Chemistry and activity of quinazoline moiety: A systematic review study

Introduction

Quinazolin-4(3H)-one and its derivatives have structural importance of nearly two hundred naturally found alkaloids which are isolated and collectted from various of species of the plants, micro-organisms and animals. The name of quinazoline was first given by Weddige as he observed that it is isomeric with two compounds i.e cinnoline and quinoxaline.

Naturally, quinazolinone alkaloids forms a basic core of febrifugine and isofebrifugine, which was found to be immense antimalarial activity and are extracted from the traditional chisnese medicine.^[1], ^[2] Chemically, quinazolin constitutes an important class of fused heterocycles six membered (benzene and pyrimidine) rings ([Figure 1]).In which two conjoined aromatic rings incorporate with two nitrogen atoms and one of the carbon oxidized with keto oxygen. The structure is also called as quinazolindiones, chemically can be called as Quinazolin-4(3H)-one. 2-quinazolinone and 4-quinazolinone are the two structural isomers have been known, but studies shows that the 4-isomers is most common ([Figure 2]).

The first quinazolinones (1) found to be synthesized in 1860 from anthranilic acid and cyanogens, which results in 2-cyanoquinazolinone (2) and methaqualone (3)^[3] ([Figure 3]). It was found to be most well known synthetic quinazolinone drug, prominent for its sedative-hypnotic activity.^[4] Quinazolinone nucleus has attracted much interest because of a wide range of pharmacological activites like antitumor,^[5], ^[6], ^[7] anticonvulsant,^[8] antitubercular,^[9], ^[10] antiviral,^[11] anti-inflammatory,^[12] analgesics,^[13] antimicrobial,^[14] antihypertensive,^[15] antioxidant^[16] activities etc ([Figure 4]). Recently quinazolinone chemistry has got new direction due to some resemblance with folic acid. The synthesis of quinazolinones is mainly cyclisation from bifunctional intermediates

In light of the growing number of applications in recent years, there has been an enormous increase in the interest among biologists and chemists in their rapid synthesis and prominent therapeutic activity of quinazolinone derivatives. Manny marketed drugs are available which contain quinazolinone nucleus are tried to list in the study.^[17], ^[18] ([Table 1]).

Chemistry of quinazolinones

Chemistry of quinazolinone is regarded as well-known region in synthesis, although still many novel and multifaceted variants of quinazolinone structures are needed to be discovered. When its structure was studied it was found that there is a lactam-lactam tautomeric interaction. This interaction also seen when 4(3H)-quinazolinone is with a methyl moiety present in 3^rd position and projected for chlorination with POCl3. It was observed that methyl group get lost and chlorination goes on. Further it was seen, when the methyl group is in 2^nd position, this tautomeric effect get exceeded resulting in an exo methylene carbon. It causes increase in the reactivity of the substituted 4-(3H)- quinazolinones. Therefore, quinazolinones are known to be a “fortunate structure” for drug discovery and development f newer pharmaceuticals ([Figure 5] ). In continuation with SAR studies of the moiety, it shows that the 2^nd, 6^th and 8^th position of the ring are very much imperative for the pharmacological studies. It is also suggests, physicochemical properties could be augmented by the inclusion of diverse heterocyclic moieties to 3^rd position of the ring. ^[17]

Quinazolinone derivatives are elevated melting crystalline products, which are generally insoluble in water and organic solvents but found to be soluble in alkali (aq) and sometimes in concentrated acids like 6N hydrochloric acid. They used to form stable salts of mono-hydrochlorides, chloro-platinate, chloro-aurates and picrates also their metal salts like silver, mercury, zinc, copper, sodium and potassium.^[19]

Methods for the synthesis of quinazolinone­­­

Very common synthetic method for quinazolinone is through condensation of anthranillic acid with amides / primary amines.

Niementowski’s synthesis

It gives 3,4-dihydro-4-oxoquinazoline when substituted formamide reacts with anthranilic acid at 125-130 C.^[20], ^[21], ^[22], ^[23], ^[24]

Grimmel, Guinther and Morgans’s synthesis

It results in disubstitued 3,4-dihydro-4-oxoquinazolines when ortho-amino benzoic acids, heated with amine and phosphorous trichloride.^[25]

Sen and Ray’s synthesis

It results in 2-propyl / 2-isopropyl-3,4-dihydro-4-oxoquinazolines when a solution isobutyrylanilides heated with urethane and phosphorous pentaoxide.^[26]

Synthesis from Anthranilic acid and urea

It results in 1,2,3,4-tetrahydro-2,4-dioxo-quinazoline when anthranilic acid fused with urea.^[26]

Synthesis from Isatins

It forms dioxoquinazoline and its derivatives when β-imino compounds heated with hydrogen peroxide in alkaline solution.^[26]

Synthesis from Benoxazones

Here benoxazones compounds reacts with primary amines and resuo form 3,4-dihydro-4-oxoquinazolines.^[26], ^[27]

Synthesis from Ureido-benzoic Acid

Here ureido-benzoic acids are synthesised from anthranilic acid with potassium cyanate by heating with acid /alkali.^[28]

From Phthalic Acid and its Derivatives

Phthalimide reacts with alkali hypobromite to form 1,2,3,4-tetrahydro-2,4-dioxoquinazoline.^[28]

S. No	Drugs	Activity	REF
1	Afloqualone	Sedative & Hypnotic, Anticancer Activity, Anti-anxiety	44,45
2	Cloroqualone	Sedative Activity & Antitussive Activity
3	Albaconazole	Antifungal Activity	40
4	Balaglitazone	PPAR- Gamma-agonist Activity, antidiabetic Activity	41
5	Diproqualone	Anxiolytic Activity, Analgesic, Antihistamine Activity & Used in Rheumatoid arthritis	42
6	Etaqualone	Anti-depressant Activity	43
7	Fluproquazone	Antipyretic activity, Used as NSAID	50,51
8	Halofuginone	Antitumor Activity, Used in Autoimmune disorders	46,47
9	Isaindigotone	Acetylcholinesterase Activity	48
10	Ispinesib	Anticancer Activity	49
11	Methaqualone	Hypnotic Activity	29
12	Nolatrexed	Anticancer Activity & Thymidylate synthase inhibitor Activity,	30
13	Piriqualone	Anticonvulsant Activity	31
14	Quinethazone	Antihypertensive Activity	32
15	Raltitrexed	Anticancer Activity	33
16	Tiacrilast	Antiallergic Activity	34
17	Rutaecarpine	Alzheimer Activity	35
18	Proquazone	NSAID Activity	36
19	Fabrifugine	Antimalarial Activity	37
20	Evodiamine	Anticancer	38
21	Fenquizone	Diuretic	39

Table 1 Tabular description of some quinazolinone nucleus containing marketed drugs with pharmacological activity

References

1. D He. Pharmaceutical prospects of naturally occurring quinazolinone and its derivatives. Fitoterapia 2017. [Google Scholar]
2. H Kikuchi. Synthesis of febrifugine derivatives and development of an effective and safe tetrahydroquinazoline-type antimalarial. Eur J Med Chem 2014. [Google Scholar]
3. Wlf Armarego. . A text book of quinazolines 1963. [Google Scholar]
4. K Kavitha, Nehla Yahoob, B Vijayakumar, K Reshma Fathima. Synthesis and Evaluation of Quinazolinone Derivatives. Asian J Res Chem 2017. [Google Scholar]
5. O Prasad. Development of certain novel N-(2-(2-(2-oxoindolin-3-ylidene) hydrazinecarbonyl)phenyl)-benzamides and 3-(2-oxoindolin-3-ylideneamino)-2-substitued quinazolin-4(3H)-ones as CFM-1 analogs: design, synthesis, QSAR analysis and anticancer activity. Eur J Med Chem 2015. [Google Scholar]
6. M Mahdavi. Synthesis and anticancer activity of N-sunstituted-2-arylquinazolinonones bearing trans-stilbene scaffold. Eur J Med Chem 2015. [Google Scholar]
7. S Yin. Design, synthesis and biological activities of novel oxazolo [4,5-g]quinazolin-2(1H)-one derivatives as EGFR inhibitors. Eur. J. Med. Chem 2015. [Google Scholar]
8. M. Zayed, M. Hassan. Design, Synthesis and Biological Evaluation Studies of Novel Quinazoline Derivatives as Cytotoxic Agents. Drug Res 2013. [Google Scholar]
9. Shashikant R. Pattan, V. V. Krishna Reddy, F. V. Manvi, B. G. Desai, A. R. Bhat. Synthesis of N-3[4-(4-Chlorophenyl) thiazole-2-yl]-2-(aminomethyl)quinazoline-4(3H)-one and Their Derivatives for Antitubercular Activity.. ChemInform 2006. [Google Scholar]
10. P Nandy. Synthesis and antitubercular activity of mannich bases of 2-methyl-3H-quinazolin-4-ones. Indian J Heterocycle Chem 2006. [Google Scholar]
11. V Pandey. Synthesis and antiviral activity of quinazolinyl syndones. Indian J Heterocycle Chem 2006. [Google Scholar]
12. M Azab. Synthesis, antimicrobial and anti-inflammatory activity of some new benzoxazinone and quinazolinone candidates. Chem Pharm Bull 2016. [Google Scholar]
13. P Pawar. Microwave assisted synthesis and analgesic screening of some thiazolyl quinazolinone. Int J Sci Dev Res 2019. [Google Scholar]
14. B Mistry. Synthesis and antimicrobial activity of newer quinazolinones. E-J Chem 2006. [Google Scholar]
15. K Wang. Studies on quinazolines and 1,2,4-benzothiadiazine 1,1-dioxides. 8.1,2 synthesis and pharmacological evaluation of tricyclic fused quinazolines and 1,2,4-benzothiadiazine-1,1-dioxides as potential alpha 1-adrenoceptor antagonists. J Med Chem 1998. [Google Scholar]
16. H Hasan. Microwave synthesis, characterization and antioxidant activity of new dihydrobenzimidazoquinazoline compounds. IQSR J Appl Chem 2018. [Google Scholar]
17. R Chakraborty. Implication of quinazolin-4(3H)-ones in medicinal chemistry: A Brief Review. Journal of Chemical Biology & Therapeutics 2015. [Google Scholar]
18. T P Selvam, V A Kumar. Quinazoline marketed drugs- A review. Res Pharm 2011. [Google Scholar]
19. A Rashmi. Quinazolinone: An overview. Int Res J Pharm 2011. [Google Scholar]
20. St. Von Niementowski. Synthesen von Chinazolinverbindungen. J Praktische Chem 1894. [Google Scholar]
21. J R Feldman, E Wagner. Some reactions of methylene-bis-amines as ammono-aldehydes. J Org Chem 1942. [Google Scholar]
22. Margaret M. Endicott, Emily Wick, Marie L. Mercury, Mary L. Sherrill. Quinazoline Derivatives.1 I. The Synthesis of 4-(4'-Diethylamino-1'-methylbutyl-amino)-quinazoline (SN 11,534) and the Corresponding 2-Phenylquinazoline (SN 11,535)2. J Am Chem Soc 1946. [Google Scholar]
23. A Grelardb. Efficient modified von niementowski. Tetrahedron Lett 2001. [Google Scholar]
24. Valérie Bénéteau, Thierry Besson. Synthesis of novel pentacyclic pyrrolothiazolobenzoquinolinones, analogs of natural marine alkaloids. Tetrahedron Lett 2001. [Google Scholar]
25. J Cossy, C Pale-Grosdemange. Convenient synthesis of amide from carboxylic acids & primary amines. Tetrahedron Lett 1989. [Google Scholar]
26. M Asif. Chemical characteristics, synthesis methods, and biological potential of quinazoline and quinazolinone derivatives. Int J Med Chem 2014. [Google Scholar] [Crossref]
27. E Hashem Hebe. Synthesis of quinazoline and quinaolinone derivatives. . [Google Scholar] [Crossref]
28. B Vijaykumar, B Prasanthi. Quinazoline derivatives & pharmacological activites review. Int J Med Chem Anal 2013. [Google Scholar]
29. J Lee. Bioavailability of methaqualone. J Clin Pharmacol 1973. [Google Scholar]
30. A Bowman. A phase I study of the lipophilic thymidylate synthase inhibitor thymilaq (nolatrexed dihydrochloride) given by 10-day oral administration. Br J Cancer 1999. [Google Scholar]
31. K Minor. Enhancement of benzodiazepine binding by methaqualone and related quinazolines. Drug Dev Res 1986. [Google Scholar]
32. E Cohen. A new class of diuretic agents. J Am Chem Soc 1960. [Google Scholar]
33. F Balis. The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (Tomudex) in a nonhuman primate model. Cancer Chemother Pharmacol 1999. [Google Scholar]
34. Ann F. Welton, Alan W. Dunton, Bonnie McGhee. The pharmacological profile and initial clinical evaluation of tiacrilast (Ro 22-3747): a new antiallergic agent. Agents Actions 1986. [Google Scholar]
35. M Decker. Novel inhibitors of acetyl and butyrylchloinesterase derived from the alkaloids dehydroevodiamine and rutaecarpine. Eur J Med Chem 2005. [Google Scholar]
36. S Mohri. Research and development of synthetic processes for pharmaceuticals: pursuit of rapid, inexpensive, and good processes. J Synth Org Chem 2001. [Google Scholar]
37. Mclaughlin. Dihydroxylation of vinyl sulfones: Stereoselective synthesis of (+) - and (-)- febrifugine and halofuginone. J Org Chem 2010. [Google Scholar]
38. Y Kobayashi. Capsaicin-like anti-obese activities of evodiamine from fruits of Evodiarutaecarpa, a vanilloid receptor agonist. Planta Med 2001. [Google Scholar]
39. J Foy. On the pharmacological actions of a diuretic, fenquizone, with particular reference to its site of action. J Pharm Pharmacol 1981. [Google Scholar]
40. L Sorbera. Albaconazole antifungal. Drugs Future 2003. [Google Scholar]
41. K Henriksen. A comparison of glycemic control, water retention, and musculoskeletal effects of balaglitazone and pioglitazone in diet-induced obese rats. Eur J Pharmacol 2009. [Google Scholar]
42. B Audeval. Comparative study of diproqualone-ethenzamide versus glafenine for the treatment of rheumatic pain of gonarthrosis and coxarthrosis. Gazette Medicale de France 1988. [Google Scholar]
43. S Parmar. Role of alkyl substitution in 2,3-disubstituted and 3-substituted 4-quinazolones on the inhibition of pyruvic acid oxidation. J Med Chem 1969. [Google Scholar]
44. T Ochial. Pharmacological studies on 6-amino-2-fluoromethyl-3-(O-tolyl)-4(3H)-quinazolinone (afloqualone), a new centrally acting muscle relaxant. (II) Effects on the spinal reflex potential and the rigidity. Jpn J Pharmacol 1982. [Google Scholar]
45. K Chen. In silico design, synthesis and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase-mediated cancer diagnosis and therapy. Mol Cancer Ther 2006. [Google Scholar]
46. M Jonge De. Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours. Eur J Cancer 2006. [Google Scholar]
47. M. S. Sundrud, S. B. Koralov, M. Feuerer, D. P. Calado, A. E. Kozhaya, A. Rhule-Smith. Halofuginone Inhibits TH17 Cell Differentiation by Activating the Amino Acid Starvation Response. Sci 2009. [Google Scholar]
48. J Tan. Isaindigotone derivatives : a new class of highly selective ligands for telomeric G-quadruplex DNA. J Med Chem 2009. [Google Scholar]
49. S P Blagden, L R Molife, A Seebaran, M Payne, A H M Reid, A S Protheroe. A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer 2008. [Google Scholar]
50. W Mohing. Comparative study of fluproquazone in the management of post-operative pain. Arzneimitlelforschung 1981. [Google Scholar]
51. D Whealtey. Analgesic properties of fluproquazone. Rheumatol Rehabil 1982. [Google Scholar]