Quinazolinone as Bioactive Pharmacophore: Synthesis and Biological Activities

ABSTRACT

Quinazolinone, a nitrogen‐containing bicyclic system having a benzene‐fused pyrimidine ring, constitutes an important organic framework that has attracted the interest of all scientists working in the pharmacological and agricultural sectors owing to its numerous biological properties. Synthetic accessibility and structural flexibility allowed this skeleton to be easily modified with certain reagents that enhance its physicochemical properties. The aim of this review is to study the structural modifications of quinazolinone by various methods, suited for controlling virulence caused by various pathogens. Synthesis of quinazolinone derivatives and their potential hybrid skeletons with different heterocyclic moieties has also been explored. Furthermore, covering its applications from the well‐established field of drug discovery to its innovative potential in crop protection, cancer treatment, microbial infections, insomnia, viral diseases, and so forth, has been reviewed with a concise discussion of their structure–activity relationships (SAR). In addition, it was deduced that modifying quinazolinone with electron‐donating and electron‐withdrawing substituents and heterocyclic moieties had escalated their biological aptitude in comparison to the basic quinazolinone moiety. This study can direct researchers working in this field to adopt a new approach for formulating and optimizing the synthesis and therapeutic potential of quinazolinone derivatives.

Quinazolinone‐based pharmacophores possess biological potential in the field of medicinal chemistry, and in treating cancer, inhibiting viral infections, and diabetes, these compounds play an essential role in drug development. Synthetic properties of quinazolinone have also opened new pathways for developing more potential derivatives. The wide biological potential of quinazolinone and its derivatives in numerous therapeutic domains is highlighted in this review.

1. Introduction

Heterocyclic compounds are of great significance in medicinal chemistry, as a large number of drugs and pharmaceuticals are composed of heterocyclic frameworks. Besides this, these compounds are building blocks of nucleic acids, vitamins, antibiotics, hormones, dyes, and agrochemicals. Further, heterocyclics have been widely used in medicine, agriculture, plastics, polymers, and many other industries [1]. Owing to their ubiquitous applications, these scaffolds have long been a subject of massive interest, and significant efforts have been made to expand synthetic strategies, which could result in the discovery of new bioactive compounds in medicinal chemistry [2].

Among these, the nitrogen‐containing compound, quinazolinone, an oxidized derivative of quinazoline, is a bicyclic system composed of fused benzene and pyrimidinone rings, is especially notable. It is one of the building blocks of approximately 150 quinazolinone‐based alkaloids that have been isolated from diverse sources across the kingdoms of plants, animals, and microorganisms [3]. Early studies conducted during the 1950s and 1960s reported that febrifugine, a quinazolinone‐based alkaloid isolated from the Chinese medicinal plant Dichroa febrifuga (commonly known as Aseru), exhibited significant antimalarial activity [4]. Both natural and synthetic quinazolinones have garnered considerable interest in organic and medicinal chemistry owing to their diverse pharmacological properties, including antimalarial, antimicrobial, antifungal, antiviral, anti‐inflammatory, antitubercular, antidepressant, anticonvulsant, herbicidal, anticancer, antidiabetic, sedative, analgesic, and antitussive activities. The presence of nitrogen atoms, planar structure, and extent of conjugation make this moiety chemically and biologically active. The nature and position of the substituents and their conjugation on the pyrimidine ring are the major contributors that alter the properties of substituted quinazolinones under different conditions. Depending upon the position of the keto or oxo group, these compounds may be classified into three types (Figure 1) [5]. Out of the three, 2(1H)‐quinazolinone, 4(3H)‐quinazolinone, and 2,4(1H,3H)‐quinazolinedione structures, 4(3H)‐quinazolinones are the most prevalent and are significant in medicinal chemistry, possessing a multitude of pharmacological actions.

FIGURE 1.

Isomers of quinazolinone.

4(3H)‐Quinazolinone is found to exhibit reactions of both keto and enol tautomer; therefore, the two forms are said to be in equilibrium with each other (Figure 2). These isomers show lactam–lactim tautomerism, leading to higher significance in chemical reactivity and pharmacological activity as shown below

FIGURE 2.

Tautomerism in quinazolinone.

It has been reported that different substituents at the 2/3 position of the 4(3H)‐quinazolinone markedly influence pharmacological activity. 2‐substituted quinazolinones have antifungal and antihyperlipidemic activities, while 3‐substituted quinazolinones possess antimalarial activities. The 2,3‐disubstituted quinazolinones possess anticancer, anticonvulsant, antimicrobial and anti‐inflammatory activities.

The 2‐cyano‐4(3H)‐quinazolinone derivative was the first quinazolinone compound synthesized, originating from anthranilic acid and cyanogens in the late 1860s by Griess [6]. Some of the quinazolinones have been successfully commercialized as drugs. Notably, synthetic thiophene‐based quinazolinone derivative raltitrexed I [7] is currently marketed as a therapeutic agent for cancer treatment (Figure 3). Afloqualone II [8] is a clinically approved drug exhibiting muscle‐relaxant properties through agonist activity at the γ‐aminobutyric acid type A (GABA‐A) receptor. A sulfonamide containing fenquizone III [9] is an approved diuretic agent that significantly inhibits sodium reabsorption in the proximal tubule. Letermovir IV, a piperazine‐based derivative of quinazolinone, is employed in the treatment of cytomegalovirus infection [10]. Inflammation due to arthritis can be cured by diproqualone V [11], a quinazolinone molecule modified at the hydroxyl group. Albaconazole VI [12], containing a quinazolinone moiety along with a triazole ring, is an approved antifungal agent that inhibits multiple CYP450 liver enzymes. Prazosin VII [13] is a piperazine and furan‐based derivative of quinazolinone, used as an antihypertensive agent. Several other promising quinazolinone derivatives are in clinical trials.

FIGURE 3.

Quinazolinone‐based drugs exhibiting various biological activities.

The emergence of drug resistance among pathogenic strains has created a critical and unmet medical need for the discovery and development of novel therapeutic agents [14]. In this context, the quinazolinone core has gained considerable attention for the design and synthesis of new bioactive compounds. Over recent years, numerous methodologies for the synthesis of quinazolinone scaffolds have been reported, enabling rapid access to structurally diverse derivatives. This structural diversity provides significant opportunities for the development of new pharmacologically active molecules. In this review, we summarize the promising synthetic strategies, biological activities, and structure–activity relationships (SAR) of various 4(3H)‐quinazolinone derivatives from 2018 to 2025.

2. General Methods for Synthesis of Quinazolinone

Quinazolinone is a privileged scaffold and can be synthesized by various methods as depicted in Table 1. Niementowski synthesis involved a reaction between anthranilic acid and amides at higher temperatures to form quinazolinone [15]. In addition, synthesis of quinazolinone can also be done by reacting anthranilic acid wth carboxylic acids or orthoesters in the presence of conventional catalysts. A common way of synthesizing quinazolinone is by reaction of isatoic anhydride with different amines [16]. Reactions of anthranilamide with aldehydes, ketones, alcohols, or nitriles in the presence of a catalyst were also carried out for the synthesis of quinazolinone [17].

TABLE 1.

Comparative methods for synthesis of quinazolin‐4(3H)‐one.

S. no.	Reactants	Product	Method	Catalyst	Additive/solvent	Reaction conditions (temperature/time)
1	Anthranilic acid, formamide	Quinazolin‐4(3H)‐one	Conventional	—	—	150°C–160°C, 8 h
2	Isatoic anhydride and (het)aryl methanamines	Quinazolin‐4(3H)‐one	Conventional	CuBr	K2CO3, TBAB, and DMSO	120°C, 8 h
3	2‐aminobenzamide and benzyl alcohol	Quinazolin‐4(3H)‐one	Electrochemical	I2	NaOH, and H2O	r.t., 6 h, I = 80 mA
4	2‐aminobenzamide, benzylamine, and oxone	Quinazolin‐4(3H)‐one	Microwave‐assisted synthesis	Cu(OAc)2	Toluene	100°C, 10 h
5	1,2,3‐benzotriazinone, benzylamine and paraformaldehyde	Quinazolin‐4(3H)‐one	Photocatalysis	fac‐Ir(ppy)3	N2, Toluene, and TFA	40°C, 12 h, 5 W blue LEDs
6	Anthranilamide and aldehydes	Quinazolin‐4(3H)‐one	Pestle‐mortar and mechanochemical ball‐milling	p‐TsOH	—	r.t., 5min
7	Anthranilic acid, acetic anhydride, and amines	Quinazolin‐4(3H)‐one	Conventional	Magnetic nanoparticle supported tungstic acid	—	80°C, 4–12 h
8	Isatoic anhydride, substituted aniline, and triethyl orthoformate	Quinazolin‐4(3H)‐one	Conventional	[Et3NH][HSO4]	—	r.t., 2 h
9	2‐aminobenzamide and benzaldehyde	Quinazolin‐4(3H)‐one	Conventional	Urea/SbCl3/HCl (deep eutectic solvent)	Ethanol	60°C, 1 h

Various transition metal catalysts like iron, cobalt, copper, palladium, ruthenium, iridium, and so forth, are used for annulation, coupling, and cascade reactions. Likewise, quinazolinone was synthesized from 2‐aminobenzamide and benzyl alcohol, catalyzed by a palladium complex, [Pd(L)Cl(PPh₃)] (L = dimethylamino benzoylhydrazone) [18]. Besides these, iodine, ammonium hexafluorophosphate, and bases like t‐butoxide, potassium phosphate, potassium carbonate, and so forth, are utilized in oxidative coupling and multi‐component reactions. Modern methods focuses on green routes for synthesis of quinazolinone, emphasizing on reducing waste, high efficiency, use of environmentally friendly solvents and catalysts. These include one pot reactions using electrochemical synthesis [19], microwave‐assisted synthesis [20], photocatalytic oxidative cyclizations [21], metal‐ or solvent‐free synthesis [22]. Use of green catalysts like magnetic nanoparticles [23], ionic liquids [24] or deep eutectic solvents [25] are also being promoted nowadays (Figure 4). These methods are prioritized as they reduce solvent waste and need for intermediate isolation and purification, providing sustainability and high yields. In addition, these processes help to achieve high‐atom efficiency, eliminates hazardous organic waste.

FIGURE 4.

General methods for synthesis of quinazolin‐4(3H)‐one.

Diverse functional groups like electron‐donating and electron‐withdrawing groups can be introduced at different positions of quinazolinone following above synthetic paths to create structural diversity in medicinal chemistry. The succeeding discussion includes the synthetic procedures using different derivatives of quinazolinone with several functional groups, active scaffolds providing active hybrid molecules by conventional and modern routes. Each synthetic pathway had provided the final compound in comparative yields.

3. Synthesis and Biological Activity of Quinazolinone Derivatives

3.1. Antimicrobial Activity

Hassan et al. synthesized a series of quinazolinone derivatives of type 4a–h in order to evaluate their antimicrobial and antibiofilm effects. Anthranilic acid 1 was reacted with chloroacetyl chloride in dichloromethane, followed by refluxing with acetic anhydride, forming intermediate 2. Further, intermediate 2 was reacted with hydrazine hydrate in n‐butanol and different amines in toluene, producing intermediate 3, followed by reaction of its ethanolic solution with various aldehydes in glacial acetic acid (GAA), yielding final compounds 4a–h (Scheme 1). It was found that derivatives 4c and 4d had shown promising results by inhibiting biofilm formation of Pseudomonas aeruginosa (P. aeruginosa) with IC₅₀ values of 3.55 and 6.86 µM, respectively. Compound 4d lowers the hydrophobicity of the bacterial cell surface, weakening cell adhesion. On the other hand, 4c and 4d had decreased the production of exopolysaccharide, which is the major component of the extracellular substance that binds biofilm components together. Moreover, these compounds reduce the mobility of Pseudomonas cells, which affects the invasiveness and toxicity of the cells. SAR studies indicate that the electron‐donating and trimethoxy groups on the phenyl ring with the pyrrolidine ring contributed to biofilm inhibition. Docking results of compounds 4c and 4d with respect to the M64 inhibitor in PqsR ligand‐binding domain (LBD) showed comparative interaction energies of −49.62, −47.61, and −52.21 kcal/mol, respectively. In compound 4c, N‐1 and the carbonyl group of the quinazolinone and pyrrolidine rings make hydrogen bonds with amino acids and hydrophobic interactions with hydrophobic chains of amino acids of the LBD of PqsR. N‐1 of the quinazolinone ring, N of the pyrrolidine ring, and the p‐nitrophenyl substituent in 4d form hydrogen bonds and show hydrophobic interactions with active amino acids of the LBD of PqsR, resulting in decreased biofilm formation by acting on PqsR [26].

SCHEME 1.

Synthesis of quinazolinone–pyrrolidine derivatives (4a–h).

Wang et al. synthesized quinazolinone derivatives of type 10a–h containing 1,3,4‐oxadiazole components (Scheme 2) [27]. Substituted phenol 5 was refluxed with ethyl bromoacetate in acetonitrile and potassium carbonate to yield intermediate 6. Compound 6, on reaction with hydrazine hydrate in acetonitrile, led to the formation of 7, which, on refluxing with potassium hydroxide in ethanol and carbon disulfide, yielded 8. It was reacted with the intermediate 9 in potassium carbonate and acetonitrile to offer the target compounds 10a–h. The synthesized compounds were evaluated for their antifungal activity against Botrytis cinerea, and results revealed that compound 10f was found to be more effective than the other compounds. The compound 10f had shown better inhibition of B. cinerea with an EC₅₀ value of 0.76 µg/mL as compared to the standard boscalid, imazalil, pyrimethanil, and penthiopyral (EC₅₀ values of 0.86, 2.15, 15.91, and 1.03 µg/mL, respectively) by forming crinkles on the surface of hyphae and increasing cell membrane permeability of B. cinerea. It was deduced that the derivatives containing chloro and methyl substituents at ortho‐ or para‐positions and the phenoxymethyl fragment had improved B. cinerea inhibition.

SCHEME 2.

Synthesis of 1,3,4‐oxadiazole derivatives of quinazolinone (10a–h).

Yan and coauthors synthesized derivatives of quinazolinone of types 13 and 14a–l containing a benzimidazole molecule as shown in Scheme 3. The reaction involved refluxing quinazolinone 11 with thionyl chloride in the presence of dichloroethane and dimethylformamide, followed by reaction with p‐hydroxybenzaldehyde, forming intermediate 12, which, on treatment with sodium bisulfite and o‐phenylenediamine, yielded 13, which, on further reaction with alkyl halides, yielded target compounds 14a–l [28]. The required compounds were tested for antifungal activity against Gibberella zeae. It was observed that compound 13, with an EC₅₀ value of 1.17 µg/mL, was found to inhibit the growth of G. zeae more efficiently by increasing permeability, followed by destruction of hyphae of the fungus, compared to the standard fungicides azoxystrobin and chlorothalonil (EC₅₀ 4.88 and 12.98 µg/mL, respectively) and other derivatives. It was concluded that an electron‐withdrawing halogen substituent had increased the antifungal efficacy of the target compound as compared to other substituents.

SCHEME 3.

Synthesis of benzimidazole‐quinazolinone hybrids (14a–l).

Zhang et al. designed novel derivatives of quinazolinone of type 19a–h. Synthetic procedure (Scheme 4) involved reaction of anthranilic acid 15 with triethyl orthoacetate to form intermediate 16, followed by reaction with 4‐aminobenzenethiol in GAA, yielding intermediate 17, which, on further reaction with 18 in the presence of K₂CO₃ and dimethylformamide at room temperature, yielded the target compounds 19a–h [29]. Compounds were analyzed for their antibacterial activity, and compound 19g was found to be more active than other derivatives against Pseudomonas syringae pv. actinidiae (Psa) and Xanthomonas oryzae pv. oryzae (Xoo) bacteria. The compound 19g had shown commendable inhibition of Psa bacterial growth with an EC₅₀ value of 39.2 mg/L as compared to standard copper thiodiazole (EC₅₀ value is 73.9 mg/L) and zinc thiazole (EC₅₀ value is 45.1 mg/L). The compound 19g had shown remarkable results in inhibiting bacteria by disintegrating the crinkled surface of bacteria. SAR declared that different positions of R ¹ and electron‐donating substituents had enhanced the antibacterial activity of compounds.

SCHEME 4.

Synthesis of quinazolinone derivatives from aminobenzenethiol (19a–h).

Zhou's group obtained new derivatives of quinazolinone of type 24a–h containing dienones (Scheme 5). 4‐(4‐Hydroxyphenyl)but‐3‐en‐2‐one 20 was reacted with different aryl aldehydes to yield intermediate 21, followed by its reaction with dibromopropane in K₂CO_3, which led to the synthesis of intermediate 22, which, on further reaction with substituted quinazolinones 23 in DMF and K₂CO₃, formed the required compounds 24a–h. The target compounds 24a–h were screened for antifungal activity against Sclerotinia sclerotiorum and Phomopsis sp., and it was found that 24f was more active than the other derivatives. Results revealed that the compound 24f was highly effective in protecting oilseed rape and kiwi fruit from S. sclerotiorum and P. sp. with EC₅₀ values of 0.70 and 3.84 µg/mL, respectively, as compared to the standard azoxystrobin (EC₅₀ values of 8.15 and 17.25 µg/mL). It was concluded that compounds with fluoro‐ and bromo‐substituents exhibit better antifungal activity than other compounds. The action of target compound 24f resulted in damage to the hyphal surface, cell wall permeability, and cytoplasmic leakage due to an increase in malondialdehyde concentration in target fungi. These observations were further supported by good hydrophobic interactions between 24f and the succinate dehydrogenase protein of S. sclerotiorum compared to azoxystrobin [30].

SCHEME 5.

Synthesis of dienone derivatives of quinazolinone (24a–h).

Manhas et al. synthesized quinazolinone derivatives of type 28a–j containing triazole conjugates (Scheme 6). The condensation between the amino derivative of quinazolinone 25 and 4‐hydroxybenzaldehyde in ethanol yielded intermediate 26, followed by its reaction with propargyl bromide in potassium carbonate and DMF to yield alkyne 27. The final compounds 28a–j were obtained by reaction of 27 with aryl azides in sodium ascorbate, CuSO₄ ^.2H₂O and DCM:water [31]. The required compounds 28a–j were evaluated for antibacterial activity against Klebsiella pneumoniae. Results revealed that the compound 28i with MIC value 607.888 µM showed impressive antibacterial activity compared to the standard ampicillin (MIC 55.89 µM), ciprofloxacin (MIC 94.3 µM), and levofloxacin (MIC 21.6 µM) and other synthesized derivatives. It was observed that the incorporation of a triazole ring was found to be effective in fighting K. pneumoniae‐related infections. Moreover, methoxy and electron gaining groups at the para‐position have increased the activity, while groups at the meta‐position decrease the inhibition.

SCHEME 6.

Synthesis of quinazolinone derivatives having triazole conjugates (28a–j).

Oduselu et al. developed novel quinazolinone derivatives of type 32a–i [32] containing an arylidene moiety (Scheme 7). The anthranilic acid 29 undergoes cyclization with anhydrides 30 to form isatoic anhydride 31, followed by its condensation with hydrazine hydrate to yield intermediate 25, which, on further reaction with different aldehydes, yields a series of quinazolinone compounds 32a–i. The synthesized compounds were evaluated for antibacterial and antifungal activity, and results revealed that compound 32i was found to be more potent than other derivatives. Compound 32i had effectively bind with the proteins of Staphylococcus aureus (S. aureus) (bacteria) with MIC value 1.95 µg/mL and Candida albicans (C. Albicans), Aspergillus niger (A. niger), Rhizopus nigricans (fungus) with MIC value 3.90 µg/mL, thus effectively inhibiting their growth compared to the standard gentamicin (MIC 1.25 µg/mL) and ketoconazole (MIC values of 3.13, 3.13 and 6.25 µg/mL), respectively. SAR study concluded that substitution of benzylidene with thiophene had increased the inhibition potential of the synthesized compound. The binding affinity of arylidene‐based quinazolinone derivatives toward target proteins (DNA gyrase, DHFR, and glucosamine‐6‐phosphate) was governed by a synergistic interaction profile involving hydrogen bonding via the quinazolinone carbonyl, $\pi$–$\pi$ stacking of aromatic substituents and optimal hydrophobic complementarity with the arylidene group enhance interaction density and binding affinity.

SCHEME 7.

Synthesis of quinazolinone–arylidine derivatives (32a–i).

Thuy et al. synthesized coumarin‐based novel mercapto‐aryl‐quinazolinone compounds of type 38a–e and 39a–e. The required compounds were obtained by reaction of anthranilic acid 33 with aromatic amines 34 in carbon disulfide under alkaline medium to obtain intermediate 35. Compound 35 further reacts in two steps: the first step involves reaction with chromenone 36, and the second with chromenyl acetamide 37 to yield target compounds 38a–e and 39a–e, respectively (Scheme 8) [33]. The target compounds were evaluated for antibacterial activity against Escherichia coli (E. coli), P. aeruginosa, Bacillus cereus, and Listeria monocytogenes. The synthesized compounds were compared with standard amoxicillin, and results revealed that compounds 38d, 39a, and 39b showed remarkable results against E. coli with inhibition zones of 13, 14, and 14 mm, respectively while compound 38d, with an inhibition zone of 23 mm had shown better activity against P. aeruginosa whereas only few compounds were able to inhibit B. cereus and no derivative could inhibit L. monocytogenes.

SCHEME 8.

Synthesis of coumarin–quinazolinone hybrids (38a–e) and (39a–e).

Mahmoud and group synthesized novel derivatives of 3‐amino‐2‐phenyl‐(3H)4‐quinazolinone of type 43a‐h (Scheme 9). The compounds were synthesized by mixing anthranilic acid 1 with benzoyl chloride in the presence of pyridine, forming aryl benzoxazinone 40, followed by condensation with hydrazine hydrate in ethanol, yielding amino aryl quinazolinone 41. Further series of compounds of type 43a–h were obtained by refluxing 41 with different acetophenones 42 in ethanol and GAA to form the required compounds 43a–h. The synthesized compounds 43a–h were tested for their antibacterial activity against two bacterial species, E. coli and S. aureus. Amongst all the compounds, 43d had effectively inhibited the growth of E. coli and S. aureus by 17.5 and 15 mg/mL, as compared to the control imipenem and nitrofurantoin (12, 13 mg/mL and 13, 13 mg/mL, respectively) [34].

SCHEME 9.

Synthesis of 3‐amino‐2‐phenyl‐(3H)4‐quinazolinone derivatives (43a–h).

Almeida et al. developed new descendants of pyrazino quinazolinone of type 48a‐d containing indole (Scheme 10) [35]. Synthesis involved the coupling of anthranilic acid 44 with different tryptophan methyl esters 45 in tetramethylammonium tetrafluoroborate (TBTU) and triethylamine, forming intermediate 46, followed by reaction with Fmoc‐protected acid chlorides in sodium carbonate and dichloromethane, producing intermediate 47, which, on further treatment with piperidine in ethyl acetate, yielded the target compound 48. The target compounds were screened for antibacterial activity against Escherichia faecalis (E. faecalis), S. aureus, P. aeruginosa, and E. coli, and for efflux‐pump‐inhibiting (EPI) capacity of E. coli and S. aureus. Compounds were unable to inhibit the activities of P. aeruginosa and E. coli, but compound 48d was found to be very effective against E. faecalis (MIC 64 µM) and S. aureus (MIC 16–32 µM) as compared to standard neofiscalin A. Compound 48c was found to exhibit the best EPI activity against the test bacterial strains. It was concluded that the presence of chloro at R ¹ and R ³ and fluoro at R ² and R ⁵ positions had increased antibacterial activity of the target compound against S. aureus and E. faecalis, respectively. The antimicrobial activity of quinazolinone derivatives is due to inhibitory action against bacterial efflux pumps by binding to the substrate‐binding site of AcrB via hydrogen bonding, involving Gln‐176, imitating known efflux pump inhibitors.

SCHEME 10.

Synthesis of pyrazino‐quinazolinone derivatives (48a–d).

6‐amino derivatives of quinazolinone 53a–b were synthesized by Ziyadullaev and coworkers. The synthetic procedure (Scheme 11) involved the refluxing of anthranilic acid 1 with formamide 49, forming quinazolinone 11, followed by reaction with a nitrating mixture of nitric acid and concentrated sulfuric acid, yielding the 6‐nitro derivative of quinazolinone 50. Compound 50 reacts with tin(II) chloride dihydrate (SnCl₂ ^.2H₂O) in ethanol and hydrochloric acid to form the 6‐amino derivative of quinazolinone 51, followed by reaction with carboxylic acid 52, yielding the target compounds 53a–b. All synthesized compounds were screened for antibacterial activity against Bacillus subtilis (B. Subtilis), S. aureus, E. coli, and P. aeruginosa and antifungal activity against C. albicans. The results revealed that the synthesized compound 50 had shown remarkable activity against B. subtilis, S. aureus, and E. coli (with growth inhibition zone values 15.04$\pm$0.10, 12.08$\pm$0.12 and 10.08 $\pm$0.12, respectively) as compared to standard ampicillin (growth inhibition zone values 28.04$\pm$0.10, 27.08 $\pm$0.12 and 25.08 $\pm$0.12, respectively) and other synthesized compounds [36].

SCHEME 11.

Synthesis of 6‐amino quinazolinone derivatives (53a‐b).

Ramani et al. synthesized novel derivatives of 8‐methyl‐2‐phenyl quinazolinone of type 58a–j [37]. The synthesis involved the reaction of 3‐methyl anthranilic acid 54 with benzoyl chloride 55 in pyridine, forming intermediate 56, which, on further reaction with hydrazine hydrate followed by reaction with different aryl aldehydes 57 in GAA, yielded the final product 58 (Scheme 12). The target compounds were evaluated for antibacterial activity against S. aureus, Staphylococcus pyogenes (S. pyogenes), E. coli, and P. aeruginosa, antifungal activity against C. albicans, Aspergillus clavatus, and A. niger, and anticancer activity against melanoma, colon, leukemia, lung cancer, breast cancer, and central nervous system (CNS) cancer. The results revealed that the compound 58d effectively inhibited E. coli (MIC 25$\pm$0.5 µg/mL), 58e and 58g inhibited P. aeruginosa (MIC 50$\pm$2.5 and 50 $\pm$1.5 µg/mL, respectively), 58g and 58j were effective against S. aureus (MIC 50$\pm$ 2 and 50$\pm$0.5 µg/mL, respectively), 58e and 58i against S. pyogenes (MIC 50$\pm$1, 50$\pm$1.5 µg/mL, respectively) as compared to control chloramphenicol, ciprofloxacin and norfloxacin; 58d was found to be effective against C. albicans (MIC 100$\pm$0.5 µg/mL), 58d and 58j against A. niger (MIC 100$\pm$0.5, 100$\pm$1.5 µg/mL, respectively) and no compound was found to be effective against A. clavatus in contrast to control nystatin and griseofulvin. It was further observed that the compound 58b was effective against melanoma, 58g against breast cancer and CNS cancer, and 58h against lung cancer compared to the reference anticancer drug doxorubicin. The study found that halogen groups at the p‐position had more potency against microbes, whereas the chloro group at the m‐position and the hydroxy group demonstrated higher anticancer activity. Docking studies indicate that potential derivatives possess superior binding affinity toward fungal pathogens such as chitinase B and bacterial efflux pumps like CusC and AcrB efflux pump, favored by good binding energies and numerous interactions stabilizing the ligand–protein complex, where antimicrobial potency was further enhanced by halogen groups.

SCHEME 12.

Synthesis of 8‐methyl‐2‐phenyl quinazolinone derivatives (58a–j).

Osarodion synthesized 6‐bromo‐2‐[o‐imino‐(4‐thiazolidinone)‐phenyl]‐3‐imino‐(4‐thiazolidinone)‐quinazolin‐4(3H)‐one 61 (Scheme 13) [38]. The synthetic procedure involved the refluxing of 2‐(o‐aminophenyl)‐3‐amino‐6‐bromo‐quinazolin‐4(3H)‐one 59 with ammonium thiocyanate in dilute hydrochloric acid, forming intermediate 60, which, on further reaction with sodium acetate in ethanol, yielded the target compound 61. The synthesized compound was screened for antibacterial activity against S. aureus, K. pneumoniae, B. species, P. aeruginosa, Aspergillus species, and E. coli, and antifungal activity against C. albicans. Results revealed that the compounds 60 and 61 showed remarkable results in the inhibition of S. aureus and A. species in the range of 10–20 mm as compared to the control ciprofloxacin and ketonaxol and these compounds were not active against C. albicans.

SCHEME 13.

Synthesis of 6‐bromo‐2‐[o‐imino‐(4‐thiazolidinone)‐phenyl]‐3‐imino‐(4‐thiazolidinone)‐quinazolin‐4(3H)‐one (61).

Priteshkumar et al. developed new hybrids of piperazine–quinazolinone 65a–d [39]. The desired compounds were synthesized by reaction of p‐chlorobenzoyl chloride 62 with anthranilic acid in pyridine, followed by reaction with hydrazine hydrate, forming intermediate 63, which, on further reaction with benzoyl chloride in sodium hydroxide, followed by reaction with piperazine, formed intermediate 64, which, on further refluxing with chloroacetyl chloride in GAA and ethanol followed by reaction with aniline yielded the final product 65 (Scheme 14). The target compounds were screened for antibacterial activity against S. aureus, E. coli, B. subtilis, and P. aeruginosa and antifungal activity against C. albicans. The result revealed that the target compounds 65b (MIC values 12.5, 12.5, 25, 12.5, and 25 µg/mL, respectively) and 65d (MIC values 12.5, 25, 50, 12.5, and 50 µg/mL, respectively) had effectively inhibited bacterial and fungal strains compared to antibiotic ciprofloxacin (MIC < 3 µg/mL) and antifungal fluconazole (MIC < 8 µg/mL), respectively.

SCHEME 14.

Synthesis of piperazine quinazolinone hybrids (65a–d).

Chang et al. derived novel derivatives of quinazolinone of type 68a–i containing a coumarin moiety (Scheme 15) [40]. The target compound was synthesized by refluxing different coumarin derivatives 66 with different types of quinazolinone 67 in the presence of acetic acid and ammonium acetate, yielding the final product 68. The target compounds were screened for antifungal activity against Fusarium moniliforme, Fusarium graminearum, Fusarium oxysporum, Rhizoctonia solani, and Phytophthora parasitica. The results revealed that the compound 68f (EC₅₀ 10.6 µg/mL) had inhibited the growth of R. solani more efficiently than other fungi, as compared to the control triadimefon.

SCHEME 15.

Synthesis of coumarin‐based quinazolinone derivatives (68a–i).

1,2,4‐Triazolo[1,5‐a]pyrimidine‐containing quinazolin‐4(3H)‐one derivatives of the type 72a–k were synthesized by Du and coworkers. The reaction involved the thioetherification and cyclization of 3‐bromoethyl quinazolinone 69 with ethyl acetoacetate in refluxing acetic acid to furnish the intermediate 70. Treatment of 70 with POCl₃ yielded the intermediate 71, followed by its reaction with arylamines in ethanol to furnish target compound 72 (Scheme 16). The synthesized compounds were screened for antibacterial activity. Results revealed that the compounds 72c, 72e, and 72h exhibited higher antibacterial efficacies against X. oryzae, exhibiting EC₅₀ values of 69.0, 53.3, and 58.9 µg/mL, respectively, than the commercial bactericide bismerthiazol (EC₅₀ value 91.4 µg/mL), but compound 72c inhibited bacterial infection of X. axonopodis with an EC₅₀ value of 71.5 µg/mL to a greater extent as compared to the commercial bactericide bismerthiazol (EC₅₀ value 60.5 µg/mL). The results were enhanced by the addition of an aniline substituent, halogen groups except fluorine, and a doubly substituted benzene ring, resulting in broad‐spectrum antibacterial activity against targeted strains [41].

SCHEME 16.

Synthesis of 1,2,4‐Triazolo[1,5‐a]pyrimidine quinazolin‐4(3H)‐one derivatives (72a–k).

Li et al. have synthesized a series of quinazolinone acyl hydrazone derivatives 77a–m containing the indole moiety (Scheme 17) [42]. The reaction involved condensation between 2‐aminobenzamide 73 and diethyl oxalate, followed by a ring closure reaction to obtain ethyl‐4‐oxo‐3,4‐dihydroquinazoline‐2‐carboxylate 74, which upon refluxing with 80% N₂H₄ ^.H₂O yielded an intermediate 4‐oxo‐3,4‐dihydroquinazoline‐2‐carbohydrazide 75. The target compound 77 was formed by refluxing 75 with compound 76 using GAA in ethanol. The synthesized compounds were screened for antibacterial activities. Results revealed that the compound 77a with EC₅₀ values of 55.13 and 56.92 µg/mL, respectively, exhibited potential activity against X. oryzae (Xoo) and Ralstonia solanacearum as compared to control bismerthiazole (EC₅₀ value 89.80 µg/mL against Xoo) and thiodiazole copper (EC₅₀ value 189.52 µg/mL against R. solanacearum), while compound 77i with an EC₅₀ value of 50.80 µg/mL was potent against X. axonopodis compared to control bismerthiazole (EC₅₀ value 56.92 µg/mL). It was declared that the substituents with halogen groups, probably at the m‐position of the phenyl ring, had increased activity compared to electron‐donating groups, and among aliphatic groups, shorter chains had given higher results than longer chains against the target species.

SCHEME 17.

Acyl hydrazone derivatives of quinazolinone of type (77a–m).

The antimicrobial activity of some potential quinazolinone derivatives against bacterial and fungal strains has been summarized in Table 2, depicting the IC₅₀, EC₅₀, and MIC values and the proteins that had been targeted by these derivatives. Mostly, positions C2, C3, C6, and C8 of quinazolinone were substituted.

TABLE 2.

Summary of quinazolinone and its derivatives as antimicrobial scaffold.

S. no.	Structure	IC50, EC50, MIC	Target protein
1		3.55 and 6.86 µM (P. aeruginosa)	PqsR
2		0.70 µg/mL (S. sclerotiorum) and 3.84 µg/mL (P. sp.)	Succinate dehydrogenase
3		1.95 µg/mL (S. aureus) and 3.90 µg/mL (C. albicans, A. niger, R. nigricans)	DNA gyrase, DHFR, and glucosamine‐6‐phosphate
4		64 µM (E. faecalis) and 16–32 µM (S. aureus strains)	Bacterial efflux pumps
5		25$\pm$0.5 µg/mL (E. coli), 50$\pm$2.5, 50$\pm$1.5 µg/mL (P. aeruginosa), 50$\pm$2, 50 $\pm$0.5 µg/mL (S. aureus), 50$\pm$1, 50$\pm$1.5 µg/mL (S. pyogenes) 100$\pm$0.5 µg/mL (C. albicans), 100$\pm$0.5, 100$\pm$1.5 µg/mL (A. niger)	Chitinase B and bacterial efflux pumps

P. aeruginosa = Pseudomonas aeruginosa; S. sclerotiorum = Sclerotinia sclerotiorum; P. sp. = Phomopsis sp.; S. aureus = Staphylococcus aureus; C. albicans = Candida albicans; A. niger = Aspergillus niger; R. nigricans = Rhizopus nigricans; E. faecalis = Escherichia faecalis; E. coli = Escherichia coli; S. pyogenes = Staphylococcus pyogenes.

3.1.1. SAR Summary of Antimicrobial Activity

The antimicrobial activity of quinazolinone had been greatly influenced by the position and the nature of substituents on the scaffold (Figure 5). Inhibition of biofilm formation was promoted by electron‐donating and trimethoxy groups on the phenyl ring with a pyrolidine moiety. Electron‐withdrawing groups like chloro and methyl at ortho‐ or para‐positions and the phenoxymethyl fragment had improved fungal inhibition. It was concluded that the antifungal efficacy of the target compound had been increased by the addition of the electron‐withdrawing halogen groups like fluorine and bromine. Moreover, it was observed that K. pneumoniae‐related infections were being effectively treated by the incorporation of a triazole ring. Further, the activity was increased by adding methoxy and electron‐gaining groups at the para‐position, while inhibition was decreased by groups at the meta‐position. The presence of heterocyclic scaffolds like thiophene on the benzylidine ring has increased the inhibition potential of the synthesized compound. In addition, the presence of chloro at C6 and C8 and fluoro at the C7 position of the quinazolinone moiety increased the antibacterial activity of the target compounds. Furthermore, halogen groups except fluorine, addition of an aniline substituent, and a doubly substituted benzene ring resulted in increased toxicity against targeted bacterial strains. Shorter aliphatic chains relative to larger chains had increased activity, and halogen groups at the m‐position of the phenyl ring, compared to electron‐donating groups, had given higher results against the targeted microbes. The bioactivity of all discussed derivatives underscores the clinical significance of the quinazolinone scaffold and confirms its capability for the development of novel antimicrobial agents.

FIGURE 5.

SAR outline for antimicrobial activity.

3.2. Antiviral Activity

Deng et al. had synthesized derivatives of quinazolinone having purine molecules of type 80a–j [43] as outlined in Scheme 18. The target compound 80 was synthesized by reacting the hydroxy derivative of quinazolinone 78 with halogen derivatives of purine 79 in the presence of K₂CO₃. The synthesized compounds 80a–j were evaluated for their antiviral activity against tobacco mosaic virus (TMV). The activity of synthesized compounds 80a–j was compared with standard ribavirin. It was found that the compound 80b exhibited effective curative (EC₅₀ 162.3 mg/L), protective (EC₅₀ 210.4 mg/L), and inactivating (EC₅₀ 78.4 mg/L) activity against TMV as compared to ribavirin (EC₅₀ 314.4, 239.5, and 79.3 mg/L). It was inferred that the target compound with an electron‐withdrawing group like fluoro and a shorter alkyl chain at R ² had improved antiviral activity.

SCHEME 18.

Synthesis of quinazolinone derivatives with purine moieties (80a–j).

Alamri and colleagues had designed the synthesis of quinazolinone of type 85a–h. The synthesis involved refluxing the fluoro derivative of anthranilic acid 81 with fluorophenyl isothiocyanate 82 in the presence of triethylamine and ethanol, yielding intermediate 83, followed by refluxing with aryl or alkyl halide 84 in anhydrous K₂CO₃ and acetone, yielding the required product 85 (Scheme 19) [44]. The target compounds were evaluated for their antiviral activity against Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). It was found that compounds 85b, 85c, 85e, 85f, and 85h with IC₅₀ values 1.58, 1.25, 1.97, 0.44, and 2.56 µM, respectively, were found to be very effective in inhibiting the growth of SARS‐CoV‐2 in contrast to other descendants and the standard ligand 3CLpro‐VR4. These compounds strongly bind to the active site of 3CLpro of SARS‐CoV‐2, containing cysteine and histidine amino acids due to an electron‐withdrawing group on the aromatic ring, thus hindering the function of 3CLpro of SARS‐CoV‐2. The inhibitory potential of quinazolinone derivatives toward SARS‐CoV‐2 3CLpro was governed by a synergistic interaction profile involving hydrogen bonding, $\pi$–$\pi$, $\pi$–sulfur and halogen interactions within the binding pocket, primarily targeting the catalytic His41‐Cys145 dyad.

SCHEME 19.

Synthesis of flouro‐quinazolinone derivatives (85a–h).

Giang et al. had developed new nitrophenyl derivatives of quinazolinone containing a peptide linkage (Scheme 20) [45]. The synthetic procedure involved the reaction of isatoic anhydride 86 with L‐glutamic acid 87 and formaldehyde 88 in the presence of potassium carbonate, water, and iodine, forming intermediate 89, followed by its reaction with 3‐nitroaniline 90 and 4‐nitrobenzyl alcohol 91 in 4‐dimethylaminopyridine (DMAP), 1‐ethyl‐3‐(3‐dimethylaminopropyl) carbodiimide (EDC), and dichloromethane (DCM), yielding the target compounds 92 and 93, respectively. Intermediate 89 reacts further with 4‐nitro‐3‐aminophenol 94 and thionyl chloride in dimethylformamide (DMF), forming 95, and in DCM under argon and tetrahydrofuran (THF)‐triethylamine (TEA), yielding 96. The synthesized compounds were evaluated for inhibition of respiratory syndrome coronavirus 2 main protease (SARS‐CoV‐2‐M^pro), and in contrast to other derivatives, compounds 92 and 96 presented commendable results. The compounds 92 and 96 with IC₅₀ values 22.47$\pm$8.93 and 24.04$\pm$0.67 µM, respectively, had inhibited the activity of the coronavirus enzyme by binding to the active sites of this enzyme, thus obstructing its activity. The peptidomimetic‐based quinazolinone derivatives exhibit potent inhibitory potential against SARS‐CoV‐2 Mpro by targeting the catalytic His41‐Cys145 dyad and oxyanion hole via extensive hydrogen bonding, $\pi$–interactions, nitro‐mediated interactions, resulting in enhanced covalent inhibition.

SCHEME 20.

Quinazolinone derivatives with peptide linkage (95) and (96).

Liu et al. have synthesized thioether quinazolinone derivatives of the type 102a–h containing myricetin derivatives (Scheme 21). Reaction involved methylation and deglycosylation of myricetin 97, forming intermediate 98, followed by its reaction with 1,3‐dibromopropane or 1,4‐dibromobutane to furnish intermediate 99. Compound 101 was formed by cyclization of anthranilic acid 100 and substituted phenyl isothiocyanates, followed by reaction of intermediate 99 and 101 at 90 C for 6 h in the presence of K₂CO₃ and DMF to yield the target compound 102 [46]. The synthesized compounds were screened for antiviral activities. Results revealed that the synthesized compound 102e possessed strong curative (67.3 $\pm$ 2.8%), protective (64.3 $\pm$ 4.3%), and inactivating (64.6 $\pm$ 6.7%) antiviral activity against TMV‐ CP and enhanced the resistance of tobacco plants against various diseases in contrast to ningnanmycin (54.1 $\pm$ 2.1%, 57.1 $\pm$ 1.9%, and 85.3 $\pm$ 3.8%, respectively) and other derivatives. It was declared that compounds containing methyl and chloro substituents had effectively inhibited TMV growth. Quinazolinone derivatives exhibit enhanced binding affinity towards TMV coat protein by forming numerous short and strong hydrogen bonds, ensuring higher binding affinity than control ningnanmycin.

SCHEME 21.

Synthesis of quinazolinone derivatives with thioether linkages (102a–h).

Deng and co‐authors have synthesized new derivatives of quinazolinone of type 106a–l containing a sulfonamide moiety (Scheme 22) [47]. The target compound was synthesized by reacting 8‐chloroquinazolin‐4(3H)‐one 103 with sulfonyl chloride (SOCl₂) in DCE and DMF, forming intermediate 104, followed by reaction with 4‐aminophenol using TEA as a catalyst, resulting in intermediate 105. Intermediate 105 was mixed with triethylamine (Et₃N) along with DCM/DMF and stirred with different sulfonyl chlorides, forming target compounds 106a–l. The synthesized compounds were evaluated for their activity against TMV and it was observed that the compounds 106f and 106i exhibited effective curative (EC₅₀ 132.1 and 278.0 mg/L, respectively), protective (EC₅₀ 152.8 and 165.3 mg/L, respectively) and inactivating (EC₅₀ 57.4 and 94.5 mg/L, respectively) activities against TMV and these derivatives had shown comparatively great results in inhibiting TMV than the standard ribavirin (EC₅₀ values 318.2, 201.5, 128.6 mg/L, respectively) and other synthesized derivatives.

SCHEME 22.

Sulfonamide derivatives of quinazolinone (106a–l).

Liu et al. had synthesized myricetin derivatives containing a quinazolinone moiety of type 107a–h. The reaction involved methylation followed by deglycosylation of myricetin 97, and intermediate 98 was obtained, which, on reaction with 1,3‐dibromopropane and 1,4‐dibromobutane, yielded 99. The target compound 107 was obtained by reaction of 99 and quinazolinone in N, N‐dimethylformamide with NaH at 90°C for 4–6 h (Scheme 23) [48]. The synthesized compounds were screened for antiviral activity against the TMV‐coat protein (TMV‐CP). Results revealed that the compound 107e had shown better curative effects (EC₅₀ 261.0$\pm$2.1 µg/mL) and protective activity (EC₅₀ 205.8$\pm$4.1 µg/mL) compared to control ningnanmycin (EC₅₀ 319.7$\pm$4.7 and 341.3$\pm$3.9 µg/mL) against TMV‐CP, this compound had shown better binding ability with the coat protein of TMV compared to control ningnanmycin and other descendants. It was concluded that electron‐withdrawing substituents had increased the antiviral activity of the target compound as compared to other substituents. Compound 107e exhibits stronger binding affinity than ningnamycin toward the TMV‐CP due to shorter hydrogen bond interactions.

SCHEME 23.

Myricetin and quinazolinone derivatives (107a–h).

Ran’s group had synthesized quinazolinone sulfide derivatives of the type 112a–l containing a dithioacetal moiety (Scheme 24) [49]. The reaction involved the formation of intermediate 109 by cyclization of anthranilic acid 108 and substituted phenyl isothiocyanates, along with the formation of another intermediate 111 by nucleophilic substitution reaction of vanillin 110 with 1,2‐dibromoethane, followed by nucleophilic substitution and further condensation with different thiols to yield the target compounds 112. Synthesized compounds were assessed for their antiviral activity, and results revealed that the synthesized compounds 112c and 112 h reduced the relative expression level of the Tomato chlorosis virus coat protein (ToCV‐CP) gene by 93.34% and 83.47%, respectively, better than the commercial antiviral agents xiangcaoliusuobingmi and ningnanmycin due to enhanced binding abilities of these compounds to ToCV‐CP. It was deduced that the compound with fluorine at R ¹ and a hydrophilic group at the R ³ position had effective binding capacity with ToCV‐CP in contrast to other substituents.

SCHEME 24.

Synthesis of dithioacetal derivatives of quinazolinone (112a–l).

Hao et al. had synthesized derivatives of luotonin A of the type 116a–m. The required compounds were synthesized by the condensation reaction between o‐nitrobenzoyl chloride and o‐aminobenzoamide 73, forming 113, followed by cyclization in KOH, resulting in the formation of 114. Reduction of 114 to form intermediate 115, followed by condensation with aldehyde, yields the required compound 116 (Scheme 25) [50]. Resulting compounds were evaluated for their antiviral activity. It was concluded that compound 116k had shown astounding inactivation (54$\pm$4%), curative (51 $\pm$1%), and protective (43 $\pm$2%) activity against TMV in contrast to other derivatives. Antiviral activity was evaluated by transmission electron microscopy and molecular docking techniques. The results of these techniques revealed that 116k compound had inhibited TMV activity by forming hydrogen bonding with the coat protein of virus followed by polymerization, leading to extensive hydrogen bonding and results shown by 116k had inhibited viral activity to the extent similar to that of control ningnanmycin (51$\pm$1%, 57 $\pm$2%, and 59$\pm$4%, respectively) and ribavirin (40 $\pm$1%, 37 $\pm 3\%,$ and 40$\pm$2% respectively).

SCHEME 25.

Luotonin derivatives of quinazolinone (116a–m).

Qiu and coworkers synthesized analogs of quinazolinone of type 120a–e [51]. The synthetic procedure (Scheme 26) involved the reaction of substituted thioxo dihydroquinazolinone 117 with different chloromethyl benzene 118 in the presence of potassium carbonate in 1,4‐dioxane, forming intermediate 119, followed by reaction with different alkylated amines in the presence of potassium carbonate in 1,4‐dioxane, yielding final compound 120. The target compounds were screened for anti‐HBV (Hepatitis B virus) and anti‐hepatocellular carcinoma (HCC) activities. The data declared that the compounds 120b and 120d had inhibited DNA replication of HBV, having IC₅₀ values of 0.63 and 0.58 µM, respectively, in contrast to the standards lamivudine and entecavir, and also the compound 120d had restricted the multiplication of HepG2, HUH7, and SK cells with IC₅₀ values of 5.44, 6.42, and 6.75 µM, respectively, as compared to control 5‐fluorouracil and sorafenib. Structural changes like substitution with a furanyl ring had increased anti‐HBV activity of quinazolinone derivatives, while substitution with a phenyl ring had lowered the inhibition.

SCHEME 26.

Synthesis of thioxo‐quinazolinone derivatives (120a–e).

Zu et al. had synthesized 4(3H)‐quinazolinone derivatives of the type 124a–j bearing a dithioacetal moiety (Scheme 27). The reaction involved stirring of substituted anthranilic acid 121 with chloroacetonitrile at room temperature for 4–6 h using sodium and methanol as solvent to yield the intermediate 122. Compound 123 was obtained by refluxing substituted 4‐hydroxybenzaldehyde with 122 for 8–12 h, which, on further reaction with substituted mercaptan at room temperature using NaHSO₄ ^.SiO₂ as a catalyst furnished a series of compounds 124a–j. The synthesized compounds were screened for their antiviral activity against ToCV. Results revealed that compounds 124e and 124j had shown excellent binding capacity to ToCV‐CP, as the gene expression of ToCV‐CP was reduced by 81.05% and 87.59%, respectively, when tomato was treated with these compounds, and the results revealed that the efficacy of these compounds was higher than control ningnanmycin (43.88%) and xiangcaoliusuobingmi (63.56%). SAR studies declared that electron‐withdrawing groups at the R ¹ position and an electron‐donating group at the R ² position had enhanced antiviral activity among other substituents [52].

SCHEME 27.

Synthetic outline for quinazolinone derivatives bearing a dithioacetal moiety (124a–j).

Chen et al. derived oxime ether‐substituted quinazolinones of type 129a–g [53]. The synthesis involved the reaction of quinazolinone 125 with formaldehyde in 1,4‐dioxane, forming intermediate 126, followed by reaction with thionyl chloride in 1,4‐dioxane, yielding intermediate 127. Treatment of 127 with oxime 128 in the presence of potassium carbonate and acetone yielded the target compound 129 (Scheme 28). The target compound was screened for its antiviral activity against TMV, and the observed data indicated that the compounds 129c, 129e, and 129g had represented commendable curative activity against TMV with EC₅₀ values 138.5, 132.9, and 125.6 µg/mL, respectively, with respect to other derivatives and the standard ningnamycin (EC₅₀ 207.3 µg/mL). Moreover, further tests showed that the compound 129g had shown binding interactions with Arg90 in the TMV‐CP to a greater extent, thus inhibiting the virulence of TMV. Chloro‐substitutions, pyridine, and quinazolinone rings enhanced the potency and exhibited strong antiviral activity.

SCHEME 28.

Synthesis of quinazolinone derivatives with oxime–ether linkages (129a–g).

The antiviral activity of some key derivatives has been summarized in Table 3, representing IC₅₀, EC₅₀, and % Inhibition values against viral species targeting specific proteins.

TABLE 3.

Summary of quinazolinone and its derivatives as antiviral scaffold.

S.No.	Structure	IC50, EC50, and % Inhibition	Target proteins
1		1.58, 1.25, 1.97, 0.44, and 2.56 µM, (SARS‐CoV‐2)	SARS‐CoV‐2 3CLpro
2		22.47$\pm$8.93 and 24.04$\pm$0.67 µM (SARS‐CoV‐2‐Mpro)	SARS‐CoV‐2 Mpro
3		67.3$\pm$2.8% (curative), 64.3$\pm$4.3% (protective), and 64.6$\pm$6.7% (inactivating) (TMV)	TMV‐CP
4		132.1 and 278.0 mg/L (curative), 152.8 and 165.3 mg/L (protective), and 57.4 and 94.5 mg/L (inactivating) (TMV)	—
5		261.0$\pm$2.1 µg/mL (curative) and 205.8$\pm$4.1 µg/mL (protective) (TMV)	TMV‐CP
6		93.34 and 83.47% (ToCV)	ToCV‐CP
7		51$\pm$1% (curative), 43$\pm$2% (protective) and 54$\pm$4% (inactivation), (TMV)	TMV‐CP
8		0.63 and 0.58 µM (HBV)	—
9		81.05% and 87.59% (ToCV)	ToCV‐CP
10		138.5, 132.9, and 125.6 µg/mL (TMV)	TMV‐CP

SARS‐CoV‐2 = Severe acute respiratory syndrome coronavirus 2; TMV = Tobacco mosaic virus; ToCV = Tomato chlorosis virus; HBV = Hepatitis B virus.

3.2.1. SAR Summary of Antiviral Activity

Biological activity of quinazolinone as an antiviral agent had been affected by the position and nature of substituents attached to the quinazolinone moiety (Figure 6). Compounds with shorter alkyl chains and electron‐withdrawing groups like fluorine on the benzene ring of quinazolinone had improved antiviral activity, while the compounds having electron‐withdrawing groups on the aromatic ring strongly bound to cysteine and histidine amino acid residues at the active site of 3CLpro of SARS‐CoV‐2, hindering the function of 3CLpro of SARS‐CoV‐2. TMV growth had been effectively inhibited by compounds containing methyl and chloro substituents. The substituents capable of forming maximum hydrogen bonds with active residues of target proteins had increased antiviral activity. Additionally, binding affinity with ToCV‐CP had been improved with compounds having fluorine on the benzene ring of quinazolinone and hydrophilic groups bonded to a sulfur atom. Heterocyclic rings like thiophene, pyridine, and furan had increased anti‐TMV and anti‐HBV activity of quinazolinone derivatives, respectively, while substitution with a phenyl ring had lowered the activity. SAR studies declared that electron‐withdrawing groups on the benzene ring of quinazolinone and electron‐donating groups on substituents bonded to quinazolinone had enhanced antiviral activity among other substituents. These SAR studies highlight the importance of unique modifications of structures in standardizing antiviral potency of quinazolinone derivatives.

FIGURE 6.

SAR outline for antiviral activity.

3.3. Anticancer Activity

Dung et al. had developed quinazolinone‐based hydroxamate bearing 1,2,3‐triazole of type 133a–i, 134a–i, 135a–i, and 136a–i for inhibiting histone deacetylase. 3‐propynyl‐quinazolinone 130 was reacted with methyl 3‐azidopropanoate 131, catalyzed by copper(I) iodide, forming intermediate 132, followed by reaction with hydroxylamine hydrochloride in sodium hydroxide, giving target compounds 133a–i, 134a–i, 135a–i, and 136a–i (Scheme 29). The synthesized compounds were treated on MDA‐MB‐231 (breast cancer), SW620 (colon cancer), and MRC‐5 (human fetal lung fibroblasts) to evaluate their potential in inhibiting histone deacetylase. Results revealed that 135 g had shown anti‐proliferative activity with IC₅₀ values of 8.68 $\pm$4.48, 7.76$\pm$0.85, and 29.23 $\pm$5.71 µM, respectively, compared to other derivatives and control suberoylanilide hydroxamic acid (SAHA) (IC₅₀ 3.75$\pm$1.15, 2.08 $\pm$0.35, and 4.58 $\pm$1.09 µM, respectively). The suppression of enzymatic activity can be due to the presence of an electron‐withdrawing group at the C‐6 position of quinazolinone, among which bromine and iodine have outperformed chlorine. Moreover, substituents having longer aliphatic chains (n = 6, 5, and 4) were more potent than shorter chains (n = 3), and hydroxamic acid binds strongly to the zinc ion, possessing good activity. Although the synthesized derivatives exhibited proper zinc chelation, favorable binding conformations, and interaction profiles within HDAC active sites, their reduced docking scores relative to SAHA were attributed to desolvation penalties arising from unfulfilled hydrogen bonding potential, resulting in comparatively lower inhibitory activity [54].

SCHEME 29.

Synthesis of 1,2,3‐triazole‐quinazolinone‐based hydroxamate derivatives (133a–i, 134a–i, 135a–i, and 136a–i).

Şenol and coauthors had developed anti‐prostate cancer agents bearing polyphenols and quinazolinone moieties [55]. In order to synthesize the target compounds 138a–j, the dimer of 3‐amino‐2‐propylquinazolinone 137 was refluxed with phenolic aldehyde in GAA (Scheme 30). Among all derivatives, 138f had shown promising characteristics of cytotoxic activity against 3T3 fibroblast and PC3 prostate cancer cell lines with IC₅₀ values of 387.65 and 5.72 µM, respectively, compared to standard doxorubicin (IC₅₀ 95.32 and 5.30 µM, respectively). The synergistic effect of 138f with mTOR is due to hydrogen bonding preferably with Asp‐2357 and Ser‐2342 and $\pi$–$\pi$ interactions with Trp‐2239 giving a binding score −15.8 kcal/mol.

SCHEME 30.

Synthesis of polyphenol‐based quinazolinone derivatives (138a–j).

Aldogan et al. synthesized quinazolinone derivatives of type 141a–f to evaluate their cytotoxic activity. The chemical synthesis began with the reaction between 3‐amino‐2‐phenylquinazolin‐4(3H)‐one 139 and different aromatic aldehydes 140 in GAA, yielding final compounds 141a–f as shown in Scheme 31 [56]. The cytotoxicity of test compounds was studied on MCF7 breast cancer cell lines and HUVEC normal endothelial cell lines, concluding that among all derivatives 141e had high selectivity towards MCF7 (IC₅₀ 74.0$\pm$3.9 µM) than HUVEC (IC₅₀ 260.4 $\pm$11.1 µM) with respect to standard drug 5‐fluorouracil (IC₅₀ 111.7$\pm$4.9 and 144.8$\pm$5.8 µM, respectively). SAR studies indicated that substituents having hydroxy groups that can form hydrogen bonds had increased the activity, while electron‐withdrawing groups like sulfonyl had reduced the activity. The target compounds were docked against estrogen receptor alpha and HER2, and 141e had shown better binding with these enzymes by stable and strong interactions with active sites through $\pi$–$\pi$ stacking, hydrogen bonding, and hydrophobic interactions.

SCHEME 31.

Synthesis of Schiff bases of quinazolinone derivatives (141a–f).

Şenol et al. had developed anticancer therapeutics involving 2‐propyl‐3‐aminoquinazolinone derivatives of type 144a–f (Scheme 32). The target compounds 144a–f were synthesized by reacting quinazolinone derivatives 142 with different aldehydes 143 in GAA. The bioactivity of synthesized derivatives revealed that 144b had high potency against PC3 cells with an IC₅₀ value of 4.29 $\pm$0.32 µM relative to other derivatives and control sorafenib (IC₅₀ 8.25$\pm$0.03 µM). Electron‐donating groups like ethoxy and methoxy had enhanced cytotoxic activity, while bulky groups had decreased the activity. The binding affinity of 144b with androgen receptors was due to an enormous network of hydrogen bonding with Gln‐711 and Arg‐752, $\pi$– $\pi$ stacking with Trp‐741 and Phe‐764 and hydrophobic interactions within the active sites of the target protein, stabilizing the protein–ligand complex [57].

SCHEME 32.

Synthesis of 2‐propyl‐3‐aminoquinazolinone derivatives (144a–f).

Abdulwahab and coworkers derived quinazoline–quinazolinone derivatives of type 147a–e as shown in Scheme 33 [58]. The synthetic procedure involved the refluxing of 2‐(aminochlorophenyl)‐7‐chloroquinazolinone 145 with different aryl aldehydes 146 in tetrahydrofuran, yielding the desired compounds 147a–e. The synthesized compounds were evaluated for their potential to inhibit the epidermal growth factor receptor (EGFR), which is responsible for lung cancer. Among all compounds, 147b was recorded to be highly antiproliferative against H1975 cells (IC₅₀ 15.9 µM) and moderately effective against A549 cells (IC₅₀ 32.9 µM) in contrast to standard gefitinib (IC₅₀ 20.2 and 34.0 µM, respectively). Moreover, 147b had successfully inhibited EGFR and PI3K and induced cell cycle arrest in H1975 cells. SAR studies confirmed that the presence of electronegative substituents like the chlorophenyl group showed hydrogen bonding and hydrophobic interactions that stabilized EGFR while binding with target compounds. The strong and stable binding of 147b with EGFR (L858R/T790M mutant) was driven by extensive hydrogen bonding with Arg841 and by pivotal hydrophobic interactions with Val726, Phe723, and Leu718, where inhibitory potential and binding affinity were enhanced by 4‐chlorophenyl substitution.

SCHEME 33.

Synthesis of quinazoline–quinazolinone derivatives (147a–e).

Abd El‐Karim's group had synthesized fresh variants of quinazolinone of type 153a–q containing N‐acetohydrazide (Scheme 34). The synthesis began with the reaction of hydroxybenzaldehyde 148 with ethyl bromoacetate 149, yielding intermediate 150, followed by its refluxing with anthranilamide 73 in the presence of copper chloride, furnishing intermediate 151. The target compounds 153a–q were obtained by treatment of 151 with hydrazine hydrate followed by condensation with different aryl aldehydes 152. The synthesized compounds were evaluated for inhibiting type II multi‐kinase enzymes and as anticancer agents. Results revealed that the compounds 153d, 153e, 153f, 153l, and 153m having IC₅₀ value ranging from 0.29 to 5.17 µM exhibited commendable inhibitory activity against effective multi‐kinase as compared to sorafenib (IC₅₀ 0.12 µM) and the compounds 153b, 153d, 153e, and 153l having mean GI₅₀ value as 6.03, 7.02, 7.16, and 2.59 µM, respectively, possessed inhibitory activity on growth of robust NCI cancer lines. Quinazolinone derivatives exhibit strong binding with kinases like FGFR‐1, VEGFR‐2, and BRAF via acquiring type II inhibitor binding modes, where the quinazolinone scaffold occupies the hinge region in kinases, forming hydrogen bonds, and the 2‐methoxyphenyl group significantly enhances the hydrophobic interactions and binding affinity [59].

SCHEME 34.

Synthesis of N‐acetohydrazide derivatives of quinazolinone (153a–q).

Noser et al. developed new quinazolinone derivatives of types 156a–d and 157a–d, including azepine moiety (Scheme 35) [60]. The chemical synthesis involved the reaction of acetylphenyl quinazolinone 154 with various aryl aldehydes in sodium hydroxide and absolute alcohol, yielding intermediate 155. Compound 155, on further reaction with 2‐aminoaniline and o‐aminophenol in acetic acid and absolute alcohol, led to the synthesis of compounds 156 and 157, respectively. The target compounds were screened for antibacterial activity against S. aureus, B. subtilis, P. aeruginosa, and E. coli, and antifungal activity against C. albicans and Aspergillus flavus, and anticancer activity against HCT‐116, MCF‐7, and HepG‐2 cancer cells. The results revealed that the compounds 156a and 157a inhibited the growth of S. aureus (inhibition zone diameter values 21.3$\pm$2.4 and 19.2$\pm$1.3 mm, respectively) and C. albicans (inhibition zone diameter 22.1$\pm$2.4 and 20.4 $\pm$3.1 mm, respectively) to greater extent as compared to control antibiotic ciprofloxacin (23$\pm$1.9 mm) and antifungal clotrimazole (24$\pm$0.9 mm) by strongly binding to their outer membrane protein A and exo‐1,3‐$\beta$‐glucanase protein. The compounds 156a (IC₅₀ 14.25$\pm$1.1, 19.21 $\pm$0.8, and 24.57 $\pm$1.8 µM, respectively) and 157a (IC₅₀ 16.95$\pm$2.4, 28.28$\pm$1.4, and 34.23 $\pm$2.0 µM, respectively) were also able to control the tumor of these cell lines very effectively as compared to the control GANT‐61 (IC₅₀ 10.19$\pm$0.3, 14.67$\pm$0.2, and 21.90$\pm$0.2 µM, respectively). It was observed that the presence of heteroatoms in the azepine ring, olefinic protons, and the phenyl group increases the hydrogen‐bonding interactions with target proteins. Molecular docking studies demonstrated that 156a and 157a exhibit superior binding affinity toward microbial targets like outer membrane protein A and exo‐1,3‐$\beta$‐glucanase, along with, cancer targets in hedgehog pathway involving smoothened and GLI‐1, surpassing standard drugs via immense $\pi$‐interactions, hydrogen bonding, and electrostatic interactions.

SCHEME 35.

Synthesis of quinazolinone derivatives having azepine moieties (156a–d) and (157a–d).

Gariganti and coworkers had developed new derivatives of quinazolinone containing amides of type 161a–j [61]. The designed compounds were synthesized by reducing the nitro group of substituted quinazolinone 158 to an amine using Raney Ni, H₂ in methanol, forming intermediate 159, followed by reaction with different acid chlorides 160, yielding final compound 161 (Scheme 36). The synthesized compounds 161a–j were evaluated for its activity against human cancer cell lines PC3 and DU‐145 (prostate cancer), A549 (lung cancer), and MCF7 (breast cancer) and results revealed that compound 161h had shown strong activity against PC3 (IC₅₀ 0.77 $\pm$ 0.086 µM), 161g against DU‐145 (IC₅₀ 1.98 $\pm$ 0.27 µM), 161c against A549 (IC₅₀ 2.91 $\pm$ 0.17 µM) and 161i and 161j against MCF7 (IC₅₀ 0.07 $\pm$ 0.0061 and 0.13 $\pm$ 0.053 µM, respectively) in contrast to control etoposide (IC₅₀ value ranging from 1.97 $\pm$ 0.45 to 3.08 $\pm$ 0.135 µM). Molecular docking revealed that quinazolinone derivatives exhibit strong binding affinity toward the EGFR tyrosine kinase domain, exhibiting the highest affinity via essential hydrogen bonding and hydrophobic interactions, enhancing anticancer potency.

SCHEME 36.

Synthesis of acetamide‐quinazolinone derivatives (161a–j).

Ayoob and Hawaiz synthesized fresh variants of bis‐quinazolinones of type 166a–f. Reaction of fumaroyl dichloride 162 and anthranilic acid 1 yielded an intermediate 163, followed by dehydration by acetic anhydride, producing bis‐benzoxazinone 164, which, on further treatment with GAA and aromatic amines, forms bis‐furamides 165 that subsequently, in the presence of sulfuric acid, yield the target compound 166. Alternatively, compound 166 can also be directly synthesized from 164 by its reaction with various aromatic amines in acetic acid and sodium acetate (Scheme 37). The test compounds were assessed for antibacterial activity against S. aureus and E. coli, antifungal activity against C. albicans, and anticancer activity against MCF‐7 cell lines. Compounds 166e and 166f were more potent against S. aureus and E. coli, respectively, as compared to the reference ciprofloxacin. Compounds 166d, 166e, and 166f have shown remarkable antifungal activity compared to standard fluconazole, and 166b possesses commendable anticancer properties with an IC₅₀ value of 0.4603 µM as compared to reference gefitinib (IC₅₀ 0.166 µM). The binding affinity of bis‐quiazolinone derivatives was attributed to effective binding with active sites of EGFR by strong hydrogen bonding with Lys745 and $\pi$‐interactions, replicating binding behaviour of reference drug, leading to enhanced inhibitory activity [62].

SCHEME 37.

Synthesis of bis‐quinazolinone derivatives (166a–f).

Ghorab et al. designed new N‐substituted‐oxophenyl dihydroquinazolinone acetamide derivatives of type 168a–k. The chemical synthesis (Scheme 38) was initiated with the reaction between anthranilic acid 1 and phenyl isothiocyanate in ethanol and triethylamine, forming intermediate 167, followed by its reaction with N‐substituted‐2‐chloroacetamide in dry acetone and anhydrous K₂CO₃, yielding the key compounds 168a–k [63]. The synthesized compounds were evaluated for cytotoxicity against the hepatocellular carcinoma cell line HepG‐2 and for inhibitory activity of EGFR, and results revealed that compounds 168f–i were more effective than other derivatives. The compounds 168f–i with IC₅₀ values of 1.11, 4.28, 5.70, and 4.69 µM, respectively, showed higher activities against the hepatocellular carcinoma cell line as compared to control doxorubicin (IC₅₀ 32.02 µM), and compounds 168f and 168g with IC₅₀ values of 73.23 and 58.26 µM, respectively, had inhibited EGFR activity more effectively as compared to standard erlotinib (IC₅₀ 9.79 µM). It was concluded from SAR studies that aryl groups at the acetamide NH had significantly increased cytotoxic efficacy of compounds, in contrast to those having N‐aliphatic chains and different substituents and positions on the aryl ring, which had varied activity. Molecular docking revealed that compounds 168f and 168g exhibit strong binding affinity toward EGFR active sites, similar to erlotinib, with comparable docking scores, and form key hydrogen bonds with Thr766 and Met769 residues and hydrophobic interactions with Lys721 residues, ensuring stable interactions and improved anticancer activity.

SCHEME 38.

Synthesis of N‐substituted‐oxophenyl dihydroquinazolinone acetamide derivatives (168a–k).

Novel descendants of quinazolinone‐containing acetamides of types 173a–g and 174a–g were synthesized by El‐Gazzar and group. The synthetic pathway included the reaction of 5‐methyl anthranilic acid 169 with phenyl isothiocyanate 170 in the presence of ethanol and triethylamine, forming mercapto phenyl quinazolinone 171, followed by its reaction with different N‐substituted‐2‐chloro‐acetamide 172 in dry acetone and anhydrous K₂CO_3, yielding S‐alkylated 173a–g and N‐alkylated 174a–g quinazolinones which were separated on the basis of their solubility in acetone (Scheme 39) [64]. The final products were screened as purine nucleoside phosphorylase (PNP) inhibitors used for the treatment of breast cancer. Results revealed that the compound 174g (IC₅₀ 0.159 $\pm$ 0.007 µM) had effectively inhibited PNP as compared to standard peldesine (IC₅₀ 0.041 $\pm$ 0.002 µM) and was very powerful against the human breast cancer cell line. It was deduced that 2‐ethylcarboxylate‐phenyl had shown the most potency due to hydrogen bonding with oxygen atoms and extensive van der Waals’ interactions due to the ethyl group of the carboxylate substituent. Moreover, the binding affinity of these derivatives with purine nucleoside phosphorylase active sites had been improved, compared to the reference drug peldesine, by hydrogen bonding with Thr242 and Asn243 residues and hydrophobic contacts with Phe200, due to the methyl group at C6 and hydrophobic groups at N1 and N3 positions of quinazolinone.

SCHEME 39.

Synthesis of quinazolinone derivatives containing acetamide moieties (173a–g) and (174a–g).

Li et al. developed novel derivatives of quinazolinone of type 177a–i. The chemical procedure involved the reaction of isatoic anhydride 86 with different amines to form intermediate 175, followed by condensation with different aryl aldehydes in potassium carbonate and methanol, forming intermediate 176, which, on further reaction with an oxidant, dichloro dicyanobenzoquinone (DDQ), and dichloromethane (DCM), yielded the desired compounds 177a–i (Scheme 40) [65]. The synthesized compounds were screened for antitumor activity against NCI‐H1975 cells. The results revealed that compound 177a with an IC₅₀ value of 5.54$\pm$2.25 µM exhibited remarkable anti‐proliferative activities as compared to the control osimertinib (IC₅₀ 0.050 $\pm$0.0042 µM) and rest of the analogs. It was declared that substituents having a cyclopentyl ring at the N3 position had increased biological potency of the target compound.

SCHEME 40.

Synthesis of oxidized quinazolinone derivatives (177a–i).

Zare and coworkers obtained novel hybrids of quinazolinone with pyrimidine of type 182a–j [66]. The chemical procedure (Scheme 41) involved the refluxing of bromo benzoxazinone 178 with different anilines 179 in acetonitrile under acidic conditions using phosphorus trichloride to yield intermediate 180, followed by refluxing with substituted uracil 181 in the presence of DIPEA to get the final products 182a–j. The target compounds were tested for antiproliferative activities against three human cancer cell lines (A549, SW‐480, and MCF‐7), and it was found that among all other analogs, compound 182 g was more potent against cancer cell lines. Compound 182g with IC₅₀ values of 5.9 $\pm$1.7, 2.3 $\pm$0.91, and 5.65 $\pm$2.33 µM exhibited commendable antiproliferative potential against three cell lines, respectively, as compared to standard cisplatin (IC₅₀ 15.37 $\pm$1.61, 16.1$\pm$1.87, and 3.2$\pm$0.8 µM). It was concluded that the analogs having a halogen group at the para‐position and the presence of bulky groups at the phenyl group exhibited enhanced antiproliferative activity compared to analogs having methyl and methoxy groups. These results were supported by enormous hydrogen bonding, $\pi$–$\pi$ interactions, and hydrophobic interactions between synthesized therapeutics and active site residues of EGFR, exceeding binding interactions with reference drug.

SCHEME 41.

Synthesis of pyrimidine–quinazolinone derivatives (182a–j).

Anticancer results of quinazolinone derivatives acting on various cancerous cell lines, targeting proteins responsible for cancer, as IC₅₀ and GI₅₀ values are depicted in Table 4. Predominantly, these derivatives were substituted at the C2, C3, C6, and C7 positions.

TABLE 4.

Summary of quinazolinone and its derivatives as anticancer scaffold.

S. no.	Structure	IC50 and GI50	Target proteins/enzymes
1		8.68$\pm$4.48 µM (MDA‐MB‐231), 7.76$\pm$0.85 µM (SW620), and 29.23$\pm$5.71 µM (MRC‐5)	Histone deacetylase
2		387.65 µM (3T3 fibroblast) and 5.72 µM (PC3 prostate)	mTOR
3		74.0$\pm$3.9 µM (MCF7) and 260.4$\pm$11.1 µM (HUVEC)	Estrogen receptor alpha and HER2
4		4.29$\pm$0.32 µM (PC3 cells)	Androgen receptors
5		15.9 µM (H1975 cells) and 32.9 µM (A549 cells)	EGFR
6		6.03, 7.02, 7.16, and 2.59 µM (NCI cancer lines)	Kinases like FGFR‐1, VEGFR‐2, and BRAF
7		14.25$\pm$1.1, 19.21$\pm$0.8, and 24.57$\pm$1.8 µM (HCT‐116, MCF‐7, and HepG‐2 cells) 16.95 $\pm$2.4, 28.28$\pm$1.4, and 34.23$\pm$2.0 µM (HCT‐116, MCF‐7, and HepG‐2 cells)	Smoothened (SMO), SUFU/GLI‐1
8		2.91 $\pm$ 0.17 µM (A549), 1.98 $\pm$ 0.27 µM (DU‐145), 0.77 $\pm$ 0.086 µM (PC3), 0.07 $\pm$ 0.0061 µM, and 0.13 $\pm$ 0.053 µM (MCF7)	EGFR tyrosine kinase
9		0.4603 µM (MCF‐7)	EGFR
10		73.23 and 58.26 µM (HepG‐2)	EGFR
11		0.159 $\pm$ 0.007 µM	Purine nucleoside phosphorylase
12		5.54$\pm$2.25 µM (NCI‐H1975 cells)	‐ (Not given)
13		5.9$\pm$1.7 µM (A549), 2.3$\pm$0.91 µM (SW‐480) and 5.65$\pm$2.33 µM (MCF‐7)	EGFR

MDA‐MB‐231 = breast cancer; SW620 = colon cancer; MRC‐5 = human fetal lung fibroblasts; PC3 = prostate cancer; MCF7 = breast cancer; HUVEC = normal endothelial cells; H1975 = non‐small cell lung cancer; A549 = lung cancer; HCT‐116 = colorectal carcinoma; HepG‐2 = hepatocellular carcinoma; DU‐145 = prostate cancer; SW‐480 = colo‐rectal cancer.

3.3.1. SAR Summary of Anticancer Activity

SAR analysis investigations of quinazolinone‐based derivatives for anticancer applications, particularly against targets such as EGFR and other tyrosine kinases, reveal that biological activity is highly dependent on the nature and position of substituents on the core scaffold (Figure 7). The presence of electron‐withdrawing groups at the C‐6 position of quinazolinone, like bromine and iodine, has suppressed the enzymatic activity. Substitutions with groups like hydroxamic acid that bind strongly with zinc ions and substituents having longer aliphatic chains (n = 6, 5, and 4) were highly potent, thus possessing good activity. Ligands having electron‐withdrawing groups like sulfonyl had reduced the activity, while substituents having hydroxy groups that can form hydrogen bonds had increased the activity. Cytotoxic activity was enhanced by electron‐donating groups like ethoxy and methoxy, while bulky groups reduced the activity. Furthermore, electronegative substituents like chlorophenyl groups were involved in immense hydrogen and hydrophobic interactions, which led to inhibition of EGFR and induced cell cycle arrest. Substituting quinazolinone derivatives with a 2‐methoxyphenyl group exhibits strong binding with kinases like FGFR‐1, VEGFR‐2, and BRAF by forming hydrogen bonds and significantly enhances the hydrophobic interactions and binding affinity. Bonding interactions with target proteins had been increased by adding heterocyclic rings like azepine, olefinic protons, and phenyl groups to the quinazolinone scaffold. N‐aliphatic chains had lowered the cytotoxic efficacy, whereas aryl groups at the acetamide NH had significantly increased the cytotoxic efficacy of compounds. The cytotoxic behavior had been influenced by hydrogen bonding with oxygen atoms and extensive van der Waals interactions between 2‐ethylcarboxylate‐phenyl and PNP. A cyclopentyl ring at the N3 position of quinazolinone increased the biological potency of the target compounds. Additionally, bulky and halogen groups at the para‐position of the phenyl group at the N3 position of the core quinazolinone exhibited enhanced antiproliferative activity compared to analogs having methyl and methoxy groups. The substituents that actively bind to the active sites of target proteins via hydrogen and hydrophobic interactions take the lead as anticancer therapeutics. Therefore, this uncovers the advantage of specific substitutions in improving biological profiles and outlining the capacity of quinazolinone derivatives as a suitable candidate for anticancer activity.

FIGURE 7.

SAR outline for anticancer activity.

3.4. Antidiabetic Activity

Şenol et al. had synthesized hybrids of thiazolidine‐quinazolinone of type 185a–k for inhibition of the aldose reductase enzyme (Scheme 42) [67]. 3‐amino quinazolinone 183 was reacted with chloroacetyl chloride in DMF, giving intermediate 184, followed by reaction with ammonium thiocyanate in ethanol, yielding the target compound 185a–k. Evaluating results of all derivatives against aldose reductase revealed that 185k had high potential for the inhibition of this enzyme with an IC₅₀ value of 10.19 µM compared to the standard drug quercetin (IC₅₀ 10.34 µM). The inhibition results vary with reference to the substituents at the C‐2 position of the quinazolinone ring. Compounds having hydrogen or aliphatic groups at the C‐2 position had lower inhibition compared to cyclic and aromatic substituents. Moreover, the strong binding affinity of 185k can be attributed to the synergistic interaction involving hydrogen bonding with His‐110 and Cys‐298, and $\pi$–$\pi$ stacking interactions with Trp‐111 and Phe‐122, ensuring stable conformation within the active sites of the target enzyme with a docking score of −10.404 kcal/mol.

SCHEME 42.

Synthesis of thiazolidine quinazolinone derivatives (185a–k).

Tokali and co‐authors had developed aldose reductase inhibitors possessing a 4‐bromo‐2‐fluorobenzene moiety incorporated in a quinazolinone scaffold of type 188a–j. The synthetic procedure involved the reaction between methyl anthranilate 186 and acyl chloride in sodium bicarbonate, followed by reaction with hydrazinium hydroxide in ethanol, forming intermediate 187, which, on further reaction with 2‐fluoro‐4‐bromobenzaldehyde, yielded target compounds 188a–j (Scheme 43) [68]. Among all the synthesized derivatives, 188h exhibited the highest potential for inhibiting the aldose reductase enzyme with a K _i value of 0.064 µM compared to standard epalrestat (K _i 0.967 µM). Inhibitory activity decreased as the chain length of the aliphatic side chain increased due to steric interactions, while the cyclohexyl ring and aromatic rings increased the activity. The stabilization of ligand–protein interaction of 188h and aldose reductase enzyme was attributed to a docking score of −10.407 kcal/mol, exhibiting $\pi$–$\pi$ stacking of the quinazolinone ring with Trp‐20 and Tyr‐209 amino acids, hydrogen bonding between the carbonyl oxygen and Trp‐111, the bromine atom of the benzylidine group was involved in a halogen bond with Ser‐302, and the cyclohexyl ring interacts with multiple residues by polar interactions.

SCHEME 43.

Synthesis of 4‐bromo‐2‐fluorobenzene quinazolinone derivatives (188a–j).

Jaiswal et al. synthesized quinazolinone‐dihydropyrimidinone hybrids of type 192a–m as antidiabetic therapeutics (Scheme 44). The synthesis involved a nucleophilic substitution reaction between 2‐aminophenyl‐3‐alkylquinazolin‐4(3H)‐one 189 and 2,2,6‐tri‐methyl‐1,3‐dioxin‐4‐one 190 in toluene, forming intermediate 191, followed by reaction with different aldehydes and urea catalyzed by ytterbium(III) trifluoromethanesulfonate, yielding final compounds 192a–m. Results revealed that 192g exhibited potent antihyperglycemic activity by inducing GLUT4 translocation in the skeletal muscle cells by activating the AMPK‐dependent pathway, compared to other derivatives and the standard drug metformin. In vivo treatment in the streptozotocin‐induced diabetic rat model had displayed a 39.5% lowering of blood glucose levels, making it a promising candidate for anti‐hyperglycemic activity. The substitution of a phenyl ring on dihydropyrimidinone enhanced the activity compared to a heterocyclic ring, moreover, electron‐withdrawing groups were preferred over electron‐donating groups on the phenyl ring. Chlorinated quinazolinone hindered the target site, therefore, unsubstituted quinazolinone was favored. Further, amide linkage at the para‐position was recommended over the meta‐position, and the dihydropyrimidinone ring had played a crucial role in increasing the activity [69].

SCHEME 44.

Synthesis of dihydropyrimidinone quinazolinone derivatives (192a–m).

Sirichai's group had designed and developed quinazolinone derivatives with a 1,2,3‐triazole moiety of type 195a–g as α‐glucosidase inhibitors (Scheme 45) [70]. The reaction procedure involved the reaction of N‐propargyl quinazolinone 193 with tert‐butyl‐1‐azido‐4‐(benzylthio)butan‐2‐ylcarbamate derivatives 194, catalyzed by copper iodide, followed by treatment with trifluoroacetic acid, synthesizing target compounds 195a–g. These compounds were evaluated for inhibitory activity of α‐glucosidase, which is responsible for converting complex carbohydrates to sugars, leading to type 2 diabetes. Results revealed that 195d had strong inhibitory potential with an IC₅₀ value of 1.72$\pm$0.046 µM compared to other derivatives and reference drug acarbose (IC₅₀ 51.23 $\pm$10.21 µM). Electron‐donating groups and hydrophobic substituents had increased the activity, while electron‐withdrawing and bulky groups had decreased the activity. Docking results had disclosed that the active derivatives had strong binding affinity towards active sites of α‐glucosidase, stabilizing complex via hydrogen bonding, $\pi$–$\pi$ interactions, and hydrophobic interactions with active residues of the target enzyme.

SCHEME 45.

Synthesis of quinazolinone derivatives with triazole moieties (195a–g).

Antidiabetic activity of derivatives substituted at C2 and C3 of quinazolinone has been depicted in Table 5, representing IC₅₀, Ki, % reduction values, target proteins, and enzymes.

TABLE 5.

Summary of quinazolinone and its derivatives as antidiabetic scaffold.

S.No.	Structure	IC50, Ki, and %reduction	Target proteins/enzymes
1.		10.19 µM	Aldose reductase
2.		0.064 µM	Aldose reductase
3.		39.5%	GLUT4
4.		1.72$\pm$0.046 µM	α‐glucosidase

3.4.1. SAR Summary of Antidiabetic Activity

SAR findings elaborate that particular structural modifications and functional groups critically affect the biological potential of these compounds (Figure 8). Like, cyclic and aromatic substituents at the C2 position had increased the inhibition compared to compounds having hydrogen or aliphatic groups. Longer aliphatic chains at the C2 position of quinazolinone cause steric hindrance, causing a decrease in the inhibitory activity of aldose reductase, whereas cyclohexyl and aromatic rings increase the activity. The pyrimidinone ring had enhanced the activity effectively, moreover, the activity was further enhanced by substituting it with a phenyl ring and an electron‐withdrawing group compared to heterocyclic rings and electron‐donating groups. Besides, this unsubstituted quinazolinone ring was preferred over the chlorinated one as it hindered the active site of the target protein. Inhibition activity of α‐glucosidase had been reduced due to electron‐withdrawing and bulky groups on substituents, while electron‐donating groups and hydrophobic substituents had increased the inhibitory potential of synthesized derivatives. As a result, these investigations focus on both steric positioning and electronic properties of substituents, which are important for increasing binding interactions, gathering further insights with in vitro and in vivo observations to develop novel lead pharmacophores.

FIGURE 8.

SAR outline for antidiabetic activity.

3.5. Miscellaneous Activity

Bai and co‐authors had developed new variants of quinazolinone of type 197a–h for inhibiting TRPC5 channels. Isatoic anhydride 86 was reacted with amine in DMF, forming intermediate 196, followed by reaction with aldehydes in acetic acid, yielding final compounds 197a–h as shown in Scheme 46 [71]. The HEK293 cells were used to evaluate the inhibitory effect of target compounds on TRPC5, which is responsible for kidney diseases and neurological disorders. Compounds 197c and 197f were able to potentially inhibit this channel with IC₅₀ values of 1.28 and 2.16 µM, respectively, in contrast to other substitutes and control ML204 (IC₅₀ 0.13 µM). Substitutions of electron‐withdrawing groups, aliphatic chains, or aliphatic or heterocyclic rings at the C‐2 position of quinazolinone have enhanced the activity. The binding affinity of compounds 197c and 197f can be attributed to a synergistic interaction profile involving $\pi$–$\pi$ stacking of aromatic rings, hydrogen bonding through the carbonyl of quinazolinone and hydrophobic interactions with non‐polar residues, ensuring stable accommodation within the active site of TRPC5.

SCHEME 46.

Synthesis of quinazolinone derivatives (197a–h).

Moftah et al. synthesized novel derivatives of quinazolinone for targeting Alzheimer's disease. The target compounds 199a–h and 200a–d were formed by reaction of N‐3‐amino‐2‐methylbenzamide‐quinazolinone 198 with different benzaldehydes and oxazolone, respectively, catalyzed by GAA (Scheme 47). The target compounds were screened for anti‐cholinesterase and anti‐inflammatory activities by using AchE inhibition activity and behavior, the Morris water maze test, and hippocampal inflammatory markers, respectively. Results revealed that compounds 199f, 199h, and 200b showed promising activity as AChE inhibitors, by inhibiting AChE at 20%, 34%, and 23.8%, respectively. Inflammatory markers such as TNF‐α, NF‐кB, IL1β, and IL6 were inhibited by 199f (23%, 22%, 23.7%, and 23.2%, respectively), 199 h (38.7%, 35.7%, 31.5%, and 27.38%, respectively), and 200b (26%, 24%, 26.3%, and 25.5%, respectively). The inhibitory activity was improved by the addition of p‐chlorobenzamide and p‐hydroxyphenyl substituents. Moreover, stiffening of 2‐phenyl‐3,5‐dihydro‐imidazol‐4‐one derivatives through cyclization increased the activity. The superior inhibitory potential of compounds 199f, 199h, and 200b (docking scores −51.6, −52.2, and −46.4 kcal/mol, respectively) is attributed to their ability to establish a robust interaction network involving $\pi$–$\pi$ stacking interaction of quinazolinone with Tyr A341, Trp A286, and Tyr A337 and hydrogen bonding of carbonyl group, amide group, and substituted benzamide with Tyr A124, Phe A295, and Arg A296, the key active‐site residues of AChE, mimicking binding pattern with reference drug donepezil [72].

SCHEME 47.

Synthesis of quinazolinone derivatives (199a–h) and (200a–d) from N‐3‐amino‐2‐methylbenzamide‐quinazolinone.

Nandi and co‐authors designed new hybrids of quinazolinone and indole of type 205a–h. The synthesis involved the reaction of quinazolinone 11 with n‐bromoalkylphthalimide 201 in acetone and potassium carbonate to yield intermediate 202, followed by refluxing with hydrazine hydrate in methanol, forming intermediate 203. The compound 205 was formed by reaction of 203 with substituted indole 204 in triethylamine and tetrahydrofuran, yielding the final product 205a–h (Scheme 48) [73]. The target compounds were screened for their activity against pancreatic lipase (PL) for treatment of obesity, and compound 205g was found to possess better inhibition potential in contrast to other descendants. The compound 205g with IC₅₀ value of 4.71$\pm$0.851 µM had shown high efficiency as compared to control orlistat (IC₅₀ 0.86 $\pm$0.090 µM). It was concluded that derivatives having electron‐donating groups had shown enhanced activity against PL. These results were further supported by the stable complex formation between indolyl oxoacetamide–quinazolinone and PL, governed by $\pi$–$\pi$, $\pi$–cation, and hydrophobic interactions, possessing high inhibitory potency compared to orlistat.

SCHEME 48.

Synthesis of indole‐quinazolinone hybrids (205a–h).

Setshedi et al. developed novel derivatives of 2‐aroyl quinazolinone of type 207a–h. The procedure involved the reaction of anthranilamide 73 with acetophenone 206 in the presence of iodine and dimethyl sulfoxide, yielding the required compound 207 (Scheme 49). The synthesized compounds were evaluated for antiparasitic activities against Trypanosoma cruzi, Trypanosoma brucei, T. brucei rhodesiense, and Leishmania infantum. Results revealed that compounds 207b and 207e exhibited commendable activity as compared to other derivatives against T. brucei rhodesiense (IC₅₀ 1.1 µM) and T. brucei (IC₅₀ 4.7 µM), and no compound was found to be effective against T. cruzi and L. infantum. The antiparasitic activity had been improved by substituting electron‐withdrawing groups at p‐position of the phenyl ring [74].

SCHEME 49.

Synthesis of 2‐aroyl quinazolinone derivatives (207a–h).

Pindjakova et al. synthesized Schiff bases of quinazolinone of type 210a–i and copper complexes of some of its derivatives (Scheme 50) [75]. The synthesis involved the condensation of 2‐aminobenzohydrazide 208 with different aryl aldehydes 209, catalyzed by phosphomolybdic acid in ethanol under microwave radiations yielding the target compound 210. Reaction of copper chloride with 210c, 210h, and 210i results in the formation of copper complexes of derivatives of type 211, 212, and 213 respectively. The synthesized compounds were assessed for antistaphylococcal activity against S. aureus, anti‐enterococcal activity against Enterococcus faecalis; antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii and M. smegmatis; antibiofilm activity against S. aureus and antileukemic activity. The synthesized compounds had not shown significant results for anti‐enterococcal and antimycobacterial activity while compounds 210c and 211 had shown 90.8% and 90.2% inhibition of S. aureus in contrast to standard ampicillin (81.9%) and ciprofloxacin (96.1%). Compounds 210c, 211, 212 and 213 had reduced biofilm formation of S. aureus by 80% and copper complexes of synthesized compounds had represented significant antileukemic activity.

SCHEME 50.

Copper complexes of quinazolinone derivatives (210a‐i).

Tokali and coworkers obtained new quinazolinone analogs of type 216a‐l by reacting quinazolinone 214 with p‐formylphenyl acetate derivatives 215 in presence of GAA (Scheme 51). The synthesized derivatives were evaluated for their inhibition properties against Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), $\propto$‐Glucosidase ($\propto$‐Glu), and Carbonic anhydrase I‐II (hCA I‐II) metabolic enzymes and results revealed that the compounds 216c, 216f, 216h, and 216j, respectively, were more potent against their respective enzymes compared to another analogs. Compounds 216c and 216f with IC₅₀ values of 13.02 and 9.84 nM had inhibited AChE and BChE enzymes more prominently, as compared to standard tacrine (IC₅₀ 136.67 and 111.27 nM), respectively. Compound 216h with an IC₅₀ value of 62.13 nM was highly effective against $\propto$‐Glu than standard acarbose (IC₅₀ 765.82 nM) and for enzyme hCA I‐II, 216j with IC₅₀ 2.18 and 1.17 nM, respectively, was highly potent in contrast to standard acetazolamide (IC₅₀ 28.16 and 21.53 nM). Docking results concluded that increased $\pi$–$\pi$ interactions, hydrogen bonding and hydrophobic interactions had improved inhibition of enzymatic activity, where synthesized derivatives had shown stable and strong binding with AChE/BchE, $\propto$‐Glucosidase and hCA I/II enzymes, having improved pharmacokinetic profile [76].

SCHEME 51.

Synthesis of acetylformate–quinazolinone derivatives (216a–l).

Several other biological activities of quinazolinone derivatives has been represented in Table 6, along with IC₅₀ and % inhibition values and target proteins and enzymes.

TABLE 6.

Summary of quinazolinone and its derivatives for miscellaneous activity.

S. no.	Structure	IC50, % inhibition	Target proteins/enzymes
1		1.28 and 2.16 µM (HEK293 cells)	TRPC5
2		20%, 34% and 23.8%	Acetylcholinesterase
3		4.71$\pm$0.851 µM	Pancreatic lipase
4		13.02 nM 9.84 nM 62.13 nM 2.18 and 1.17 nM	Acetylcholinesterase Butyrylcholinesterase $\propto$‐Glucosidase Carbonic anhydrase I‐II

HEK293 = kidney cells.

3.5.1. SAR Summary of Miscellaneous Activity

SAR investigations demonstrated that bioactivity of quinazolinone based derivatives depends on nature and position of substituent on core scaffold (Figure 9). Substituting C‐2 position of quinazolinone with electron‐withdrawing groups, aliphatic chains, or aliphatic or heterocyclic rings had effectively enhanced the activity against TRPC5. The inhibitory potential against AChE had improved by addition of p‐chlorobenzamide and p‐hydroxy phenyl substituents, and stiffening of 2‐phenyl‐3,5‐dihydro‐imidazol‐4‐one derivatives through cyclization also increased the inhibition. Electron donating groups on indole ring substituted with quinazolinone had shown enhanced activity against PL. Alternately, electron‐withdrawing groups at p‐position of phenyl ring at C2 position of quinazolinone had shown good antiparasitic activity. Alkyl chains were responsible for inhibition properties against AChE, BChE, $\propto$‐Glu, and Carbonic anhydrase I‐II metabolic enzymes. Therefore, strategic optimization of steric factors and electronic properties is necessary for enhancing biological activities of quinazolinone derivatives with respect to target pathogen or enzyme.

FIGURE 9.

SAR outline for miscellaneous activity.

4. Conclusion and Future Perspective

Being the most privileged scaffold, quinazolinone can be validated as a leading molecule in field of synthetic chemistry and drug discovery. The structural flexibility, electronic distribution and extent of conjugation allow it to interact with proteins and enzymes of target pathogens. In addition, their lipophilic nature enables researchers to design the drugs that can interact with the biological systems with ease. Furthermore, the stability and proficiency of this framework to be easily modified with other proactive substituents outshines them among others. Review studies clearly indicate that transformation of substituents around the quinazolinone scaffold had improved biological activity due to their enhanced physiochemical properties.

In this review synthetic procedures to obtain various key structural features of quinazolinone had been explored and biological activity of several hybrid molecules and derivatives obtained from classical methods has also been studied. The pyrimidinone ring of quinazolinone was preferably attacked by functional groups for substitutions. Majorly, C2 and N3 were selected by most of the authors, followed by modifications on C4. Additionally, SAR revealed that appropriate positioning of electron‐donating and electron‐withdrawing groups had played a vital role in development of active biological agents. Resulting, this skeleton can be considered as a lead chemical compound for further discovery of novel drugs. The multi‐diverse biological potential had opened a broad scope for digging deep into study of quinazolinone.

However, many reviewed methods had suffered from drawbacks like use of harsh reagents, lack of substrate versatility. Therefore, it is necessary to tweak some of these procedures to get better reaction outcomes, like using suitable reagents to minimize side products and reactions and improve final yield of target compounds. Moreover, green chemistry principles should be adopted to develop eco‐friendly approaches. By addressing the limitations of existing drugs of quinazolinone, they can also be chemically modified. Understanding, the reviewed biological studies, functional groups or structural scaffolds may be incorporated to enhance physicochemical properties and binding affinities with respect to target sites, diversifying activity range and combating resistance. In addition, except in vitro studies, focus should be more shifted towards in vivo and in silico studies for more specific and enhanced results relative to toxicity and drug efficacy within the living system and to make research cost effective. Further, structurally novel derivatives of quinazolinone should be designed for exploring wide range of biological applications. We aspire that the synthetic and biological studies of quinazolinone discussed in this review will be insightful for the respective scientific community for further developments in their drug synthesis and drug design efforts.

Author Contributions

Divya Utreja: writing – original draft, writing – review and editing, methodology, supervision. Shivali Sharma: conceptualization, writing – original draft, validation, writing – review and editing, supervision. Mehak Aggarwal: writing – review and editing, methodology, formal analysis.

Conflicts of Interest

The authors declare no conflicts of interest.

Biographies

Mehak Aggarwal is currently pursuing her PhD in Chemistry from Punjab Agricultural University, Ludhiana (India) under the guidance of Dr. Shivali Sharma. Her research area is to evaluate synthetic and biological evaluation of heterocyclic compounds, viz., quinazolinone.

Shivali Sharma received her MSc (HS) in Chemistry in 2008 from Guru Nanak Dev University, Amritsar (India). She obtained her PhD degree in 2015 from Guru Nanak Dev University, Amritsar. She joined as an Assistant Professor in the Department of Chemistry, Punjab Agricultural University, in March 2020. Her research interest focuses on synthesis and biological studies of varied heterocyclic moieties.

Divya Utreja received her MSc (HS) in Chemistry in 2005 from Guru Nanak Dev University, Amritsar (India). She obtained her PhD degree in Organic Chemistry in 2010 from the same University. She joined as an Assistant Professor in the Department of Chemistry, Punjab Agricultural University, Ludhiana, in May 2011. Her research area includes regioselective elaboration of heterocyclic moieties and their biological activity studies

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study