Biological Activity of Quinazolinones

The chemical structure of quinazolinones includes benzene ring fused with 2-pyrimidinone (1), 4-pyrimidinone (2) or 2,4-pyrimidinedione (3) ring, and are named as quinazolin-2(1H)-one, quinazolin-4(3H)-one or quinazolin-2,4(1H, 3H)-one, respectively. The chemical structure of quinazolinones constitutes a crucial scaffold of natural and synthetic compounds with various therapeutic and biological activities. Quinazolinones are first synthesized by Stefan Niementowski (1866–1925) and named after Niementowski quinazolinone synthesis. Quinazolinones have strongly attracted the interest of medicinal chemist as they constitute a large class of compounds that exhibited broad spectrum of biological activities including antimicrobial, antimalarial, anticonvulsant, anticancer, anti-leishmanial, anti-inflammatory, etc. This chapter provides a brief overview on the recent advances on chemical and pharmacological aspects of quinazolinone derivatives published in the last decade. inhibitions by ovine COX and carrageenan-induced rat paw oedema methods. Four compounds showed potent anti-inflammatory activity with oedema inhibition percentage of 49 ± 1.16, 45 ± 0.82, 46 ± 1.36 and 54 ± 1.83 using indomethacin drug as reference.


Synthetic methods of quinazolinones
The number of synthetic methods of quinazolinone cores has intensely increased from year to year. These advancements in methods of synthesis lead to the access to new and effective quinazolinone compounds with augmented structural diversity starting from affordable and easily accessible substrates. In this chapter, we depict different methods of synthesis of quinazolinone derivatives from cheap and readily available starting precursors.
Quinazolin-4(3H) one compound 12 have been developed by Yang et al. via selective cleavage of the triple bond of ketoalkynes. A reasonable mechanism was suggested for this reaction (Figure 3). Michael addition of the amino group of the anthranilamide to the triple bond of the ketoalkyne generated the enaminone intermediate which upon acid catalyzed intramolecular cyclization with subsequent C-C bond cleavage afforded final product 12.
Reddy et al. [42] reported a CuI/DMSO-catalyzed domino oxidative method for the synthesis of tryptanthrin compound 20 through the interaction of 2-aminoacetophenone and isatoic anhydrides (Figure 6).

Biological applications of quinazolinones
Natural quinazolinones that widely used in traditional folk medicines are isolated from the plants and microorganisms while the major quinazolinone derivatives are accessed through synthetic process by some chemical reactions. Quinazolinone compounds constitute most privileged class of biologically active heterocyclic compounds. Because of their wide spectrum of biological activities, quinazolinones either from natural source or from synthetic origin, have prompted the medicinal chemist for structural design of these active compounds to develop high selective and potent pharmacological activities.

Anticancer activity
The natural cytotoxic quinazolinones are depicted in Figure 7. The Chinese herbal medicinal plant, Luotonin A 23, Figure 7 is a cytotoxic natural alkaloid possessing pentacyclic fused-quinazolinone moiety. It was first isolated from Peganum migellastrum in 1997 and it is in clinical use as anticancer agent and showed low human human topoisomerase-I inhibitor activity [46].
Topoisomerases being major targets for anticancer drug design, the luotonin A was used as a lead compound for development of analogs with increased potency [47]. In comparison with the luotonin A, the majority derivatized analogs explored higher activity for topoisomerase I inhibition and better in vitro cytotoxicity than lutonin A [47]. In view of these results, luotonin A is considered as a pharmacophoric core for the design of new topoisomerase I inhibitors [48].
Ahmed and Belal reported 2-furylquinazolinone derivatives including compound 38 that explored IC50 value equal to 7 μM/mL on MCF7 cells, and promising inhibitory activity against EGFR-TK [60], and compound 39 depicted a 24-fold higher potency than doxorubicin on HCT116 cancer cells, with IC50 values of 0.2 nmol/mL. Also, compound 39 showed a similar potency to the doxorubicin on MCF7 cell lines and remarkable EGFR inhibitor activity compared with erlotinib standard drug [61].

Anti-inflammatory activity
The inflammation is a biochemical reactions response that protects the body from infection and injury. It reflects the response of the organism to various stimuli and is related to many disorders such as arthritis, asthma and psoriasis which require prolonged or repeated treatment. The major cause of inflammation the release of chemicals from tissues such as the prostaglandins, histamine, leukotrienes, bradykinin, platelet-activating factor and interleukin-1. Corticosteroids inhibit the synthesis of both PGs and LTs through the release of lipocortin, which inhibits phospholipase A2 and subsequently reduces arachidonic acid release alleviating the inflammation of either rheumatoid arthritis or asthma. While nonsteroidal anti-inflammatory drugs NIASID relieve the inflammation through the inhibition of the cyclooxygenase enzyme and reducing the synthesis of prostanoids [62]. Figure 8 shows the chemical structure of the anti-inflammatory quinazolinone compounds. Spiro [(2H,3H) quinazoline-2,10-cyclohexan]-4(1H)one compounds 40 and 41 were reported as potent anti-inflammatory and analgesic activity of superior GIT safety margin in rats model compared with indomethacin (10 mg/kg) and tramadol (20 mg/kg) as reference standards [63].

Anticonvulsant activity
Epilepsy is defined a chronic neurological syndromes and marked by neuronal firing and neuronal hyperexcitability. Although, the available antiepileptic therapeutics explore satisfactory seizure control in about 70% of epileptic patients, it has become very urgent to search for new antiepileptic compounds with fewer sideeffects and less toxicity.  [69]. Against electroshock induced convulsions methaqualone is 1.5 times more potent anticonvulsant than phenytoin sodium and against pentylenetetrazol-induced seizures it is 10 times more potent than troxidone [70]. Methaqualone produces anticonvulsant effects, through the GABA type A receptors, at low doses while at higher doses, it produces muscle-relaxant and sedative effects [71].
El-Hashash et al. [79] reported the synthesis of quinazolinones bearing sulfonamide moiety (71-73) as antimicrobial against Gram-positive bacteria S. aureus and B. cereus and Gram-negative bacteria S. marcescens and P. mirabilis and as antifungal agents against A. ochraceus Wilhelm and P. chrysogenum using ampicillin and mycostatin as standards, respectively. Figure 10 shows the chemical structure of antimicrobial compounds (58-73).

Antimalarial activity
Malaria is a parasitic disease caused by Plasmodium species parasite. It is widespread in several regions in Africa, Asia and South America. These parasites have developed a drug resistance to almost all the commercially available antimalarial drugs. The good antimalarial potency and the less side effects of quinazolinone compounds promote the researchers for the development of new antimalarial compounds [80].

Cathepsin inhibitor activity
Cathepsins B and H are cysteine proteases that plays a major role in cancer progression as they degrade extracellular matrices facilitating invasion, angiogenesis and metastasis. Therefore the research community has been prompted to the discovery of potent cathepsins inhibitor hemotherapeutics [85].

Topoisomerase inhibitor activity
The DNA replication process is controlled essentially by DNA topoisomerase I (Top1) through the relaxation of the nucleic acid's supercoiled structure. Basically,  DNA Top1 attracts the interests of research community as a cancer chemotherapy target [88]. Efforts to overcome side effects of these clinically used anticancer Top1 inhibitors, particularly bladder toxicity, had led to the development of luotonin A alkaloid and discovery of its Top1 inhibitory activity [89].
Kamata et al. have prepared series of pyrimidoacridones (101), Pyrimidocarbazoles (102) and pyrimidophenoxadines (103) (Figure 14), and as topoisomerase II inhibitors [92]. Against P388 and KB cell lines, pyrimidocarbazoles and pyrimidophenoxadines were more potent than pyrimidoacridines. Pyrimidocarbazoles inhibited the in vivo tumor growth of mouse sarcoma M5076 with T/C values of 42% at 3.13 mg/kg/d, and increased the level of DNA-topo II cross-linking in P388 cells.

α-Glucosidase inhibitor activity
Diabetes is a reduced ability to convert glucose into energy inside the body. The role of insulin is the glucose transfer from blood into cells. A large number of antidiabetic agents with different mechanism of action are available in the market.

Thymidine synthase inhibitor activity
Thymidylate synthase enzyme (TS) plays a crucial role in the DNA biosynthesis that it catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), one of the nucleotides that constitute the DNA. Inhibition of TS results in imbalance of deoxynucleotides that increase the level of dUMP and finally leads to DNA damage [97]. TS is considered as interesting chemotherapeutic target for treatment of pancreatic, colorectal, ovarian, breast and gastric cancers [98].
In 1998, raltitrexed (117) a quinazolin-4-(1H)-one compound that has been clinically approved by EMA for treatment of colorectal cancer. Also, pemetrexed (118) is a quinazolin-4(1H)-one compound that is clinically approved by EMA and FDA in 2001. Both raltitrexed and pemetrexed are considered as classical antifolates as they are folate analogs containing a pterin ring and a charged glutamate tail, therefore they need active internalization into the cells through folate carrier system [99].

Monoamine oxidase inhibitor activity (MAO)
In human, monoamine oxidases (MAOs) are mitochondrial bound enzymes that are responsible for oxidative deamination metabolism of neurotransmitters such as dopamine, serotonin, norepinephrine and epinephrine. In the brain, MAO-A enzyme isoform metabolizes serotonin, therefore specific MAO-A inhibitors are used the treatment of anxiety and depression disorder [103]. On the other hand, MAO-B enzyme metabolizes dopamine in the brain thus MAO-B specific inhibitors are prescribed for the treatment of Parkinson's disease [104].
Quinazolinone moiety, one of numerous MAO inhibitor scaffolds, it has been explored as lead for the further development of potent MAO inhibitors. Compounds (123-127; Figure 17   Khattab et al. [107] reported a series of quinazolinone bearing amino acid ester or amino acid hydrazides (129-131; Figure 17) that revealed competitive higher inhibitory activity toward MAO-A than MAO-B. The anti-MAO-A activity were comparable with that of the standard reference clorgyline (IC50 = 2.9 × 10 −9 M). Compounds (130, 131) were the most selective MAO-A inhibitors with selectivity index of 131 (SI = 39,524) superior to that of the reference drug clorgyline (SI = 33,793).

Marketed quinazolinone drugs
Proquazone is non-steroidal anti-inflammatory drug (Biarison®) (132; Figure 18) manufactured by Novartis pharmaceutical company. Also, it is used in the treatment of degenerative joint disease.
Nolatrexed [108] compound (133; Figure 18) is a thymidylate synthase inhibitor drug manufactured by Agouron pharmaceutical company under trade name Thymitaq®. In 1998, Zarix licensed Thymitaq® from Agouron. It is used in treatment of liver cancer.
Quinethazone or Hyromox® [109] (134; Figure 18) has been marketed as antihypertensive drug by Lederle pharmaceutical company and was recently withdrawn from the market.
Fenquizone's brand name is Idrolone® (135; Figure 18) [110], it is marketed by Maggioni pharmaceutical company. It is a low-ceiling diuretics used in the treatment of oedema and hypertension.
The brand name of albaconazole [111] is Albaconazole® (136; Figure 18). It was marketed by GlaxoSmithKlyne pharmaceutical company as an oral and topical antifungal agent.
Febrifugine, Dichroin B® or ChangShan® (137; Figure 18) [112] was isolated from Chinese herb Dichroa febrifuga as potent antimalarial drug and was marketed by Hawaii Pharm pharmaceutical company. The brand name of afloqualone is Arofuto® (138; Figure 18) [113]. It is marketed by Mitsubishi Tanabe Pharma pharmaceutical company as sedative and muscle relaxant drug.
Evodiamine (139; Figure 18) [114] has been isolated from the Evodia plants and was found to reduce fat uptake in animal model. It is used for bodybuilding as over the counter supplements.

Conclusions
This chapter depicts different methods of synthesis of quinazolinone derivatives starting from affordable and easily accessible substrates including 2-aminobenzoic acid, 2-aminobenzamide, o-substituted aniline in addition to the synthetic methods of spiroquinazolinones and heterocycle-fused quinazolinones. Also, the chapter discusses different biological applications of both natural and synthetic quinazolinones. The last section in this chapter lists common quinazolinone drugs that have been approved in the market.