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Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives

The heterocyclic fused rings quinazoline and quinazolinone have drawn a huge consideration owing to their expanded applications in the field of pharmaceutical chemistry. Quinazoline and quinazolinone are reported for their diversified biological activities and compounds with different substitutions bring together to knowledge of a target with understanding of the molecule types that might interact with the target receptors. Quinazolines and quinazolinones are considered as an important chemical for the synthesis of various physiological significance and pharmacological utilized molecules. Quinazolines and quinazolinone are a large class of biologically active compounds that exhibited broad spectrum of biological activities such as anti-HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, antidepressant, antimalarial, antioxidant, antileukemic, and antileishmanial activities and other activities. Being considered as advantaged scaffold, the alteration is made with different substituent.


Introduction
Quinazolines and quinazolinones are classes of fused heterocycles that are of considerable interest because of the diverse range of their biological properties [1]. Many substituted quinazoline and quinazolinone derivatives possess a wide range of bioactivities such as antimalarial, anticancer, antimicrobial, antifungal, antiviral, antiprotozoan, anti-inflammatory, diuretic, muscle relaxant, antitubercular, antidepressant, anticonvulsant, acaricidal, weedicide, and many other biological activities. Quinazoline and quinazolinone compounds are also used in preparation of various functional materials for synthetic chemistry and also present in various drugs molecules ( Figure 1). This review is an attempt to expand the huge potentiality and focused on the various biological activities of quinazolines and quinazolinones [2].

History
In 1869 Griess prepared the first quinazoline derivative, 2-cyano-3,4-dihydro-4-oxoquinazoline, by the reaction of cyanogens with anthranilic acid. The bicyclic product was called bicyanoamido benzoyl and used this name until 1885 [5]. The preparation of the quinazoline came many years later when Bischler and Lang obtained it by decarboxylation of the 2-carboxy derivative. A more satisfactory synthesis of quinazoline was subsequently devised by Gabriel in 1903. The name was proposed by Widdege. Other names such as phenmiazine, benzyleneamidine, benzo-1,3diazine, 5,6-benzopyrimidine, and 1,3-diazanapthaline have occasionally been used. The presence of a fused benzene ring alters the properties of the pyrimidine ring considerably. The two nitrogen atoms are not equivalent, and the marked polarization of the 3,4-double bond is reflected in the reactions of quinazoline. The properties of substitute's quinazolines depend largely on (a) the nature of the substituents, (b) whether they are in the pyrimidine ring or in the benzene ring, and (c) whether or not complete conjugation is present in the pyrimidine ring [6][7][8] (see Scheme 2).

Methods for the Synthesis of Quinazoline and Quinazolinone Derivatives (Benzoylene Urea)
Some methods were reported for the synthesis of quinazolines and quinazolinones are as follows.

Biological Importance of Quinazoline Derivatives
The quinazoline and quinazolinone skeleton is frequently encountered in medicinal chemistry. The various substituted quinazolines and quinazolinones are having significant antihypertensive, antineoplastic, antidepressant, and antipsychotic activities whereas some derivatives of quinazoline and quinazolinones are found to be effective agents such as analgesic, antipsychotic, antiarrhythmic, sedative hypnotics, antibacterial, anti-inflammatory, antifungal, antimalarial, anticonvulsant, anticoccidial, anti-Parkinsonism, cancer and other activities [6][7][8].
A series of few 4,6 di-substituted-(diaphenylamino)quinazolines derivatives (8a-b) were evaluated for antitumor activity was considered as potent EGFR inhibitors [19]. A series of quinazoline derivatives (9a-c) were Scheme 24 evaluated for their function as EGFR inhibitors by applying radioiodination. All these compounds were further evaluated for potential SPECT activity for molecular imaging of breast cancer [20] (see Scheme 24). A series of novel 6-furanylquinazoline derivatives (10-13) were subsequently evaluated for their biological activity as a potent ErbB-1/ErB-2 tyrosine kinase inhibitor [21] (see Schemes 25 and 26).

Quinazolinones as Antifungal Activity.
Octahydroquinazoline (58) was obtained by a modification of the Biginelli reaction with phenacyl bromide and bromo malononitrile to furnish thiazolo [2,3-b] quinazoline and they found the interaction of compound with formamide, formic acid, and phenyl isothiocyanate yielded the corresponding pyrimidino thiazolo [2,3-b] quinazolines and exhibited antifungal activity against Candida albicans [51].
A series of few novel S-substituted-6-fluoro-4-alkyl (aryl) thioquinazoline derivatives (59a-c) were evaluated for their pharmacological activity as antifungal [52] (see Scheme 49). All of these compounds exhibited good antifungal activity, especially compound 59c, having a wide spectrum of bioactivity; it shows potent inhibitory activity on the growth of most of the fungi with EC 50 values ranging from 8.3 to 64.2 g/mL.
6.6. Quinazolinones as Antimutagenic Activity. The (S)-4-aminoquinazoline alcohols (66) were prepared from enantiomerically pure from (S)-quinazolinone alcohols. Mutagenic and antimutagenic properties of the (S)-4aminoquinazoline alcohols were investigated by using Salmonella typhimurium and E. coli WP2uvrA tester strains at 0.01, 0.1, and 1 lg/plate concentrations. (S)-4aminoquinazoline alcohols were found to be genotoxically safe at the tested concentrations. Among the tested (S)-4aminoquinazoline alcohols, the best antimutagenic activity was obtained with a methyl derivative at 0.1 g/plate dose [60].

Anti-Inflammatory and Analgesics Agents.
A series of quinazoline derivatives (70,71) showed potent analgesic and anti-inflammatory activity. All these compounds demonstrated potent activity as anti-inflammatory analgesic more than the reference compound indomethacin [63] (see Scheme 55).
All the compounds showed anticonvulsant activity in MES screen; however, compound 78a showed potency similar to standard drug (phenytoin, carbamazepine) without any neurotoxicity.
Compounds with the above substituents showed potent CNS depressant activity. Compound 79a showed anticonvulsant activity at 0.5 and 4 h in different test models, whereas 79c showed anticonvulsant activity at 4 h in MES screen and at 0.5 and 4 h in subcutaneous PTZ screen.
6.10. Quinazolinones as Antimalarial Agents. The 2,4-diamino-6-[(aryl)thio]quinazoline compounds were known to their antimalarial properties wherein the 4-amino group was replaced by hydrazine and hydroxyamino moieties and they found that such changes reduce markedly the antimalarial properties of this series. The compound (89) was tested against a normal drug-sensitive strain of Plasmodium berghei in mice by the parenteral route [81]. A series of quinazoline derivatives (90) were evaluated for their antiplasmodial activity [82] (see Scheme 65).
Compounds with the above substituents exhibited favourable antiplasmodial activity on THP1 and HepG2 human cell lines. 88 Ar   antioxidant activity by DPPH radical assay, nitric oxide scavenging activity, and hydrogen peroxide scavenging activity and reported that synthesized compounds (97)(98)(99) were found to be the most potent antioxidant activity [86] (see Scheme 68).
6.12. Antileishmanial Agents. Compounds of both synthetic and natural origin comprising a diverse group of chemical structure have been reported as antileishmial agents. These include mostly nitrogen heterocyclic such as quinolines, purine, pyrimidine, acidine, phenothiazines, bisbenzamides,  compounds protected the animals from histamine induced bronchospasm significantly [92].

Quinazoline as Antiprotozoan Agents.
A series of quinazoline derivatives (107a-b) were evaluated for their activity as a potent inhibitor of trypanosoma cruzi dihydrofolate reductase [93] (see Scheme 72).

Discussion
Heterocyclic compound containing quinazoline and quinazolinone nucleus plays most important role in the field of medicinal chemistry. It shows wide range of activities for medication purpose. A large number of quinazoline compounds have been synthesized and evaluated for their different biological activities. Some marketed quinazoline and quinazolinone nucleus containing drugs have different types of pharmacological activities. The quinazoline and quinazolinone based pharmaceuticals are becoming very important class of therapeutic agents and are likely to replace many obtainable organic based pharmaceuticals in the very near future. The quinazoline and quinazolinone based pharmaceuticals will be created on a large scale by different research development processes and will become available commercially for therapeutic uses. The biological profiles of this new generation of quinazoline and quinazolinone represent much progress with regard to the older compounds. This study gets an efficient way of understanding about the target pharmacophore relationship which can further aid the process of drug design developments. This study may also accelerate the designing processes to generate a larger number of therapeutically active molecules. The molecular treatment of potentially lead molecules is still a major line of approaches for the discovery and development of new drug molecules [94][95][96][97][98][99]. Combination of two or more 24 International Journal of Medicinal Chemistry moieties into one is a general procedure of handling and this can probably result in the raise of biological activities and deduction of untoward side effects.

Conclusion
The various structural modifications around the fused ring of quinazoline and quinazolinone subsequently evaluate are for their usefulness in treating various disease conditions. Quinazoline and quinazolinone, being the central body of the pharmacophore, hold different types of substituent. Based on their various physicochemical properties, they exerted a diversified range of therapeutic efficacy. Thus we can conclude that this review will definitely provide the researchers with a thorough understanding of the structure activity relationship study, which further helps in designing good large number of quinazoline and quinazolinone compounds with a strong impact in curing many fatal disorders.