Quinazolines biologically active

Many quinazolines possessing a wide variety of biological activities are known. The antimalarial activity of febrifugine spurred the preparation and testing of a number of quinazolines, and several 

Wfeelogle, Survey of Antimalarial Drugs 1941-46. Edward Brothers, Ann Arbor, Michigan, 1946. 

Several 2,3-disubstituted-4(3/f)quinazolinones were active against Plasmodium gallinaceum and showed antiinflammatory action on experimental edemas in animals. 6-(m-Amidinophenyldiazoamino)- 

4-amino-l -dimethylquinazolinium chloride hydrochloride (58) was found very effective against the protozoan parasite Babesia cards. 

Amino- and hydrazino-quinazolines exhibited antibacterial ac-tivity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was rnade. The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by. 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines.  

A vast number of quinazolines have been synthesized for biological screening, and a variety of activities were observed. Several derivatives are being used clinically. Space does not permit a discussion of all the available literature, and only the various biological activities will be listed together with the respective structures. A few of the many references for each activity are provided, and Chemical Abstracts should be consulted for further references. Much of the data are in the Patent literature. 

There was continuing interest in the effects of 3-arylquinazolin-4-ones on the central nervous system (CNS) which resulted from the known activity of methaqualone (117 Ar = o-tolyl R = Me R = H). A most extensive literature is available on the metabolism, pharmacology, and analytical chemistry of methaqualone. The effects of varying the group R on CNS-depressant activity were reported. The structure 117 was associated with CNS-depressant and tranquilizing activities, and 3-o)-aminoalkyl- 

2-dihydro- and 2,3-polymethylene-quinazolin-4-ones also possessed activity toward the CNS. 4-Substituted aminoquinazolines (antidepressants and stimulants) and 4,4-dimethyl-3,4-dihydroquinazolin-2(l//)-ones (anticonvulsants) had CNS activity. 3-c/ -Aminoalkyl- and 2-substi-tuted quinazolin-4-ones ° and thiones/ 2,4-diaminoquinazo-lines, 3-ethoxycarbonylmethyl-3,4-dihydroquinazolin-2(lW)-ones, and 2,3-dihydroimidazo[l,2-c ]quinazolines possessed hypotensive activity. 

The analgesic (5-ethoxy-2--dimethylaminomethyl-3-methylquinazoIin-4-one and 4,2 -thienyIquinazolines ), antithrombic and anticoagulant (2-vinyl-l,4-dihydroquinazolines), and antifibrillatory (l-aminoacyl-1,2-dihydroquinazolin-4-ones) action of quinazoline derivatives were patented, and 2-phenoxycarbonyloxymethyl-3-substituted-quinazolin-4-ones were potentially useful drugs for the treatment of arteriosclerosis. The effects of Quinazodine (118) as a cardiac stimulant and its hemodynamic 

Bernard , A. Bonsignori, S. Coda, and G. K. Suctiowsky, German Patent 1,958,515 

Many more l,2-dihydroquinazolin-4-ones with the general structure 119 were tested for diuretic activity in attempts to improve on the activity of Quinethazone. 284 

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The present review covers the literature to the end of 1967 and all original sources have been consulted. Syntheses of each of the four ring systems are summarized separately, but physical, chemical, and biological properties are considered generally. Many pjTidopyri-midines were initially synthesized for a study of biological activity or physical properties because of the close structural relationship of these systems to the quinazolines (5) and pteridines (6). Recent reviews have discussed these related compounds. 

It should be also noted that, in a very recent publication, Liu and coworkers were successful in applying microwave radiation within their domino approach towards the synthesis of pyrrolo[2,l-fc]quinazoline alkaloids such as deoxyvasicinone, 8-hy-droxydeoxyvasicinone, mackinazolinone and isaindigotone, which exhibit a promising broad spectrum of biological activities. In the case of isaindigotone, the authors were able to extend their strategy to a three-component procedure, which comprises the domino conversion of anthranilic acids and Boc-protected amino acids into the tricyclic core skeleton [43]. 

Quinazolines have become increasingly important as biologically active principles, e.g., as antiseptics or antimalarials. An interesting approach to this class consists of a combination of the aza-Wittig reaction with photochemical processes, as shown in Scheme 76. o-Azidocinnamates (206) are cyclized with the aid of triethyl phosphite to afford 2-alkoxyquinolines... 

Quinazoline alkaloids are known as biologically active compounds. Arborine inhibits the peripheral action of acetylcholine and induces a fall in blood pressure. Febrifugine is an anti-malarial agent and vasicine acts as a uterine stimulant. Glomerin and homoglomerin are alkaloids of the defensive system in some organisms (e.g., in the glomerid millipede). 

Taking the number of references as a measure of how extensively the synthesis of the title compounds were studied, one may conclude that great efforts have been directed towards this goal. This may plausibly be rationalized in terms of academic interests as well as diverse biological activities attributed to these compounds. Nevertheless, much remains to be accomplished regarding the synthesis of many of the possible, but unprepared, heterocyclo[n,m-a,b, or c]quinazolines. 

Volume 52 of Advances in Heterocyclic Chemistry comprises three chapters. M. A. E. Shaban, M. A. M. Taha, and E. M. Sharshira have systematically reviewed those tri-ring systems in which another heterocyclic ring is fused onto the pyrimidine ring of quinazoline. No previous survey is available for these compounds, many of which show significant biological activity. 

The quinazoline moiety is present in a variety of biologically active compounds that are known to interact with G-protein-coupled receptors and enzymes [177-181]. In addition, quinazolines are often used as tyrosine kinase inhibitors... 

Various biological activities were found in the following derivatives 2,4-bis(dialkylaminoalkyl)quinazolines (curare mimetics), l-((o-dimethyl-aminoalkyl)-3-substituted quinazoline-2,4-diones (inhibition of gastric secretions), 4-alkoxycarbonylmethylthioquinazolines (radioactivity protecting agents), and 2-amino-6-hydroxymethyl(or formyl)quinazolin-4-ones (xanthine oxidase inhibitors). ... 

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