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At least 19 recordsLinked to original sources
PubMed2000

Synthesis and antifungal activity of novel pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines, pyrido[2',3':4,5]thiazolo[2,3-b]quinazolines and pyrazolo[2',3':4,5]thiazolo[2,3-b]quinazolines.

The starting materials thiazolo[2,3-b]quinazolines (5a,b) were obtained in one pot synthesis by treating octahydroquinazoline (2) with chloroacetic acid and aromatic aldehydes. Thiazoloquinazoline (5) was reacted with CH2(CN)2/piperidine and CH2(CN)2/NaOH (CH3OH), to furnish pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines (6a,b) and pyrido[2',3':4,5]thiazolo[2,3-b]quinazoline (7), respectively. Refluxing of 5a with NH2CSNH2/KOH and hydrazines in ethanol furnished the corresponding, [1,3]thiazino[4'5':4,5]thiazolo[2,3-b]quinazoline (10) and pyrazolo[3',4':4,5]thiazolo[2,3-b]quinazolines (11a,b), respectively. Antifungal activity was shown for some of the synthesized compounds.

Antifungal Agents↗
PubMed1998

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 alpha1-adrenoceptor antagonists.

A series of 2-substituted methyl 2,3-dihydroimidazo[1, 2-c]quinazolin-5(6H)-ones (4), 3-substituted methyl 2, 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones (16a,b), 3-substituted methyl 2,3-dihydro-1H-imidazo[1,2-b][1,2, 4]benzothiadiazine 5,5-dioxides (33a,b), 2-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (42-45a,b), 3-substituted methyl imidazo[1,2-c]quinazolin-5(6H)-ones (50-53a,b), 3-substituted methyl 5H-thiazolo[2,3-b]quinazolin-5-ones (55-56a,b), and 3-substituted methyl 5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (57) were synthesized as compound 1conformational rigid congeners for pharmacological evaluation as potential alpha1-adrenoceptor antagonists. Compounds 4, 5, 33a,b, 44a,b, 45a,b, 52a,b, 53a,b, and 57 were found to possess high affinity for the alpha1-adrenoceptor. Compounds 5 and 57 were the most highly selective and potent alpha1 antagonists with Ki = 0.21 +/- 0.02 and 0.90 +/- 0.08 nM, respectively. The S-enantiomers of these two compounds (Ki = 0.13 +/- 0.01 nM for (S)-(-)-5; Ki = 1.0 +/- 0.2 nM for (S)-(+)-57) were 144-200-fold more potent than the R-enantiomers (Ki = 26 +/- 8 nM for (R)-(+)-5; Ki = 144 +/- 23 nM for (R)-(-)-57). Compound 4 showed 8-fold higher affinity to alpha1A-AR better than alpha1B-AR. These compounds possessed weak to no activity against the 5-HT1A receptor.

Adrenergic alpha-Agonists↗
PubMed2001

Synthesis, evaluation and structure-activity relationships of 5-alkyl-2,3-dihydroimidazo[1,2-c] quinazoline, 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-thiones and their oxo-analogues as new potential bronchodilators.

With an aim to obtain potent bronchodilators, two series of 5-alkyl-2,3-dihydroimidazo[1,2-c]quinazolines (Va-1), 2,3-dihydroimidazo[1,2-c]quinazolin-5-(6H)-thiones (VIIIa-d) and their oxo-analogues (IXa-d) have been designed. The compounds Va-1 were synthesized by two alternative routes. The former (Method A) based on the dehydrocyclization of 4-(1-hydroxyethyl)-aminoquinazoline (IV) and the latter (Method B) involves the usage of 2-aminobenzonitrile (VI) which on reaction with ethylenediamine leads to the formation of the key intermediate 2-(2-aminophenyl)-4,5-dihydro-1H-imidazoles (VII). Finally the intermediate VII on condensation with different acidanhydrides yielded the title compound V. In general method-A resulted the compound V in quantitatively higher yields. 2,3-Dihydroimidazo[1,2-c]quinazolin-5 (6H)-thiones (VIII) were obtained by condensing VII with carbon disulfide and a further oxidation of VIII gave their corresponding oxo-analogues (IX). The title compounds V, VIII and IX were evaluated for their bronchodilator activity using in vitro and in vivo (standard animal models) methods. All the test compounds exhibited bronchodilatory activity. The structure activity relationship studies indicated good correlation between the nature of the substituent and bronchodilatory activity. In the 5-alkyl substituted compounds V, a longer alkyl chain showed higher bronchodilatory activity. Compounds VIII and IX were found to be less potent and replacement of sulphur with oxygen showed no significant effect on the biological activity. The presence of halogens altered the biological activity in both the series. Among the compounds tested, 9-lodo-5-(n-propyl)-2,3-dihydroimidazo[1,2-c]quinazoline (VI) was found to be the most potent (percentage protection = 87.1%; relative activity = 1.1 compared to the standard aminophylline).

Animals↗
PubMed1993

Studies on quinazolines. 5. 2,3-dihydroimidazo[1,2-c]quinazoline derivatives: a novel class of potent and selective alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 2-[(substituted phenylpiperazin-1-yl)methyl]- and 2-[(substituted phenylpiperidin-1-yl)methyl]-2,3-dihydroimidazo[1,2- c]quinazolin-5(6H)-ones or -5(6H)-thiones, and 3-[(substituted phenylpiperazin-1-yl)methyl]-2,3-dihydroimidazo[1,2-c]quinaz oline derivatives were synthesized, as conformationally restricted analogues of SGB-1534 and ketanserin, for evaluation as alpha-antagonists and antihypertensive agents. Most compounds containing a (substituted phenylipiperazinyl)methyl side chain displayed high binding affinity for alpha 1-adrenoceptor with no significant activity at alpha 2-sites. Compounds having a (substituted phenylpiperazinyl)methyl at the 3-position of 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one ring system had a better activity than those with the same substituent at the 2-position. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented and indicate that compounds with substitution at the ortho position on the benzene ring of the phenylpiperazine side chain moiety are more potent than those without substitution and/or substitutions at the 3- and 4-positions. Computer-assisted superimposition of SGB-1534 and 20b showed little structural correspondence between the quinazolinone and 2,3-dihydroimidazo[1,2-c]quinazoline nucleus, and specific interactions of these molecular fragments with the receptor protein appear unlikely. Antihypertensive activity was evaluated via intravenous administration of each compound to spontaneously hypertensive rats, and compounds (16a, 16b, 20b, and 28b) illustrated similar efficacy to SGB-1534 when assessed after 6 h. The pA2 value for 16a against phenylephedrine in rat aorta was much higher than that of prazosin. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compounds 20b and 28b warrant further evaluation.

Adrenergic alpha-Antagonists↗
PubMed1979

Folate antagonists. 15. 2,3-Diamino-6-(2-naphthylsulfonyl)quinazoline and related 2,4-diamino-6-[(phenyl and naphthyl)sulfinyl and sulfonyl]quinazolines, a potent new class of antimetabolites with phenomenal antimalarial activity.

Oxidation of an array of 2,4-diamino-6-(arylthio)quinazolines provided the corresponding arylsulfinyl and arylsulfonyl analogues. A variety of these nonclassical analogues of methotrexate exhibited suppressive antimalarial activity superior to that of the parent thioquinazolines against drug-sensitive lines of Plasmodium berghei in mice and P. gallinaceum in chicks, and several displayed potent prophylactic activity against P. gallinaceum. The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine-, cycloguanil-, and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Coadministration of one of the most active of these compounds, 2,4-diamino-6-(2-naphthylsulfonyl)-quinazoline (35), with sulfadiazine to monkeys infected with P. falciparum of P. vivax led to greatly enhanced activity and prevented the development of quinazoline resistance.

Animals↗
PubMed1977

2,3-Dihydro-9H-isoxazolo[3,2-b]quinazolin-9-ones and 3,4-dihydro-(1,2)-oxazino [3,2-b]quinazolin-10(2H)-ones.

Two series of compounds, 2,3-dihydro-9H-isoxazolo[3,2-b]quinazolin-9-ones and 3,4-dihydro-(1,2)-oxazino-[3,2-b]quinazolin-10(2H)-ones, were synthesized and evaluated for anti-inflammatory, antipyretic and analgesic activity. The isoxazolo compounds were generally more active than their oxazino homologs. Three compounds, i.e., 2,3-dihydro-9H-isoxazolo [3,2-b]quinazolin-9-one (W-2429) and its 2- and 3-methyl congeners, were the most active of all compounds tested in this study. On the basis of the biological results herein reported, W-2429 is considerably more effective than acetylsalicylic acid in inhibiting carrageenan-induced edema and in reducing brewer's yeast-induced fever in rats. Also, it was found to be more potent than propoxyphene hydrochloride in the Randall-Selitto test for analgesic activity.

Animals↗
PubMed2003

Substituted quinazolines, part 2. Synthesis and in-vitro anticancer evaluation of new 2-substituted mercapto-3H-quinazoline analogs.

A new series of 2-substituted mercapto-3H-quinozolines bearing 6-iodo and 2-heteroarylthio functions was synthesized and screened for their in vitro antitumor activity. Eighteen compounds were identified as active anticancer agents. N'-[(3-Benzyl-4-oxo-6-iodo-3H-quinazoline-2-yl)thioacetyl]-N(3)-ethylthiosemicarbazide (10), N-benzoyl-N'-[2-(3-benzyl-4-oxo-6-iodo-3H-quinozolin-2-yl)thioacetyl]hydrazine (12), and 2-[(3, 6-dioxo-pyridazin-4-yl)thio]-3-benzyl-4-oxo-6-iodo-3H-quinazoline (20) proved to be the most active members in this study. They showed MG-MID, GI(50) values of 12.8, 11.3, and 13.8 microM, respectively. The detailed synthesis and biological screening data are reported.

Antineoplastic Agents↗
PubMed2006

Synthesis and evaluation as NOP ligands of some spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones and spiro[piperidine-4,5'(6'H)-[1,2,4]triazolo[1,5-c]quinazolines].

Some spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones 3 and spiro[piperidine-4,5'(6'H)-[1,2,4]triazolo[1,5-c]quinazolines] 4 were synthesized and evaluated as ligands of the nociceptin receptor. The examined compounds showed partial agonistic activity, except compounds 3, 4n that proved to be pure antagonists.

Benzyl Compounds↗
PubMed2006

Synthesis of tetrahydrobenzimidazo[1,2-b]quinazolin-1(2H)-one and tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-one ring systems under solvent-free conditions.

Tetraheterocyclic benzimidazo[1,2-a]quinazolin-4(1H)-one and tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-one were synthesized in relatively high yields by the condensation reaction of an aldehyde and a cyclic beta-diketone with 2-aminobenzothiazole, 2-aminobenzimidazole or 3-amino-1,2,4-triazole without using any catalyst under solvent-free conditions.

Aldehydes↗
PubMed1997

Synthesis and biological evaluation of a series of quinazoline-2-carboxylic acids and quinazoline-2,4-diones as glycine-NMDA antagonists: a pharmacophore model based approach.

The synthesis and glycine-NMDA binding activity of a series of quinazoline-2-carboxylic acids 1 and quinazoline-2,4-diones 2, containing all the essential and optional pharmacophoric descriptors required by a putative glycine antagonist model, are reported. The binding results show that only three of the title compounds displayed micromolar receptor affinity, demonstrating how disappointing the synthesis of receptor ligands based only on interaction models can be.

Animals↗
PubMed1978

Folate antagonists. 13. 2,4-Diamino-6-](alpha,alpha,alpha-trifluoro-m-tolyl)thio]quinazoline and related 2,4-diamino-6-[(phenyl- and naphthyl)thio]quinazolines, a unique class of antimetabolites with extraordinary antimalarial and antibacterial effects.

An array of nonclassical thioquinazoline analogues (VIII) of methotrexate was prepared by cyclization of the requisite 2-amino-5-(arylthio)benzonitrile with chloroformamidine hydrochloride (28--79%). The aminonitrile precursors were obtained by SnCl2-HCl reduction (28--99%) of the corresponding 2-nitro-5-(arylthio)benzonitriles, which were synthesized by the condensation of the appropriate 5-chloro-2-nitrobenzonitriles with various arylthiols (36--83%). Many of the thioquinazolines (VIII) showed suppressive antimalarial activity comparable with or superior to chloroquine, cycloguanil, and pyrimethamine against drug-sensitive lines of Plasmodium berghei in mice and Plasmodium gallinaceum in chicks, and several displayed potent prophylactic activity with P. gallinaceum. Moreover, the thioquinazolines retained potent antimalarial effects against chloroquine-, cycloguanil-, pyrimethamine- and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys. The most active compound, namely, 2,4-diamino-6-[alpha,alpha,alpha-trifluoro-m-tolyl)thio]quinazoline, was designated for preclinical toxicological studies. Numerous substances exhibited in vitro activity against a broad spectrum of pathogenic bacteria at concentrations of less than 0.25 microgram/mL. The thioquinazolines also prove to be potent folate antagonists, causing 50% inhibition of Streptococcus faecalis R (ATCC 8043) at drug concentrations ranging from 0.2 to 2.0 ng/mL. Structure--activity relationships are discussed.

Animals↗
PubMed1987

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.

Animals↗
PubMed2003

Studies on quinazolines. 11. Intramolecular imidate-amide rearrangement of 2-substituted 4-(omega-chloroalkoxy)quinazoline derivatives. 1,3 -O --> N shift of chloroalkyl groups via cyclic 1,3-azaoxonium intermediates.

The omega-chloroalkylation of 2-substituted quinazolin-4(3H)-one derivatives 1 and 2 with Br-(CH(2))(n)-Cl (n = 2-4) and the intramolecular imidate-amide rearrangement of the alkylated products are described. At room temperature, the 2-phenyl substituent promoted O-alkylation, whereas the less steric 2-benzyl group led to a higher ratio of N-alkylation. The investigation of the O-alkylated products, 4-omega-chloroalkoxyquinazolines, revealed that the migration of omega-chloroethyl and omega-chloropropyl groups from oxygen to nitrogen should be intramolecular via five- and six-membered cyclic 1,3-azaoxonium intermediates, respectively. Competition between rearrangement and nucleophilic substitution results in the formation of 7a,b and 8a,b from the nucleophilic substitution of 4a,b and 6a,b, respectively.

Alkylation↗
PubMed1997

Electrical and mechanical effects of a novel antihypertensive quinazoline derivative, 3-[[4-(2-methoxyphenyl) piperazin-1-ly]methyl]-5-(methylthio)-2,3-dihydroimidazo [1,2-c]quinazoline, on guinea pig ventricular muscles.

Electrical and mechanical effects of 3-[[4-(2-methoxyphenyl)piperazin-1-ly]methyl]-5-(methylthio)-2,3-+ ++dihydroimidazo[1,2-c]quinazoline (DL-017), a new synthesized antihypertensive agent, were studied in guinea-pig ventricular papillary muscles. In muscle fibers driven at 1 Hz, DL-017 decreased the twitch force in a concentration-dependent manner and significantly increased the action-potential duration and decreased intracellular Na+ activity (ai(Na)) and maximal rate of upstroke of action-potential (Vmax) when concentrations were greater than 1 microM. Phenylephrine in the presence of 1 microM propranolol produced a concentration-dependent positive inotropy. DL-017 (0.01 microM) antagonized the positive inotropic effect of phenylephrine and shifted the concentration-response curve to the right. In K+-depolarized muscle fibers, 0.1 microM DL-017 significantly decreased the contractile force without changing the slow action potential. In low-[K+]o and high-[Ca2+]o solutions, a train of stimuli triggered a spontaneous rhythm that could be abolished by 3 microM DL-017. Our results suggest that DL-017 not only exhibits an alpha1-antagonistic effect but also induces negative inotropy by a decrease in myofibrillar calcium sensitivity and inhibits Na+ channels at higher concentrations, contributing to the drug's negative inotropic and type-I antiarrhythmic effects.

Action Potentials↗
PubMed1979

Studies on the 2,4-diamino-6 substituted quinazolines. I. Antimalarial activities of 2,4-diamino-6-[(3,4-dichlorobenzyl)-nitrosoamino]-quinazoline (CI-679) as exhibited in rhesus monkeys infected with the Ro or Ro/PM strains of Plasmodium cynomolgi.

This report summarizes the results of appraisals of various activities of CI-679 (a 2,4-diamino-6-amino-substituted quinazoline) in rhesus monkeys infected with the Ro and Ro/PM strains of Plasmodium cynomolgi. In subjects inoculated with sporozoites, CI-679, administered in appropriate schedules in doses up to and including the maximum tolerated level, neither prevented development of infections with these strains nor cured those already established. Although these evaluations showed that CI-679 was devoid of activity against both early and late tissue schizonts, they indicated that this compound had significant blood schizonticidal activity and suggested that such activity was much greater in infections with the Ro strain than in those with the Ro/PM strain. This latter suggestion, contrary to results of earlier experiments in mice infected with Plasmodium berghei, led to studies of the activities of CI-679 in trophozoite-induced infections. These showed that the total course dose of CI-679 required for cure of previously untreated infections with the Ro/PM strain was tenfold that required for cure of comparable infections with the Ro strain. They also showed that infections with either strain, treated previously with subcurative doses, were often not cured by doses of CI-679 that eradicated previously untreated infections regularly. Subsequent studies showed that emergency of parasites resistant to CI-679 was responsible for these retreatment failures and that this resistance was retained through mosquito transfer.

Animals↗