Synthesis and pharmacological study of some 3-(isoxazol-5-yl)-quinazolin-4(3H)-ones.

A number of new 3-(isoxazol-5-yl)-quinazolin-4(3H)-ones was prepared and tested, together a few analogues previously obtained, for their analgesic, antipyretic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effects. In the carrageenan rat foot edema model one of the tested compounds showed activity and LD50 comparable to that of ASA, but the ulceration index approximated zero value.     

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.     

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.     

Researches on antiinflammatory agents. Studies on some 1-methyl- or 1-phenyl-6-(2-substitutedphenyl)-pyrazolo[3,4-d]-1,3-oxazin-4(1H)-ones.

Following our research on analgesic and antiinflammatory active compounds containing the pyrazole nucleus, a number of new 1-methyl- or 1-phenyl-6-(2-substitutedphenyl)-pyrazolo[3,4-d]-1,3-oxazin- 4(1H)-ones was synthesized and tested, together with a few analogues previously obtained, for their analgesic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effects. One of the tested compounds showed activity comparable to that of phenylbutazone and, at the same time, higher LD50 and a very low ulceration index.     

5-Acyl-3-substituted-benzofuran-2(3H)-ones as potential antiinflammatory agents

A series of 5-acyl-3-substituted-benzofuran-2(3H)-ones and their respective ring-opened o-hydroxy acids were synthesized. The antiinflammatory activity was evaluated in terms of their ability to improve adjuvant induced arthritis in rats. Their effect on the production of both cyclooxygenase (CO) and lipoxygenase (LO) metabolites of arachidonic acid in guinea pig peritoneal polymorphonuclear neutrophils (PMNs) was also examined. No correlation between the antiinflammatory activity and increasing stability of the lactones could be found. The degree of activity in general shown by the benzofuranones was similar to that of their corresponding o-hydroxy acids. This, coupled with the evidence from studies on opening of the lactone ring, suggests an in vivo transformation of the former into the latter. Benzofuranones displayed a dual inhibition of CO and LO products, while a moderate reduction in CO metabolites was shown by their acids.     

Synthesis and antileukemic activity of new 3-(5-methylisoxazol-3-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones

3-(3-Methylisoxazol-5-yl) and 3-(pyrimidin-2-yl)-2-styrylquinazolin-4(3H)-ones 8a-l and 9a,c-e,h-l were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 6 and 8 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 8a-l and 9a,c-e,h-l were tested in vitro for their antileukemic activity against L-1210 (murine leukemia), K-562 (human chronic myelogenous leukemia) and HL-60 (human leukemia) cell lines showing in some cases good activity.     

Synthesis and pharmacological evaluation of some 3-(2-methylphenyl)-2-substituted amino-quinazolin-4(3H)-ones as analgesic and antiinflammatory agents

A variety of novel 3-(2-methylphenyl)-2-substituted amino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 2-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one was synthesized from 2-methyl aniline. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. Among these, the compound 2-(1-ethylpropylidene)-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one emerged as the most active compound for analgesic activity, while the compound 2-(1-methylbutylidene)-hydrazino-3-(2-methylphenyl)-quinazolin-4(3H)-one showed most potent anti-inflamma-tory activity of the series and was moderately more potent in its anti-inflammatory activity when compared to the reference standard diclofenac sodium (CAS 15307-86-5). Interestingly, the test compounds showed only mild ulcerogenic potential when compared to acetylsalicylic acid (CAS No: 50-78-2).     

Synthesis and antileukemic activity of new 3-(1-phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones

3-(1-Phenyl-3-methylpyrazol-5-yl)-2-styrylquinazolin-4(3H)-ones 14a-q and 15a-q were synthesized by refluxing in acetic acid the corresponding 2-methylquinazolinones 12 and 13 with the opportune benzoic aldehyde for 12 h. The synthesized styrylquinazolinones 14a-q and 15a-q were tested in vitro for their antileukemic activity against L1210 (murine leukemia), K562 (human chronic myelogenous leukemia) and HL60 (human leukemia) cell lines showing in some cases good activity.     

Design and synthesis of some new quinazolin-4-(3H)-ones as anticonvulsant and antidepressant agents

A series of 3-[(4-substituted-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-ones (5a–k) were synthesized by reacting 3-amino-2-phenyl-1H-quinazolin-4-one with p-hydroxybenzaldehyde, and then further with various alkyl/benzyl halides or substituted phenacyl bromides. The structures of the compounds were confirmed on the basis of IR, NMR, MS and elemental analysis. Anticonvulsant activities were evaluated using the MES and scPTZ tests. Some of the selected compounds were evaluated for antidepressant activity by forced swim pool test. Compound 3-[(4-butoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one was emerged as the most promising anticonvulsant agent without any motor impairment effect. The whole brain GABA estimation of brain homogenate indicated that the anticonvulsant activity of above mentioned quinazolinone derivatives might be due to an increased GABA concentration.     

Dimeric 2-(2-chlorophenyl)-quinazolin-4-ones as potential antimicrobial agents

3-(Aryl)-2-(2-chlorophenyl)-6-{2-[2-(2-chlorophenyl)-4-oxo(3-hydroquinazolin-3yl)]ethyl}-3-hydroquinazolin-4-ones had been selected as target bio-active molecules. Several quinazoline derivatives were prepared by using anthranilic acid, acid chloride, 2-amino-ethanol, and different amines. Newly synthesized compounds were screened for their antibacterial and antifungal activities on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus pyogenes, Candida albicans, Aspergillus niger, and Aspergillus clavatus. The compounds 5e, 5g, and 5h are shown to have excellent activity, while 5c, 5d, 5i, 5k, 5l are shown to have very good activity against several strains of bacteria. The structures of the synthesized compounds were firmly established by well-defined spectral analysis techniques like IR, ¹H-NMR, ¹³C-NMR, and Mass spectra.     

Synthesis and pharmacological investigation of some novel 2-methyl-3-(substituted methylamino)-(3H)-quinazolin-4-ones as histamine H1-receptor blockers

A series of 2-methyl-3-(substituted methylamino)-(3H)-quinazolin-4-ones were synthesized from 3-amino-2-methyl-(3H)-quinazolin-4-one. Their structures were confirmed by spectral data (IR, NMR and MS) and the purity was ascertained by microanalysis. When tested for H1-receptor blocking activity on isolated guinea pig ileum all the test compounds inhibited histamine induced contraction whereas compound 5 (IC50 0.22 x 10(3) ng/ml) was found to be four times more potent than chlorpheniramine maleate (IC50 1 x 10(3) ng/ml) and it showed lesser sedation (8%) than the standard (32%).     

Synthesis and pharmacological activities of novel 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives

Several new 3-(isoxazol-3-yl)-quinazolin-4(3H)-one derivatives were synthesized and tested for their analgesic and antiinflammatory activities, as well as for their acute toxicity and ulcerogenic effect. A few compounds were as active as phenylbutazone in the writhing and acetic acid peritonitis tests. They had a very low ulcerogenic effect.     

Synthesis and pharmacological investigation of some novel 2,3-disubstituted quinazolin-4(3H)-ones as analgesic and antiinflammatory agents

A series of novel 2-substituted quinazolin-4(3H)-ones have been synthesized by condensing the aromatic primary amine of 2-substituted quinazolines with different aldehydes and ketones. The synthesized compounds were confirmed by their spectral data (IR, NMR and MS) and the purity was ascertained by elemental analysis. When these compounds were evaluated for analgesic and antiinflammatory activities, compounds I-VIII exhibited more potent analgesic activity than diclofenac sodium, while the compounds IV, V, VI and VII exhibited more potent antiinflammatory activity than diclofenac sodium. The activity values were found to be significant as compared to those of controls.     

New antiinflammatory agents. 2. 5-Phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones: a new class of nonsteroidal antiinflammatory agents with potent activity like glucocorticoids.

We previously described new antiinflammatory agents, 4-hydroxy-2-oxo-1-phenyl-1H-1,8-naphthyridine-3-carboxamides 1. Further modification of the compounds bearing 1-phenyl-1,8-naphthyridin-2-one as a mother skeleton led to 5-phenylimidazo[4,5-c][1,8]naphthyridin-4(5H)-one derivatives 2 and 3. Regioselective synthesis of these compounds bearing a substituent at the 1- or 3-position was conducted according to the method shown in Schemes I and II. In this series of compounds, antiinflammatory activities were greatly influenced by the position and nature of substituents on imidazole. 3-Alkyl or 3-benzyl substitution result in the potent activity, but 1-substitution did not. Minor modification of the benzyl group reduced or eliminated the activity. Detailed examination of structure-activity relationships led to 3-benzyl-5-phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (22), which exhibited potent oral antiinflammatory activities in carrageenan-, zymosan-, and reversed passive Arthus reaction-induced rat paw edemas (ED40 = 5.3, 0.37 mg/kg, ED50 = 0.47 mg/kg, respectively). This broad activity of 22 was like that of glucocorticoids. Compound 22 did not affect activities of CO and 5-LO enzymes and receptor binding of various ligands. As one of the mechanisms of action, induction of release of glucocorticoids was postulated. These results suggest that 22 represents a novel class of antiinflammatory agents.     

Synthesis of 6-substituted 2-phenyl-3-(5-substituted mercapto-1,3,4, thiadiazol-2-yl)quinazolin-4-(3H)-ones as antitubercular agents

2-Amino-5-mercapto-1,3,4-thiadiazole was condensed with various 6-substituted 2-phenylbenzoxazin-4 (3H)-ones to yield the compounds 1 . When these compounds were subjected to mercaptoetherification the title compounds 2–4 were obtained. They were screened for their antitubercular activity against Mycobacterium smegmatis and Mycobacterium tuberculosis H₃₇ Rv in vitro. Structure-activity relationships were established.     

Synthesis, antibacterial and antifungal activity of some novel 3-[5-(4-substituted phenyl) 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones

A series of novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones were synthesized and evaluated for antibacterial activity against pathogenic strains of Staphylococcus aureus (MTCC no. 96), Bacillus subtilis (MTCC no. 619), Pseudomonas aeruginosa (MTCC no. 424) and Escherichia coli (MTCC no. 40) and antifungal activity against Aspergillus niger, Candida albicans and Fusarium oxysporum. The cup-plate method was employed to determine the minimum inhibitory concentration (MIC) value of the compounds. Some of the compounds exhibited activity comparable to Norfloxacin. The present report reveals that synthesized 2-styryl-quinazoline-4(3H)-one exhibited better antibacterial than antifungal activity.     

Synthesis and antimicrobial activity of some new 3–[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2- styrylquinazoline-4(3H)-ones

Several 3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2-yl]-2-styryl quinazoline-4(3H)-one were synthesized and screened for antibacterial activity against Staphylococcus aureus , Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli and antifungal activity against Aspergillus niger and Fusariumoxysporum by the serial dilution technique. Compounds were prepared by reacting corresponding 2-methtyl quinazolinone and 4-subustituted benzaldehydes in glacial acetic acid. Physicochemical and spectral data were consistent with newly synthesized compounds. The prepared compounds were compared with previously synthesized 2-methyl-3-[5-(4-substituted)phenyl-1,3,4-oxadiazole-2-yl]-quinazoline-4(3H)-ones for antimicrobial activity. The present study revealed that styryl moiety at the second position of 4(3H) quinazolinone marginally increased the biological activity and exhibited better antibacterial than antifungal activities.     

Cardiotonic agents. 3. Synthesis and biological activity of novel 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones

Several 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones were synthesized and evaluated for positive inotropic activity. The 1H-imidazol-4-yl regioisomers 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (25a) and 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (28a) were potent positive inotropic agents. By contrast, the corresponding 1H-imidazol-5-yl regioisomers 25b and 28b were only weak positive inotropic agents. Compounds 25a and 28a were also potent inhibitors of cardiac phosphodiesterase fraction III.