International Journal of Medicinal Chemistry
Quinazoline and quinazolinone compounds and their uses

Afatinib Albaconazole
O N N
O
N Cl N N N
CH3 HN OH
N
HN
H3 C N O
O CH3
F F
F
Antifungal
Cl
Tyrosine kinase inhibitor
Balaglitazone
O
Alfuzocin H3 C
N
CH3 O
H O
H3 CO N N N O N
O
N O S
H3 CO
Anticancer Antidiabetic and hypolipidimic
Cediranib
F
Barasertib
N NH CH3
O N
H H
N
N N H3 C O N
O
HO O N O
P CH3 O
N O N
OH F
Acute myeloid leukemia Hematological cancer, liver metastases
Dacomitinib Verubulin
H3 CO N CH3
N
N
HN N
N HN Cl
O N OCH3
H3 C
F
Anticancer Anticancer
GS1101(CAL101) Ispinesib
F O
H3 C CH3
O
N H
N O
N N
N N N
H3 C
H3 C
N NH NH2
Cl
Antihaematological cancer To treat solid tumors
Letermovir
F3C OCH3 Milciclib

H COOH H3 C
N H
N
N
N N H
N N N
N CH3
CH3
H3 CO H3 C N O
F CH3
Human cytomegalovirus Anticancer
(a)
Figure 1: Continued.
International Journal of Medicinal Chemistry 3
Sotrastaurin
Nolatrexed O
H H
H2 N N N
HN
N
CH3 O
O S N
N N CH3
N
N
Antisolid tumours Psoriasis, ulcerative colitis
Varlitinib
Tandutinib N
N
N N N HN
H3 C
H HN Cl
N N CH3 N
O
N N
O CH3 O
O
OCH3 H S
Glioblstoma Anticancer drug
Elinogrel
H O
N O
H
N O S
H3 C N S Cl
N O
F H
O
Antithrombosis
(b)
Figure 1: Some marketed available drugs contain quinazoline and quinazolinone moiety [2].
O O
N N NH NH
N N O N N O
H H
Quinazoline 2(1H)quinazolinone 4(3H)quinazolinone 4(1H,3H)quinazolinedione
Scheme 1
Gabriel in 1903. The name was proposed by Widdege. Other 3. Chemical Properties of Quinazolines
names such as phenmiazine, benzyleneamidine, benzo-1,3-
diazine, 5,6-benzopyrimidine, and 1,3-diazanapthaline have The chemistry of quinazoline was reviewed by Williamson in
occasionally been used. The presence of a fused benzene 1957 and then by Lindquist in 1959 and brought up to date by
ring alters the properties of the pyrimidine ring consider- Armarego in 1963.
ably. The two nitrogen atoms are not equivalent, and the Quinazolines is stable in cold dilute acid and alkaline
marked polarization of the 3,4-double bond is reflected solutions, but it is destroyed when these solutions are
in the reactions of quinazoline. The properties of substi- boiled. O-Aminobenzaldehyde, ammonia, and formic acid
tute’s quinazolines depend largely on (a) the nature of the are formed when quinazoline is boiled with hydrochloric
substituents, (b) whether they are in the pyrimidine ring acid.
or in the benzene ring, and (c) whether or not com-
plete conjugation is present in the pyrimidine ring [6–8] 3.1. Hydrolysis, Oxidation, and Reduction. Oxidation of
(see Scheme 2). quinazoline in dilute aqueous acid with two equivalents of
NH
N CN
2-Cyano-3,4-dihydro-4-oxoquinazoline
Scheme 2
O
HOOC
N KMnO4 N N H2 O NH
+
OH H
N HOOC N N N
Scheme 3
NaBH4 or H
N N N N
Na/Hg LiAlH4
N [H] NH N [H] NH
Scheme 4
N N N N
Sodamide NH2 NH2
N N N N
NH2 NHNH2
Scheme 5
Conc HNO3 O2 N
N N
Conc H2 SO4
N N
Scheme 6
hydrogen peroxide at room temperature gave 3,4-dihydro- 3.2. Nucleophilic and Electrophilic Substitution Reactions. The
4-oxo quinazoline. In alkaline medium, the anhydrous neu- two known nucleophilic substitution reactions of quinazoline
tral species of quinazoline were predominantly undergo are sodamide and hydrazine most probably proceed via the
oxidation with KMnO4 and yielded 3,4-dihydro-6 4-oxo intermediate addition products, and gave 4-amino and 4-
quinazoline. hydrazine quinazoline (see Scheme 5).
3.1.1. Oxidation. Catalytic hydrogenation of quinazoline

3.2.1. Electrophilic Substitution Reaction of Quinazoline.
stopped after the absorption of one molecule of hydrogen and
Nitration is the only known electrophilic substitution reac-
gave 3,4-dihydro quinazoline (see Scheme 3).
tion of quinazoline. The expected order of reactivity is at
positions 8 > 6 > 5 > 7 > 4 > 2. Quinazoline gives 6-
3.1.2. Reduction. Reduction with sodium amalgam gave nitroquinazoline with fuming nitric acid in concentrated
1,2,3,4-tetrahydroquinazoline. Lithium aluminum hydride H2 SO4 . No oxidation of the heterocyclic ring can occur under
and sodium borohydride gave 3,4-dihydro and 1,2,3,4- these conditions because the hydrated cation is not present
tetrahydroquinazoline (see Scheme 4). (see Scheme 6).
OH OR󳰀
R R R
N+ R󳰀 OH N+ OH− N
N RX
+
N N N N
H+
Scheme 7
O
COOH
R󳰀 CONH2 NH
R R
󳰀
NH2 R = H(OR)CH3 N R󳰀
Scheme 8
COOH R󳰀
N
+3R󳰀 NH2 + PCl3 3 +H3 PO4 + 3HCl + 3H2 O
NHCHOR N R
Scheme 9
O O O
R R
O RNH2 N CH(OC2 H5 )3 N
H
N O NH2
H N
Scheme 10
3.3. Alkylation Reactions. Alkylation of quinazoline 4.1. Niementowski’s Synthesis. Compound 3 or 4-substituted
takes place on N atom, 3-methyl, 3-ethyl-3-alkyl, and anthranilic acid when reacted with formamide at 125–130∘ C
3-benzylquinazolinium salts that readily take up a molecule gave 3,4-dihydro-4-oxoquinazoline (see Scheme 8).
of alcohol to form the corresponding 4-alkoxy-3-alkyl-3,4-
dihydro quinazolinium salts. These salts gave the pseudo 4.2. Grimmel, Guinther, and Morgan’s Synthesis. The o-amino
bases, 3-alkyl-3,4-dihydro-4-hydroxy quinazolines on benzoic acids, when heated with an amine together with
treatment with strong alkali (see Scheme 7). phosphorous trichloride in toluene for two hours, gave 2,3-
disubstituted 3,4-dihydro-4-oxoquinazolines (see Scheme 9).
3.4. Addition Reactions. Quinazoline is highly reactive
towards anionic reagents which attack on position 4. Sodium 4.3. From Isatoic Anhydride. Isatoic anhydride was read-
bisulphate, hydrogen cyanide, acetone, 2-butanone, ace- ily reacted with amines to dihydro-4-oxoquinazolines by
tophenone, and cyclohexanone add across the 3,4-double refluxing ethyl orthoformate for 1–6 hrs without isolating the
bond of quinazoline. Methyl, ethyl, isopropyl, benzyl, t-butyl, intermediate amides (see Scheme 10).
and phenyl magnesium halides and phenyl lithium also add
across the 3,4-double bond to give the corresponding 4- 4.4. From 3,1,4-Benoxazones (Acylanthranils) and Amines.
substituted 3,4-dihydroquinazolines. 3,1,4-Benoxazones react with amines to give 3,4-dihydro-4-
oxoquinazolines. Primary aliphatic amines and anilines react
with 2-methyl-5-nitro-4-oxoquinazolines (see Scheme 11).
4. Synthesis of Quinazoline Compounds
Various methods were reported for the synthesis of oxoquina- 4.5. From Ethyl 2-Acetamido-5-nitrobenzoate. Ethyl 2-
zolines. acetamido-5-nitrobenzene and alcoholic ammonia when
NO2 O NO2 O
RNH2 R
O N
N CH3 N CH3
Scheme 11
O
COOC2 H5 CONHR 󳰀
R󳰀
C2 H5 OH N
R󳰀 –NH2
NHCOR NHCOR N R
Scheme 12
H2 NCOOC2 H5 , P2 O5 NH
R R
Xylene, 3–5 hrs
NHCOR󳰀 N O
󳰀 H
(R = Me, OMe, OEt; R = Me, Et, Pr, Iso-Pro, Ph)
Scheme 13
O
COOH
NH2 CONH2 NH
R R
NH2 N O
H
Scheme 14
heated gave 3,4-dihydro-methyl-6-nitro-4-oxoquinazoline 5.2. From O-Ureidobenzoic Acid. The o-ureidobenzoic acids
(see Scheme 12). are prepared from the corresponding anthranilic acid and
potassium cyanate. The ureido acids are then easily cyclized
4.6. Sen and Ray’s Synthesis. Boiling a solution of normal or to the respective 1,2,3,4-tetrahydro-2,4-dioxoquinazolines by
isobutyrylanilides with urethane and phosphorous pentox- heating with acid or alkali (see Scheme 15).
ide in xylene gave 2-propyl and 2-isopropyl-3,4-dihydro-4-
oxoquinazolines (see Scheme 13). 5.3. From O-Ethoxy Carbonylaminobenzoic Esters or Amides.
When o-ethoxycarbonylamino benzamide and its 4-methyl
5. Methods for the Synthesis of derivatives are heated over their melting points, then they lose
Quinazoline and Quinazolinone Derivatives water and form 1,2,3,4-tetrahydro-2,4-dioxoquinazoline (see
Scheme 16).
(Benzoylene Urea)
Some methods were reported for the synthesis of quinazo- 5.4. From Phthalic Acid Derivatives. The derivatives of
lines and quinazolinones are as follows. phthalic acid used for the preparation of dioxoquinazoline
necessitate rearrangement of the Hoffmann Curties or Lossan
5.1. From Anthranilic Acid and Urea. The fusion of type. Reaction of phthalamide or phthalimide, N-methyl,
anthranilic acid with urea gave 1,2,3,4-tetrahydro-2,4-dioxo- and N-ethyl phthalimide with alkali hypobromite gives the
quinazoline (see Scheme 14). 1,2,3,4-tetrehydro 2,4-dioxoquinazoline (see Scheme 17).
O
󳰀 󳰀
COR COR
KNCO NH
R R
NH2 NHCONH2 N
H O
Scheme 15
O
⌉
⌋
COOR COOR CONHR R
ClCOOC2 H5 RNH2 󵄨󵄨
󵄨 󵄨󵄨󵄨 N
NH2 NHCOOC2 H5 ⌉ NHCOOC2 H5⌋ –C2 H5 OH N O
H
Scheme 16
O O
NaOBr N–R
N–R
N O
O H
Scheme 17
NR N–R O
H2 O2 O N–R
O
OH
N N O N O
H H H
Scheme 18
5.5. From Isatins. 𝛼-Isatin oxime rearranges to 1,2,3,4- N-arylation conditions afforded the corresponding quinazo-
tetrahydro-2,4-dioxoquinazoline on heating with dilute lines [10]. Treatment of benzoxazine with hydrazine hydrate
sodium hydroxide; 𝛽-imino derivatives of isatin, on the in ethanol prepared 3-amino-2-phenyl quinazolin-4-(3H)-
other hand, require oxidation with hydrogen peroxide in one, which upon condensation with aldehydes gives the
alkaline solution in order to form the dioxoquinazoline (see corresponding 3-arylidenoamino derivatives. Cyclization of
Scheme 18). these derivatives using mercaptosuccinic acid afforded 1,3-
thiazolidin-4-one ethanolic acid, which after esterfication
with N-hydroxyphthalimide or N-hydroxysuccinamide via
5.6. From 2-Aminobenzylamine. The 2-aminobenzylamine
acid chlorides produced the respective ethanolic esters [11]. A
reacts with butyrolactone which involves forming interme-
series of quinoxalin-2(1H)-one-3-hydrazone derivatives were
diate compound and further condensed with benzaldehyde
synthesized via condensation of 3-hydrazinoquinoxalin-
to give 3-(2-chlorobenzylidene)-1,2,3,9-tetrahydropyrrolo-2-
2(1H)-one with the corresponding ketones under microwave
quinazoline (see Scheme 19).
irradiation and gave hydrazones in high yield in less
reaction time compared to conventional method [12].
5.7. From 2-Azido-4-chlorobenzoic Acid. The 2-azido-4- The (hydroxyimino)(2-phenyl(1,2,3,4-tetrahydroquinazolin-
chlorobenzoic acid reacts with benzyl nitrile and formed 2-yl)) methane and (hydroxyimino) (2-(2-thienyl)(1,2,3,4-
7-chloro-3-phenyl-[1, 2, 3]triazolo[1,5-a]quinazoline-5-one tetrahydro quinazolin-2-yl)) methane were synthesized by
[9] (see Scheme 20). the condensation of 2-(hydroxyimino)-1-phenylethan-1-one
Condensation of o-iodobenzaldehydes with amidine and 2-(hydroxyimino)-1-(2-thienyl) ethan-1-one with 2-
hydrochlorides under ligand-free copper catalyzed Ullmann aminobenzylamine (2-ABA). Complexes of these ligands
O Cl
NH2 Cl
O N CHO N
+
NH2
N N
Scheme 19
O
N3
COOH NH
C6 H5 CH2 CN
Cl N
Cl
N N
Scheme 20
O O
O O
N
N S
Cl
S N
N
O
O Cl
1 2
Scheme 21
with Co3+ were prepared with a metal: ligand ratio of 1 : 2 [13]. hypnotics, antibacterial, anti-inflammatory, antifungal, anti-
The [4+2]cycloaddition between 2,4-diphenylpyrimidine malarial, anticonvulsant, anticoccidial, anti-Parkinsonism,
ortho-quinodimethane and dimethyl acetylenedicarboxy- cancer and other activities [6–8].
late leads to 2,4-diphenylquinazoline-6,7-dicarboxylate. 2,4-
Diphenylfuro [3,4-g]quinazoline-6,8-dione is also obtained 6.1. Quinazolinones as Anticancer Activity. Some new 3-
by basic hydrolysis of compound, followed by the closure substituted quinazolin-4(3H)-ones and 3,4-dihydro-quina-
of the resulting diacid in acetic anhydride [14]. A series zolin-2(1H)-one derivatives are reported that compounds
of triazoloquinazolinones and benzimidazoquinazolinones 2-[2-(4-chlorophenyl)-2-oxo-ethylthio]-3-(4-methoxyphen-
has been achieved under microwave irradiation by the yl)quinazolin-4(3H) one (1) and 3-(4-chlorophenyl)-2-[2-
reaction of aromatic aldehydes with 5-amino-1(H)-1,2,4- (4-methoxyphenyl)-2-oxo-ethylthio]quinazolin-4(3H)-one
triazole (or 2-aminobenzimidazole) and dimedone in DMF (2) as broad-spectrum antitumors show effectiveness toward
[15]. numerous cell lines that belong to different tumor subpanels
[16] (see Scheme 21).
A series of novel quinazoline derivatives (3–6) containing
6. Biological Importance of thiosemicarbazide moiety and evaluate their biological activ-
Quinazoline Derivatives ity as antitumor agents [17]. The therapeutically important
candidates are shown in (see Scheme 22).
The quinazoline and quinazolinone skeleton is frequently A series of phenyl N-mustard-quinazoline derivatives
encountered in medicinal chemistry. The various substi- (7a–d) were evaluated for their antitumor activity [18] (see
tuted quinazolines and quinazolinones are having signif- Scheme 23).
icant antihypertensive, antineoplastic, antidepressant, and A series of few 4,6 di-substituted-(diaphenylam-
antipsychotic activities whereas some derivatives of quina- ino)quinazolines derivatives (8a-b) were evaluated for anti-
zoline and quinazolinones are found to be effective agents tumor activity was considered as potent EGFR inhibitors
such as analgesic, antipsychotic, antiarrhythmic, sedative [19]. A series of quinazoline derivatives (9a–c) were
F Cl
F OCH3
H3 CO
O O O O
NH NH NH NH NH NH NH
N N N N NH
N HN N HN N HN N HN
S S S S
3 4 5 6
Scheme 22
R2 R1
Compd R R1 R2 R3
R3 –OCH3 –OCH3
R 7a –H –OCH3
N 7b F Cl H H
Cl HN N 7c H Cl F H
N
7d H C CH H H
NH
Cl N
O H
(7a–d)
Scheme 23
N F
N
NH HN Cl
Br NH R
N
R N
(8a-b) R = 8a –OH; 8b –Cl (9a–c) R 9a –NHCO(CH2 )2 Br;
9b –NHCO(CH2 )2 I; 9c –NH2
Scheme 24
evaluated for their function as EGFR inhibitors by applying New combi-triazenes (18, 19) for targeting solid tumors
radioiodination. All these compounds were further evaluated express the epidermal growth factor receptor (EGFR) or its
for potential SPECT activity for molecular imaging of breast closest homologue HER2 (see Scheme 29).
cancer [20] (see Scheme 24). A series of novel quinazoline derivatives (20a–c) showed
A series of novel 6-furanylquinazoline derivatives (10– potent ALK5 inhibitory activity [23] (see Scheme 30).
13) were subsequently evaluated for their biological activity Quinazoline-based (21a-b) anticancer molecule is dual
as a potent ErbB-1/ErB-2 tyrosine kinase inhibitor [21] (see irreversible kinase inhibitors [24] (see Scheme 31).
Schemes 25 and 26). A series of quinazoline derivatives (22a-b) were evaluated
A series of quinazoline derivatives (14–17) were evaluated for their biological activity against tyrosine kinase (EGFR)
for their activity as potent inhibitors of specific isoforms [25] (see Scheme 32).
of Cdc2-like kinases (Clk) and dual specificity tyrosine- A series of 4-piperazin-1-yl-quinazoline template based
phosphorylation regulated kinases (Dyrk) [22] (see Schemes aryl and benzyl thiourea derivatives (23–26) showed
27 and 28). potent, selective, and orally bioavailable antagonist of
O
O S CH3 O
O S O
N
HN HN Cl HN Cl
O N F O F
N
N N
10 11
Scheme 25
O O
O S CH3 O O S CH3 O
O HN Cl NCH2 C N HN Cl
O N F O N F
N N
12 13
Scheme 26
O O
S O S CH3 O
NH N
N N
N N
14 15
Scheme 27
O O
N CH3 O H3 C O
H3 C N H3 C NH
S H3 C
N N
N N
16 17
Scheme 28
H2 C O O H2 C O O
+
H3 C N N H3 C H
N
N
HN Cl N HN Cl
N CH3 N
N N
N N
18 19
Scheme 29
R1 R R1
HN
20a 6-Methyl-2-pyridinyl Pyridine-4-yl
N 20b 6-Methyl-2-pyridinyl 1H-indazol-5-yl
R
N (20a–c) 20c 6-Methyl-2-pyridinyl 4-Pyrimidnyl
Scheme 30
H3 C CH3 O O
N R R1 R2
21a –F H –OCH3
HN O
H R 21b –F –F –OCH3
N
N R1
O N
R2 (21a-b)
Scheme 31
R3
R R1 R2 R3
R2
HN 22a OCH3 OCH3 H Br
R1 22b NO2 H F H
N
R N (22a-b)
Scheme 32
H
S N N
N
23 R1 = O , R2 = CF3;
N N N
R2
O 24 R1 = , R2 = Cl
R 1 H3 C N
O N
Scheme 33
platelet-derived growth factor (PDGF) receptor [26] (see for their inhibitory activity against Aurora B kinase as potent
Schemes 33 and 34). antitumour agents [29] (see Scheme 37).
A series of 4-[4-(N-substituted(thio)carbamoyl)-1- Some quinazolines were evaluated as antitumor
piperazinyl]-6,7-dimethoxyquinazoline derivatives (27a-b) agents, the biological activity of some 2,3-di-substituted 8-
were evaluated for their potential antagonizing activity arylamino-3H-imidazo[4,5-g]quinazoline derivative (31 and
against Platelet-Derived Growth Factor Receptor (PDGF) 32) as a potent antitumor agent. Compound 32 possessed
[27] (see Scheme 35). the highest activity on the A549 cell line [30] (see Scheme
A series of quinazoline derivatives (28a-b and 29a-b) 38).
showed potent inhibitory activity against Aurora kinase [28] A series of novel C-5 substituted anilinoquinazoline
(see Scheme 36). derivatives and evaluated their activity as an inhibitor of
A series of 1-acetanilide-4-aminopyrazole substituted epidermal growth factor receptor tyrosine [31]. Few novel 4,6-
quinazoline derivatives (30a–c) were subsequently evaluated disubstituted quinazoline derivatives (33–36) showed good
H H
S N S N
N N N N
N N N
CF3
H3 C O N H3 C
O
N
N N
O N O N
25 26
Scheme 34
H R R1
O N
27a –OC2 H5 –OCH3
27b –COOCH3 H
N
O
N
R1
N
R N (27a-b)
Scheme 35
H H
N N R2 N N R2
O
N O N O
HN HN
N R1 N R1
N N
O N O N
R (29a-b)
(28a-b)
R1 R2
R R1 R2
29a –OCH3 3-Cl–4F–C6 H3
28a H OCH3 3-Cl–C 6 H4
29b –OCH3 3-Cl–C6 H4
28b OH OCH3 C6 H5
Scheme 36
N 30a H
N
N 30b –OCH3 HO
HN 30c –OCH3
O
HN N
R1 F HO
N
CH3
R2 O N F N OH
(30a–c)
Scheme 37
Cl
F
F
HN
O HN
H3 C N
N O N
N
H3 C N N
H3 CO N C4 H9
31 32
Scheme 38
R F R1
N
COOH
O HN Cl
N
N
R
N
H3 CO N
34 R = I, R1 = CH3 ; 35 R = H,
(33a-b) 33a R = –CH3 ; 33b R = H
R1 = CH3 ; 36 R = I, R1 = CH2 C6 H5
Scheme 39
R1 COOH
HN
O2 N
N O HN
N N N R O2 N
N
O
H H (37a–c)
N N
R R1 H
37a 3,4-Cl–C6 H3 4-COOH–C6 H4 38
37b 4-CF3 –C6 H4 4-COOH–C6 H4
37c 3-CF3 –C6 H4 4-COOH–C6 H4
Scheme 40
anti-inflammatory and anticancer activity (cytotoxic) against Microwave-assisted synthesis and the SAR studies of
U937 leukemia cell lines [32] (see Scheme 39). modified 9-oxo-thia-zolo[5,4-f] quinazoline-2-carbonitriles
A series of quinazoline derivatives (37 and 38) have allowed identification of new amidine and imidate derivatives
strong inhibition on human Pin1 [33] (see Scheme 40). as potent and dual CDK1/GSK-3 inhibitors. Combination of
A series of quinazoline derivatives (39–42) were evalu- lead optimization and molecular modeling studies allowed a
ated for their biological activity as potential antitumor agents dual CDK1/GSK-3 inhibitor with submicromolar values [35].
[34] (see Schemes 41 and 42). Novel 2,3-disubstituted quinazoline-4(3H)-ones (43) were
HEPG2 human liver cell line was proved to be sensitive screened for cytotoxicity and for antiviral activity against
toward compounds 39, 40, and 41 with IC50 concentration influenza A [36]. The 6-Arylbenzimidazo [1,2-c]quinazoline
range of 4.17–5.99 𝜇g/mL. Regarding HELA cervix cell line, derivatives were act as a tumor necrosis factor alpha (TNF-
higher sensitivity was observed with compounds 39, 41, and 𝛼) production inhibitors. These compounds were tested for
42 with IC50 concentration range of 3.56–5.39 𝜇g/mL. With their in vitro ability to inhibit the lipolysaccharide (LPS)
regard to broad-spectrum antitumor activity, compounds 42, induced TNF-𝛼 secretion in the human promyelocytic cell
41, and 39 showed IC50 of 3.35–5.59 𝜇g/mL against the three line HL-60. The compound 6-Phenyl-benzimidazo [1,2-
cell lines. c]quinazoline, coded as G1, resulted as the most potent
NO2 O
HN
S S
N N N
CH3 CH3
Cl N C2 H5 O Cl N
39 40
Scheme 41
S H2 N NH
NC N N
CH3 CH3
Cl N Cl N
41 42
Scheme 42
O O
R SO2 R
R1 N N
N
N N N
R2 N Cl Cl
O N O N O
43 44 45
Scheme 43
inhibitor and with no significant cytotoxic activity. Thus, 6- subtilis, and two gram negative bacteria, namely, Escherichia
arylbenzimidazo [1,2-c]quinazoline derivatives may have a coli and Certium at two different concentrations 100 𝜇g/mL
potential as anti-inflammatory agents [37]. Docking studies and 50 𝜇g/mL [40]. Quinazolinone derivatives (DK-1, DK-2,
of few synthesized 6,7-dialkoxy-4-anilinoquinazoline deriva- DK-3, DK-4, DK-5, DK-6, and DK-7) by treating 2-chloro-
tives which showed EGFR-TK inhibitory activity were con- N-(4-oxo-2-phenylquinazolin-3(4H)-yl)acetamide with the
ducted [38]. The 3-(3-methylisoxazol-5-yl) and 3-(pyrimidin- different substituted phenols. The synthesized compounds
2-yl)-2 styrylquinazolin-4(3H)-ones (44, 45) were pre- were evaluated for antibacterial activity by cup plate method
pared by refluxing in acetic acid the corresponding 2- by measuring inhibition zone. The compound DK-2 (47)
methylquinazolinones with the benzoic aldehyde and tested showed more potent antibacterial activity than the standard
for their in vitro antileukemic activity against L-1210 (murine drug ampicillin [41]. A series of quinazolines derivatives were
leukemia), K-562 (human chronic myelogenous leukemia), evaluated for their biological activity on various bacterial
and HL-60 (human leukemia) cell lines showing in some cultures [42] (see Schemes 44 and 45).
cases good activity [39] (see Scheme 43). Compounds 49 and 50 showed comparative activity
against K. pneumoniae as compared to ciprofloxacin. Com-
pound 48 exhibited greater activity against S. sonnei, E. fae-
6.2. Quinazolinones as Antibacterial Activity. A series of calis, and P. aeruginosa as compared to ciprofloxacin. A series
new 2-[2-(2,6- dichlorophenyl) amino] phenyl methyl-3-[(5- of some novel substituted iodoquinazoline derivatives are
substitutedphenyl)-1,5-dihydro-1H-pyrazol-3-yl-amino]-6- evaluated for their antimicrobial activity [43]. Compounds 52
iodoquinazolin-4(3H) ones compounds (46) were tested and 53 showed remarkable activity towards the gram negative
for their antibacterial activity in vitro by measuring zone bacteria E. coli, whereas compounds 51, 52, and 54 showed
of inhibition in mm against different strains like two gram potent activity against S. aureus, B. subtilis, S. Cerevisiae, and
positive bacteria, namely, Staphylococcus aureus and Bacillus C. albicans (see Scheme 46).
O
H
N N I
HN N
N N
Cl
H N NH
N O
O O O N+
Cl O−
46 47
Scheme 44
CH3
H3 C N HOOC
N N N
N O N O N
H3 C N H3 C N H3 C N
48 49 50
Scheme 45
I
N S
O N N
HN N
N HN S
N S N N N
I S
I O H
N N
S I
51 52 53 54
Scheme 46
The 3-[5-(4-substituted phenyl)-1,3,4-thiadiazole-2- that of gram negative bacteria. The most effective of
yl]-2-styryl quinazoline-4(3H)-ones (55) reported their quinazoline structure series were condensed [1,2,4]tri-
antibacterial and antifungal activity [44]. The 6,7,8,9- azoloquinazolines and 10H-[1,2,4]triazino[5,4-b]quina-
tetrahydro-5(H)-5-nitrophenylthiazolo[2,3-b]-quinazolin- zolin-10-ones [49]. The 6-bromo-2-alkyl/aryl-3{[phenyl(phe-
3(2H)-one derivatives showed antimicrobial activity [45]. The nyldiazenyl)methylene]amino}quinazolin-4(3H)-ones were
3-[(2-hydroxy-quinolin-3-ylmethylene)-amino]-2-phenyl- exhibited antimicrobial activities [50].
3H-quinazolin-4-one (56) and its metal (II) complexes
were reported for their antimicrobial activity [46]. Some
quinazoline derivatives (57) act as potential antimicrobial 6.3. Quinazolinones as Antifungal Activity. Octahydroquina-
agents [47] (see Schemes 47 and 48). zoline (58) was obtained by a modification of the Biginelli
Condensing 2-methyl/phenyl/chloro methyl disubsti- reaction with phenacyl bromide and bromo malononitrile
tuted benzooxazine-4-one and 1-(2-amino ethyl)-4-substi- to furnish thiazolo [2,3-b] quinazoline and they found the
tuted benzylidene-2-phenyl-1H-Imidazoles-5(4H)-one gave interaction of compound with formamide, formic acid, and
imidazolo-quinazoline-4-one derivatives. These compounds phenyl isothiocyanate yielded the corresponding pyrimidino
have shown promising antibacterial and antifungal activity thiazolo [2,3-b] quinazolines and exhibited antifungal activ-
[48]. The antibacterial activities of substituted quinazolines ity against Candida albicans [51].
against bacterial strains E. coli, P. aeruginosa, B. subtilis, and A series of few novel S-substituted-6-fluoro-4-alkyl (aryl)
S. aureus were investigated. The sensitivity of the gram pos- thioquinazoline derivatives (59a–c) were evaluated for their
itive bacteria to the tested quinazolines was higher than pharmacological activity as antifungal [52] (see Scheme 49).
N
O N N
N
N S R N
N Ar HO N
55 56
Scheme 47
O H
N O
S
R = 2-chlorophenyl, Ar = different aryl groups
N Ar
N N N
R
57
Scheme 48
S F R
F 59a = –SCH2 CH=CH2 ,
NH F
HN N 59b = –SCH2 CH2 –CH3 ,
N 59c = –SCH2 CH3
O F F
58 (59a–c)
Scheme 49
Cl O N R
O O HN 62a –C2 H5
N N 62b –C3 H7
N 62c –C4 H9
Cl S 62d –CH(CH3 )2
O R
O
60 61 (62a–d)
Scheme 50
All of these compounds exhibited good antifungal activ- activity against Mycobacterium tuberculosis strain HRv [53].
ity, especially compound 59c, having a wide spectrum of A series of quinazoline derivatives (62a–d) were evalu-
bioactivity; it shows potent inhibitory activity on the growth ated for their pharmacological activity as anti-TB [54] (see
of most of the fungi with EC50 values ranging from 8.3 to Scheme 50).
64.2 𝜇g/mL. 1,4-Disubstituted 3-[3󸀠 -(2󸀠 -phenyl-4󸀠-oxo-quinazolinyl)]-
2-azetidinones showed antifertility activity [55]. 6-sub-
stituted-2-phenyl-3-(5-substituted mercapto-1,3,4-thiadia-
6.4. Antitubercular Activity. Some quinazolinones were zole-2-yl)quinazoline-4-(3H)-ones showed anti-TB activity
reported as potent chemotherapeutic agents in the treatment [56]. Most of the synthesized compounds exhibited anti-TB
of tuberculosis (TB). For example 3-aryl-6,8-dichloro- activity against the strains of Mycobacterium tuberculosis,
2H-1,3-benzoxazine-2,4(3H)-diones (60) and 3-arylquina- M. avium, M. fortuitum, M. kansasii, and M. intracellulare.
zoline-2,4(1H,3H)-diones (61) are as anti-TB agents and The modification process with various hydrophobic chains
quinazolinone derivatives as anti-TB agents [4]. clearly suggests the existence of hydrophobic pocket in the
A series of 2-alkylthio-6-iodo-3-substituted-quinazolin- active site of the target of various strains of Mycobacterium
4-one derivatives were screened for their in vitro anti-TB spp., which eventually raise the therapeutic efficacy.
O R R1
N R1 63a C6 H5 2-OH–C6 H4
N 63b C6 H5 4-OCH3 –C6 H4
63c C6 H5 C6 H5
N
(63a–c)
Scheme 51
Cl
O
HN Cl
N
H3 C HN N
NH
O H CS N
N 3
64 65
Scheme 52
6.5. Quinazoline as Antiviral Agents. A series of Schiff 6.7. Quinazolinones as Anticoccidial Activity. A series of
bases of some 2-phenyl quinazoline-4(3)H-one derivatives 3-(2-(2-methoxyphenyl)-2-oxoethyl) quinazolinone deriva-
are evaluated for their activity as antiviral agents [57] (see tives (67) are anticoccidial agents by modifying the quinazo-
Scheme 51). line ring of febrifugine against Eimeria tenella in the chicken
Compound 63a exhibited antiviral activity against her- at a dose of 9 mg/kg. 3-(2-(2-Methoxyphenyl)2-oxoethyl)
pes simplex virus-1 (KOS), herpes simplex virus-2(G), her- quinazolinone derivatives (68) possess high anticoccidial
pes simplex virus-1 (TK- KOS ACV), and vaccinia virus activity and may serve as a lead compound for the develop-
ment of anticoccidial drugs in the future [61]. A series of 4-(2-
in HEL cell culture at selectivity index of 100, 100, 100,
methoxyphenyl)-2-oxobutylquinazoline (69) derivatives are
and 125, respectively, whereas cytotoxicity was observed at
reported for their anticoccidial activity [62] (see Schemes 53
100 𝜇g/mL. Compounds 63b and 63c demonstrated good
and 54).
activity against herpes simplex virus-1 (KOS), herpes sim-
plex virus-2 (G), and vaccinia virus. The protein kinase
6.8. Anti-Inflammatory and Analgesics Agents. A series
inhibitory activity and anticytomegaloviral activity showed
of quinazoline derivatives (70, 71) showed potent anal-
few quinazoline (64) compounds [58]. Quinazolinones
gesic and anti-inflammatory activity. All these compounds
act as anti-HIV activity whereas compounds 3-amino-2-
demonstrated potent activity as anti-inflammatory analgesic
methyl mercaptoquinazolin-4(3H)-one (65) were synthe- more than the reference compound indomethacin [63] (see
sized by condensing the acidic imino group of isatin with Scheme 55).
formaldehyde and secondary amines and evaluated for anti- A series of novel 2-(2,4-disubstituted-thiazole-5-yl)-3-
HIV activity against HIV-1 III B in MT-4 cells [59] (see aryl-3H-quinazoline-4-one (72) derivatives which became
Scheme 52). good inhibitors of NF𝜅B and AP-1 mediated transcrip-
tion activation [64]. A series of 3-phenyl-2-substituted-3H-
quinazolin-4-one (73a–c) derivatives were evaluated for their
6.6. Quinazolinones as Antimutagenic Activity. The (S)-
pharmacological activity as analgesic and anti-inflammatory
4-aminoquinazoline alcohols (66) were prepared from
agents [65] (see Scheme 56).
enantiomerically pure from (S)-quinazolinone alcohols. A series of some novel 2,3-disubstituted quinazolinone
Mutagenic and antimutagenic properties of the (S)-4- derivatives by condensing 2-methyl/2-phenyl/6-bromo-
aminoquinazoline alcohols were investigated by using 2-methyl/6-bromo-2-phenyl/6,8-dibromo-2-methyl/6,8-
Salmonella typhimurium and E. coli WP2uvrA tester dibromo-2-phenyl benzoxazines with compounds containing
strains at 0.01, 0.1, and 1 lg/plate concentrations. (S)-4- amino group were evaluated for their analgesic activity and
aminoquinazoline alcohols were found to be genotoxically they reported that compound (74) shows promising analgesic
safe at the tested concentrations. Among the tested (S)-4- activity compared to standard drug Diclofenac sodium [66].
aminoquinazoline alcohols, the best antimutagenic activity Various 2-(substituted phenyl methylene imino) amino acetyl
was obtained with a methyl derivative at 0.1 𝜇g/plate dose methylene-3-(2󸀠 -substituted indol-3󸀠 -yl)-halo substituted-
[60]. 4(3H) quinazolinone and 2-(substituted phenyl amino
O
NH2
N O
N N
HO
N
O
66 67
Scheme 53
O H3 COC
N O
N N
N O
O
68 69
Scheme 54
N N N N N
N N
70 71
Scheme 55
O R R1
Cl R1
HN H
N 73a C6 H5 N
N CH3
N N R CH3
H
S R 73a–c 73b C6 H5 N
N NH N CH3
N CH3
H3 C H
73c C6 H5 N CH3
N C CH3
(72a-b) 72a R = –CH3 ; H2
72b R = 3Cl–C6 H4
Scheme 56
methylene acetyl-4󸀠 -oxo-1󸀠 -thiazolidinyl-3-(2󸀠󸀠 -substituted A series of 5-(4-chlorophenyl)-9-iodo-3-substituted-

indol-3󸀠󸀠 -yl)4(3H)-quinazolinones reported that compound l,2,4-triazolo[4,3-c]quinazoline and 2-(4-chlorophenyl)-6-
(75) exhibited good anti-inflammatory activity [67] (see iodo-4-substituted-quinazoline were evaluated as anti-
Scheme 57). inflammatory agents. The result revealed that some
A series of novel 8/10-trifluoromethyl-substituted- compounds have activity comparable to indomethacin [69].
imidazo [1,2-c] quinazolines are evaluated in vivo for A number of substituted oxoquinazolines were reported
their anti-inflammatory activity and in silico to recognize for their analgesic and antibacterial activity [70]. A series
the hypothetical binding motif with the cyclooxygenase of novel 3-(6-substituted-1,3-benzothiazole-2-yl)-2-[{(4-
isoenzymes (COX-1 and COX-2) employing GOLD (CCDC, substituted phenyl)amino} methyl]quinazolines-4(3H)-ones
4.0.1 version) software and found that compounds (76 and and quinazolines-4-one derivative were investigated for their
77) show good anti-inflammatory activity against standard: anti-inflammatory and antibacterial activity [71]. A series
indomethacin [68] (see Scheme 58). of some 2-[(E)-2-furan-2-yl-vinyl]-quina-zolin-4(3H)-ones
O
O I NH H3 CO
Br
N NH2 NH
N N
N C6 H5 O S
Br O
74 75
Scheme 57
F
N F F N
N N
F
N N
F
F
O NH2 OH O NH2 OH
76 77
Scheme 58
R R1
O N N
R 78a C6 H5 C6 H5
S
N 78b 4-Cl–C6 H4 C6 H5
N R1 78c 4-Cl–C6 H4 p-OCH3 C6 H5
(78a–c)
Scheme 59
incorporated into pyrazoline, isoxazoline, pyrimidine, 79c showed anticonvulsant activity at 4 h in MES screen and
or pyrimidine-thione ring systems at position 3 of the at 0.5 and 4 h in subcutaneous PTZ screen.
quinazoline ring. These compounds showed antimicrobial The 3-aryl-4(3H)-quinazolinone-2 carboxaldehydes,
activity and anti-inflammatory effect of [72]. their corresponding Schiff ’s base, and thiosemicarbazone
derivatives reported (80–82) as anticonvulsants [75] (see
6.9. Quinazoline as Antidepressant and Anticonvulsant. A Scheme 61).
series of novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2- Several 1-(4-substitutedphenyl)-3-(4-oxo-2-phenyl/ethyl-
styryl quinazoline-4(3H)-ones (78a–c) derivatives were eval- 4H-quinazolin-3-yl)-urea derivatives (83a–h and 84a–h)
uated for their activity as antidepressant agents [73] (see were screened for their anticonvulsant activity by MES and
Scheme 59). scPTZ-induced seizure models in mice and found that these
All the compounds showed anticonvulsant activity in compounds were active in the MES screen whereas some
MES screen; however, compound 78a showed potency simi- compounds were found to be active in the scPTZ screen [76]
lar to standard drug (phenytoin, carbamazepine) without any (see Scheme 62).
neurotoxicity. Two regioisomer series, 2-(3-ethyl-4(3H)-quinazolinone-
A series of some novel 3-[5-substituted 1,3,4-thiadiazole- 2-ylmercaptoacetylhydrazono)-3-alkyl/3-aryl-5-methyl-4-
2-yl]-2-styryl quinazoline-4(3H)-one. thiazolidinones (85) and 2-arylimino-3-(3-ethyl-4(3H)-
(79a–c) derivatives were evaluated for their activity quinazolinone-2-yl mercaptoacetylamino)-5-methyl-4-thia-
as CNS depressant and anticonvulsant agents [74] (see zolidinones were reported for their anticonvulsant activity
Scheme 60). [77]. Substituted quinazolinonyl-2-Oxo/thiobarbituric acid
Compounds with the above substituents showed potent derivatives showed anticonvulsant activity against MES
CNS depressant activity. Compound 79a showed anticonvul- and scPTZ models [78]. A series of halogenated
sant activity at 0.5 and 4 h in different test models, whereas derivatives, 3-methyl, 3-ethyl and 3-phenyl-6-mono, and
R Ar
O N N
79a C6 H5 p-ClC6 H4
R
N S p-ClC6 H4
79b p-OCH3 C6 H4
N Ar
79c p-ClC6 H4 N
(79a–c)
Scheme 60
S S S
N N N N
N N CH3 N C2 H5
N N
H NH2 H NH H NH
I N N N
I I
O O O
F F F
80 81 82
Scheme 61
84a –H
O O O O –NO2
84b
NH NH
84c p(CH3 )
N NH N NH
84d –OC2 H5
C2 H5 C6 H5 84e –Cl
R1 R1 84f –Br
(83a–h) (84a–h) 84g –I
84h –OCH3
Scheme 62
6,8-disubstituted-3H-quinazolin-4-one derivatives exhibited derivatives (90) were evaluated for their antiplasmodial
anticonvulsant activity and phenobarbitone sodium was used activity [82] (see Scheme 65).
as a reference drug [79]. Some thiadiazolyl and thiazolid- Compounds 90a and 90c show a high potential activity
inonyl quinazoline-4(3H)-ones (86) screened them for (resp., W2 IC50 values = 0.95 and 1.3 𝜇M) in comparison with
anticonvulsant activity against MES induced convulsions in chloroquine and doxycycline. A series of new 6-ureido-4-
animal models [80] (see Scheme 63). anilinoquinazolines (91–94) were evaluated for their potent
A series of novel 3-[5-substituted phenyl-1,3,4 thia- activity as antimalarial agents [83] (see Scheme 66).
diazole-2-yl]-2-styryl quinazoline-4(3H)-one is screened for A series of 4-thiophenoxy-2-trichloromethyquinazolines
antidepressant activities with the help of the forced swim derivatives (95a-b) were evaluated for their antiplasmodial
pool method and found that compound (87) was most active activity against the human malarial parasite Plasmodium
against antidepressant activity [73]. The 3-[5-substituted- falciparum was determined [84]. Compounds 95a and 95b
1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones (88) showed good activity against K1 Plasmodium falciparum
and their antidepressant activity were screened with the help (IC50 = 1.9 𝜇M and 0.9 𝜇M, resp.), whereas IC50 value
of forced swim pool method [73] (see Scheme 64). of chloroquine is 0.5 𝜇M. A series of (96a–d) in 4-aryl-
2-trichloromethylquinazolines (96a–d) were evaluated for
6.10. Quinazolinones as Antimalarial Agents. The 2,4-diam- their antiplasmodial activity [85] (see Scheme 67).
ino-6-[(aryl)thio]quinazoline compounds were known to Compounds with the above substituents exhibited
their antimalarial properties wherein the 4-amino group was favourable antiplasmodial activity on THP1 and HepG2
replaced by hydrazine and hydroxyamino moieties and they human cell lines.
found that such changes reduce markedly the antimalarial
properties of this series. The compound (89) was tested 6.11. Quinazolinones as Antioxidant Activity. A series of novel
against a normal drug-sensitive strain of Plasmodium berghei thiazolo quinazoline derivatives by condensation of different
in mice by the parenteral route [81]. A series of quinazoline aromatic aldehydes with 4-nitro aniline are screened for
O
O N N
H
N S O O
S
X H N N
N NH
N X N
CH3
S H N X󳰀
N
R O H
85 X = H, R = H or p-OCH3 󳰀
86 X = H or Cl, X = O
Scheme 63
S
O
N N O N N
N
R
N S
N
N Ar
87 88 Ar = C H
6 5 , R = p OCH 3
Scheme 64
R2 R1 R R1 R2
90a CF 3 H H
90b H F H
R 90c Cl H H
NH2 F
F O
N
H2 N F N O S
O2 N CH3
N S
N
89 90
Scheme 65
R3 91 R1 = H, R2 = Cl, R3 = H, R4 = F;
H 92 R1 = Cl, R2 = CH3 , R3 = H, R4 = F;
R1 N O R4 93 R1 = CF3 , R2 = Cl, R3 = H, R4 = CF3 ;
HN
94 R1 = CF3 , R2 = Cl, R3 = OCH3 , R4 = OCH3 .
HN
R2 N
N
(91–94)
Scheme 66
antioxidant activity by DPPH radical assay, nitric oxide scav- 6.12. Antileishmanial Agents. Compounds of both synthetic
enging activity, and hydrogen peroxide scavenging activity and natural origin comprising a diverse group of chemical
and reported that synthesized compounds (97–99) were structure have been reported as antileishmial agents. These
found to be the most potent antioxidant activity [86] (see include mostly nitrogen heterocyclic such as quinolines,
Scheme 68). purine, pyrimidine, acidine, phenothiazines, bisbenzamides,
R1 R R1 R1 R R1
S
95a –CCl3 –S–C6 H5 96a –CCl3 4-F–C6 H4
95b –CCl3 –S–C6 H5 –4Cl N 96b –CCl3 4-Cl–C6 H4
N
N 96c –CCl3 4-OCH3 –C6 H5
N R
R 96d –CCl3 2-Naphthyl
(95a-b) (96a–d)
Scheme 67
O O O OH OH
N O N N
S S S
N N N
HO HO HO
HN HN HN
O O− O
N+ N+ N+
O− O O−
97 98 99
Scheme 68
N N N
N NH N NH N NH
Cl F F
100 101 102
Scheme 69
pyrazolol, pyridine, benzothiazole, and imidazolines [87]. antagonist for melanin concentrating hormone receptor 1
The 4-(substituted-benzylidine)-2-substituted-5,6-dihydro- (MCHR1) [90] (see Scheme 71).
benzo[h]quinazoline and 4-(substituted benzylidine)-2-sub-
stituted-3,4,5,6-tetrahydrobenzo[h]quinazoline from 2-(sub- 6.15. Antihypertensive Agents. A series of 3-benzyl-2-
stituted-benzylidine)tetralone-1 and several substituted substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones have
guanidine sulfates are evaluated for their in vitro anti- been synthesized by the cyclocondensation of 3-amino-2-
leishmanial activity and they reported that compounds benzylamino-3H-quinazolin-4-one. The compounds were
(100–102) show promising antileishmanial activity against evaluated for their in vivo antihypertensiveactivity. All the test
Leishmania donovani [88] (see Scheme 69). compounds exhibited significant antihypertensive activity; 3-
benzyl-2-methyl-3H-[1,2,4]triazolo[5,1-b] quinazolin-9-one
exhibited antihypertensive activity more than the reference
6.13. Quinazoline as Neuroprotective Agents. Few quinazoline drug prazocine [91].
derivatives (103a–c) were evaluated for their activity as potent
and highly selective PDE5 inhibitors to be employed for male
6.16. Anti-H1 -Antihistaminic Agents. A series of 1-substi-
erectile dysfunction [89] (see Scheme 70).
tuted-4-benzyl-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones
were synthesized by the cyclization of 2-hydrazino-3-
6.14. Quinazoline as Antiobesity Agents. A series of quina- benzyl-3H-quinazolin-4-one. When tested for their in
zoline derivatives (104–106) are to be considered as an vivo H1 -antihistaminic activity on guinea pigs, all the test
Cl R R1 R2
HN 103a C3 H7 OCH3 NHCOCF3
R2 OCH3 103b CH2 CH2 OH OCH3 NHCOCH3
N
103c CH2 CH2 OH OCH3 NHCOC2 H5
R1 N
R (103a–c)
Scheme 70
H3 C
Cl
O
HO HO
Cl Cl
O
HN
N N HO
N N
O O
N
N N
N N
H H N
CH3 H3 C N
H3 C H
104 105 106
Scheme 71
OCH3
NH2
N O
O
H
R
H2 N
107a R = –OC2 H5 ; 107b = OCH3
Scheme 72
compounds protected the animals from histamine induced types of pharmacological activities. The quinazoline and
bronchospasm significantly [92]. quinazolinone based pharmaceuticals are becoming very
important class of therapeutic agents and are likely to replace
many obtainable organic based pharmaceuticals in the very
6.17. Quinazoline as Antiprotozoan Agents. A series of quina- near future. The quinazoline and quinazolinone based phar-
zoline derivatives (107a-b) were evaluated for their activity maceuticals will be created on a large scale by different
as a potent inhibitor of trypanosoma cruzi dihydrofolate research development processes and will become available
reductase [93] (see Scheme 72). commercially for therapeutic uses. The biological profiles
of this new generation of quinazoline and quinazolinone
7. Discussion represent much progress with regard to the older compounds.
This study gets an efficient way of understanding about the
Heterocyclic compound containing quinazoline and quina- target pharmacophore relationship which can further aid
zolinone nucleus plays most important role in the field the process of drug design developments. This study may
of medicinal chemistry. It shows wide range of activities also accelerate the designing processes to generate a larger
for medication purpose. A large number of quinazoline number of therapeutically active molecules. The molecular
compounds have been synthesized and evaluated for their treatment of potentially lead molecules is still a major
different biological activities. Some marketed quinazoline line of approaches for the discovery and development of
and quinazolinone nucleus containing drugs have different new drug molecules [94–99]. Combination of two or more
moieties into one is a general procedure of handling and this [11] S. Shweta, S. Chirag, T. Bhawana, and J. Talesara, “Synthe-
can probably result in the raise of biological activities and sis of phthalimido or succinimido[2-aryl-4-oxo-3-2-phenyl-
deduction of untoward side effects. 4(3H)-quinazolinon-3-yl-1,3-thiazolidin-5-yl]ethanoate,” Jour-
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International Journal of Medicinal Chemistry

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1. Introduction position of the keto or oxo group, these compounds may be

Quinazoline and quinazolinone compounds and their uses

F3C OCH3 Milciclib

3.1.1. Oxidation. Catalytic hydrogenation of quinazoline

methylene acetyl-4󸀠 -oxo-1󸀠 -thiazolidinyl-3-(2󸀠󸀠 -substituted A series of 5-(4-chlorophenyl)-9-iodo-3-substituted-

107a R = –OC2 H5 ; 107b = OCH3

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