Synthesis of 2, 3-disubstituted-Quinazolin-4-(3H)-ones

The present review covers a concise account of the synthesis of bioactive 2, 3-disubstituted-quinazoline-4(3H)-ones and the recent developments in the area of versatile quinazolinones with a special emphasis on new synthetic routes and strategies.     

Thromboxane synthetase inhibitors and antihypertensive agents. 4. N-[(1H-imidazol-1-yl)alkyl] derivatives of quinazoline-2,4(1H,3H)-diones, quinazolin-4(3H)-ones, and 1,2,3-benzotriazin-4(3H)-ones

The quinazolinedione, quinazolinone, and 1,2,3-benzotriazinone title compounds were prepared as analogues of N-[(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-diones which were the subject of a previous report from our laboratories. These compounds were evaluated as thromboxane (TX) synthetase inhibitors and as antihypertensive agents. While each series of compounds had activity both as TX synthetase inhibitors and as antihypertensives, the best compounds were N-[(1H-imidazol-1-yl)alkyl]quinazoline-2,4(1H,3H]-diones (V). In general these compounds were all selective enzyme inhibitors at least equipotent with the standard dazoxiben. These compounds were also very active antihypertensive agents as determined in SHR. The SAR is discussed for both types of activity. Compound 20a was further evaluated for TX formation inhibiting properties in several other platelet types both in vitro and ex vivo and is between 100 and 1000 times more potent than dazoxiben.     

2-(4-氯-3-甲基苯基)-1,2,4-三嗪-3,5(2H,4H)-二酮的合成

对硝基邻甲苯胺经重氮化、氯代、还原、闭环、水解、脱羧6步反应得到2-（4-氯-3-甲基苯基）-1,2,4-三嗪-3,5（2H,4H）-二酮,总收率约40%。     

Synthesis and antiproliferative activity of novel 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives.

Several new 3-(indazol-3-yl)-quinazolin-4(3H)-one and 3-(indazol-3-yl)-benzotriazin-4(3H)-one derivatives 5 and 6 were synthesized and tested for their in vitro antiproliferative activity against Raji, K562, and K562-R cell lines. The pharmacological screening showed that some 2, 6, or 7-substituted quinazolinones 5 posses a significant antiproliferative activity, with a percentage growth inhibition ranging from 44.8% to 100% at 50 microM, which was higher than that showed by the unsubstituted derivative 5a previously synthesized. For the most active compounds 5d, 5f, and 5g the IC50 were recorded.     

Darstellung,Kristallstruktur und Wirkung von 2-Methyl-3-(4-oxo-3-phenyl-thiazolidin-2-ylidenamino)-4-(3H)-chinazolinon

Quinazolinones, I: Preparation, Crystal Structure, and Activity of 2-Methyl-3-(4-oxo-3-phenylthiazolidine-2-ylidenamino)-4(3H)-quinazolinone The cyclisation of 1-(3,4-dihydro-2-methyl-4-oxo-3H-quinazoline-3-yl)-3-phenylthiourea (2) with chloroacetic acid leads to 2-methyl-3-(4-oxo-3-phenyl-thiazolidine-2-ylidenamino)-4(3H)-quinazolinone (3) and not to the isomer 4 . The crystal structure of 3 has been determined and refined until R = 0.0715. Compound 3 possesses good hypnotic and anticonvulsant activities.     

Design, synthesis and antihistaminic (H1)activity of some condensed 2-(substituted)arylaminoethylpyrimidin-4(3H)-ones

The synthesis and potential H1 receptor antagonistic activity of two novel series of condensed 2-arylaminoethylpyrimidin-4(3H)-ones (4, 5) and 4-amino-2-arylaminoethyl pyrimidines (6) have been reported. All the novel compounds were found to antagonize histamine in a competitive and reversible manner. When tested on guinea-pig ileum, compounds exhibited H1-antagonistic activity, (pA2 values) in the range of 8.6 to 9.7. Some of the lead compounds were evaluated by an in vivo method and were found to protect the guinea pigs against the histamine induced asphyxic shock at the doses comparable to or lower than those of the standard drugs, cetirizine (CAS 83881-51-0) and terfenadine (CAS 50679-08-8). The pA2 acetylcholine values of some of the lead compounds reflect about 1000-fold selectivity for histamine (H1) receptors. The 4-aminopyrimidines (6) were found to be more selective than their 4-one analogs (4, 5). In the radioligand binding study, one of the lead compounds, 6e, was found to bind reversibly at the histamine H1 receptor with the K1 value of 1.3 mumol/l and IC50 of 3.8 mumol/l. The lead compounds were found to have negligible sedative potential when tested in vivo. An indirect type of molecular modeling approach, using temelastine (CAS 86181-42-2) as the standard ligand, indicates that the potent activity of 4, 5 and 6 may be due to the increased spacer chain length between the pyrimidine nucleus and the side-chain aromatic ring.     

Synthesis of 3H, 2H4, and 14C‐MK 3814 (preladenant)

MK 3814 is a potent and selective antagonist of the A_2a receptor. A_2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [³H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [¹⁴C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [²H₄]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method. This paper discusses the synthesis of 3 isotopically labelled forms of MK 3814.     

Synthesis and analgesic, anti-inflammatory activities of 3-(3-methoxyphenyl)-2-substituted amino-quinazolin-4(3H)-ones

A variety of novel 3-(3-methoxyphenyl)-2-substituted amino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(3-methoxyphenyl)-quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(3-methoxyphenyl)-quinazolin-4(3H)-one was synthesized from 3-methoxy aniline. The title compounds were investigated for analgesic, anti-inflammatory, and ulcerogenic behavior. Among these the compound 2-(1-methyl butylidene-hydrazino)-3-(3-methoxyphenyl)-3H-quinazolin-4-one (AS3) emerged as the most active compound for the analgesic activity, while the compound 2-(1-ethyl propylidene-hydrazino)-3-(3-methyoxyphenyl)-3H-quinazolin-4-one (AS2) showed most potent anti-inflammatory activity of the series and these compounds are moderately more potent when compared to the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid.     

Synthesis of 3H, 2H4 and 14C‐SCH 417690 (Vicriviroc)

Vicriviroc or SCH 417690 is a potent and selective antagonist of the CCR5 receptor. CCR5 receptor antagonists have the potential for the treatment of HIV infections. Four distinct isotopically labelled forms of SCH 417690 were synthesized. Low specific activity [³H]SCH 417690 was prepared for a preliminary absorption, distribution, metabolism and excretion evaluation of the compound and [¹⁴C]SCH 417690 for more definitive absorption, distribution, metabolism and excretion work, including an absorption, metabolism and excretion study in man. In addition, high specific activity [³H]SCH 417690 was prepared for CCR5 receptor binding work and [²H₄]SCH 417690 was prepared as an internal standard for a liquid chromatography–mass spectrometry bioanalytical method. The paper discusses the synthesis of four isotopically labelled forms of SCH 417690.     

Synthesis,SAR Study and Evaluation of Mannich and Schiff Bases of Pyrazol-5(4H)-one Moiety Containing 3-(Hydrazinyl)-2-phenylquinazolin-4(3H)-one

In the present investigation, a series of 12 Mannich bases (QP1-12) and 5 Schiff bases (QSP1-5) of pyrazol-5(4H)-one moiety containing 3-(hydrazinyl)-2-phenylquinazolin-4(3H)-one has been synthesized and characterized by physicochemical as well as spectral means. The synthesized Mannich and Schiff bases were screened for their preliminary antimicrobial activity against Gram-positive and Gram-negative bacterial as well as fungal strains by the determination of zone of inhibition. Mannich bases (QP1-12) were found to be more potent antibacterial agents against Gram-positive bacteria, whereas Schiff bases (QSP1-5) were more potent against Gram-negative bacteria and fungi. Minimum inhibitory concentration result demonstrated that Mannich base compound (QP7) having ortho -OH and para -COOH group showed some improvement in antibacterial activity (minimum inhibitory concentration of 48.88×10⁻³ μM/ml) among the tested Gram-positive organisms and it also exhibit minimum inhibitory concentration of value of 12.22×10⁻³ μM/ml for Klebsiella pneumoniae. The antitubercular activity of synthesized compounds against Mycobacterium tuberculosis (H₃₇Rv) was determined using microplate alamar blue assay. Compound QP11 showed appreciable antitubercular activity (minimum inhibitory concentration of 6.49×10⁻³ μM/ml) which was more active than the standard drugs, ethambutol (minimum inhibitory concentration of 7.60×10⁻³ μM/ml) and ciprofloxacin (9.4×10⁻³ μM/ml). Compounds QP11, QP9, QSP1, QSP2, and QSP5 have good selective index and may be selected as a lead compound for the development of novel antitubercular agents.     

Researches on antiinflammatory agents. Studies on some new 3-(pyrazol-5-yl)-1,2,3-benzotriazin-4(3H)-ones and -quinazolin-4(3H)-ones

Following our research on analgesic and antiinflammatory active compounds containing the pyrazole nucleus, a number of 3-(pyrazol-5-yl)-1,2,3-benzotriazin-4(3H)-ones and quinazolin-4(3H)-ones was synthetized and tested. The results of tests for analgesic, antiexudative and antioedema activities, as well as for induction of lesion in the gastric mucosa, are reported and discussed.     

Design,synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents

In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides ( 5 ), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure–activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.     

Pharmacological studies on quaternized 4(3H)-quinazolinones.

Locomotor activity-inhibiting, anticonvulsant, muscle relaxant, analgesic, and antimicrobial properties of 2-methyl-3-pyridinium-acetylamino-4(3H)-quinazolinone chloride (1), 2-methyl-3-(4-methylpyridinium)acetylamino-4(3H)-quinazolinone chloride (2), 2-methyl-3-(4-ethylpyridinium)acetylamino-4(3H)-quinazolinone chloride (3), 2-methyl-3-(3-carboxamidopyridinium)acetylamino-4(3H)-quinazolinon e chloride (4), and 2-methyl-3-(4-carboxamidopyridinium)-acetylamino-4(3H)- quinazolinone chloride (5) were investigated. The locomotor activity-inhibiting properties and anticonvulsant activity of 2 were almost equal to those of methaqualone. The analgesic activities of 2 and 3 in the hot-plate test were equal to that of aspirin, whereas in the Koster test, the analgesic activity of 2 was higher. The compounds did not exhibit antimicrobial or muscle relaxant properties. Most active compounds had higher lipophilicity values than those of inactive compounds.