ABSTRACT
Acetic acid derivatives of [1,2,4]triazino[4,3-a]benzimidazole (TBI) were synthesized and tested in vitro and in vivo as a novel class of aldose reductase (ALR2) inhibitors. Compound 3, (10-benzyl[1,2,4]triazino[4,3-a]benzimidazol-3,4(10H)-dion-2-yl)acetic acid, displayed the highest inhibitory activity (IC(50) = 0.36 microM) and was found to be effective in preventing cataract development in severely galactosemic rats when administered as an eyedrop solution. All the compounds investigated were selective for ALR2, since none of them inhibited appreciably aldehyde reductase, sorbitol dehydrogenase, or glutathione reductase. The activity of 3 was lowered by inserting various substituents on the pendant phenyl ring, by shifting the acetic acid moiety from the 2 to the 3 position of the TBI nucleus, or by cleaving the TBI system to yield benzimidazolylidenehydrazines as open-chain analogues. A three-dimensional model of human ALR2 was built, taking into account the conformational changes induced by the binding of inhibitors such as zopolrestat, to simulate the docking of 3 into the enzyme active site. The theoretical binding mode of 3 was fully consistent with the structure-activity relationships in the TBI series and will guide the design of novel ALR2 inhibitors.
Subject(s)
Acetates/chemical synthesis , Aldehyde Reductase/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Triazines/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding Sites , Cataract/etiology , Cataract/prevention & control , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Galactosemias/complications , Humans , Models, Molecular , Ophthalmic Solutions , Protein Binding , Rats , Stereoisomerism , Structure-Activity Relationship , Triazines/chemistry , Triazines/pharmacologyABSTRACT
The synthesis of benzimidazoquinazoline derivatives bearing different alkylamino side chains is reported. All new compounds tested by means of an in vitro assay exhibit antiproliferative activity toward human tumor cell lines. The cytotoxic effect depends on the type of side chain inserted in the planar nucleus and in some cases it is comparable to that of the well-known drug ellipticine. In order to understand the mechanism of action of these compounds, the interaction with DNA has been investigated. Linear flow dichroism measurements allowed us to verify the formation of a molecular complex with DNA and the corresponding geometry of interaction. Intrinsic binding constants have also been evaluated by performing fluorimetric titrations.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , DNA, Neoplasm/drug effects , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Circular Dichroism , DNA/chemistry , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Kinetics , Magnetic Resonance Spectroscopy , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , Tumor Cells, CulturedABSTRACT
A series of N'-phenylindol-3-ylglyoxylohydrazides, isosters of the N-benzylindol-3-ylglyoxylamide derivatives previously described by us, were synthesized and tested for their ability to displace [3H]Ro 15-1788 from bovine brain membranes. These compounds were designed with the aim of obtaining products which could exert an in vivo activity, thanks to a higher hydrosolubility and consequently a better bioavailability. Affinity was restricted to the derivatives unsubstituted in the 5 position of the indole nucleus (1, 6, 9, 12, 15, 18, 23, and 26), with Ki values ranging from 510 to 11 nM. The most active compounds (6, 9, 23, and 29) proved to be effective in antagonizing pentylenetetrazole-induced seizures. Molecular modeling studies were performed to rationalize the lack of affinity of hydrazides with a chloro or a nitro group in the 5 position of the indole nucleus. It was hypothesized that the conformational preference of the hydrazide side chain, characterized by a gauche disposition of lone pairs and substituents about the N-N bond, prevents all hydrazides from binding to the receptor similarly to other classes of indole analogues previously investigated. The potency of 5-H hydrazides was attributed to a binding mode which is not feasible for 5-Cl and 5-NO2 counterparts. This theoretical model of ligand-receptor interaction permitted a more stringent interpretation of structure-affinity relationships of hydrazides and of recently described benzylamide derivatives (Da Settimo et al. J. Med. Chem. 1996, 39, 5083-5091).
Subject(s)
Brain/metabolism , Glyoxylates , Hydrazines , Indoles , Models, Molecular , Receptors, GABA-A/drug effects , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Anticonvulsants/metabolism , Anticonvulsants/pharmacology , Binding, Competitive , Cattle , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Convulsants/chemical synthesis , Convulsants/chemistry , Convulsants/metabolism , Convulsants/pharmacology , Diazepam/pharmacology , Flumazenil/metabolism , GABA Modulators/metabolism , Glyoxylates/chemical synthesis , Glyoxylates/chemistry , Glyoxylates/metabolism , Glyoxylates/pharmacology , Hydrazines/chemical synthesis , Hydrazines/chemistry , Hydrazines/metabolism , Hydrazines/pharmacology , In Vitro Techniques , Indoles/chemical synthesis , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Ligands , Mice , Molecular Conformation , Receptors, GABA-A/metabolism , Seizures/chemically induced , Structure-Activity RelationshipABSTRACT
A number of benzyl and phenylethyl esters of indol-3-ylglyoxylic acid were synthesized and tested for their ability to displace [3H]Ro 15-1788 binding from bovine brain membranes. In these new compounds the oxygen atom of the ester function replaced the amide NH group of a class of previously described indolylglyoxylylamides, since it is reported in literature that in the beta-carboline series an ester function is more favourable to the activity than an amide group. However, none of the compounds showed an affinity at the Benzodiazepine receptor higher than that of the corresponding amides, demonstrating that the presence of the amide NH group is favourable to the interaction of ligands with the receptor site.
Subject(s)
Amides/chemistry , Esters/chemistry , Glyoxylates/chemistry , Indoles/chemistry , Receptors, GABA-A/metabolism , Amides/metabolism , Animals , Brain/metabolism , Cattle , Cell Membrane/metabolism , Esters/metabolism , GABA-A Receptor Antagonists , Glyoxylates/metabolism , In Vitro Techniques , Indoles/metabolism , Molecular StructureABSTRACT
A number of N-(indol-3-ylglyoxylyl)benzylamine derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. Some of these derivatives (9, 12, 14, 15, 17, 27, 34, 35, 38, 41, and 45) exhibited high affinity for the benzodiazepine receptor (BzR) with Ki values ranging from 67 to 11 nM. The GABA ratio and [35S]-tert-butylbicyclophosphorothionate binding data, determined for the most active compounds, showed that they elicit an efficacy profile at the BzR which depends on the kind of substituent present on the phenyl ring of the benzylamine moiety. Moreover, lengthening (propylamine derivatives 1-3) and shortening (aniline derivatives 46-54) of the distance between the phenyl ring and the amide group of the side chain gave compounds with a drastically lower binding potency. The biological results are discussed in the light of a recently proposed pharmacophore model and compared, by molecular modeling studies, with those obtained from effective BzR ligands.
Subject(s)
Indoles/chemical synthesis , Receptors, GABA-A/drug effects , Animals , Brain/drug effects , Brain/metabolism , Cattle , Indoles/chemistry , Indoles/pharmacology , Mice , Models, Molecular , Radioligand Assay , Receptors, GABA-A/metabolism , Structure-Activity RelationshipABSTRACT
A number of 6-substituted 1, 2-benzisothiazole-1, 1-dioxide alkanoic acids were synthesized and evaluated for crude rat lens aldose reductase inhibitory activity. The inhibitory potency of the acetic (6a, 10a), propionic (6b, 10b, 11b), and isopropionic (6c, 10c, 11c) derivatives was very similar and generally lower than that of the reference compound, Sorbinil. The presence of an acyl moiety on the amino group in position 6, as in the acetic and propionic derivatives 14a-f and 15a, b, respectively, resulted in a significant increase in activity. A good potency was shown by compounds 14g and 15g, in which a second carboxylic function is present on the 6-acylamino group. Also the open products 16, which contain the phenylsulfonyl fragment found in several known inhibitors of aldose reductase, were obtained and tested in the rat lens assay.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Animals , Enzyme Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/pharmacologyABSTRACT
A number of furoylindoles were synthesized with the aim of obtaining structurally more restrained analogues of the previously described indoleglyoxylylamides, which are high affinity ligands at the benzodiazepine receptor. In these new compounds, the oxygen atom of the oxalyl CO(2) is inserted into the rigid furan ring. However, unlike the glyoxylylamides, they proved to be incapable of interacting with the benzodiazepine receptor. To rationalize these results, molecular electrostatic potentials were calculated; these indicated a positive electrostatic potential region for the furan oxygen, which thus prevents the formation of a hydrogen bond necessary for interaction with the receptor. Nevertheless, these findings confirmed that the CO(2) of the indoleglyoxylylamide derivatives represents one of the principal points of interaction with the receptor site for these kinds of ligands, as previously hypothesized by us.
Subject(s)
Furans/metabolism , Indoles/metabolism , Receptors, GABA-A/metabolism , Animals , Cattle , Furans/chemistry , Indoles/chemistry , Ligands , Models, Molecular , Receptors, GABA-A/chemistryABSTRACT
The synthesis of a series of 2-aminobenzimidazole and indole amide derivatives containing the adamantyl moiety is described. The compounds, evaluated for in vitro anti-HIV and antitumor activities, were found to be moderately active or inactive, versus drug-treated controls, used for comparison purposes.
Subject(s)
Adamantane/analogs & derivatives , Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Benzimidazoles/chemistry , HIV/drug effects , Adamantane/chemistry , Adamantane/pharmacology , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Cell Line , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Tumor Cells, CulturedABSTRACT
A series of 1-alkyl substituted 2-methylaminobenzimidazole derivatives was prepared and tested. Some of them were assayed orally in the rat for antiinflammatory and analgesic properties. The compounds did not exhibit any significant activity compared with reference drug levels.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzimidazoles/chemical synthesis , Animals , Anti-Inflammatory Agents , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzimidazoles/chemistry , Benzimidazoles/therapeutic use , Female , Male , Mice , Molecular Conformation , Rats , Rats, Sprague-Dawley , Reference Standards , Structure-Activity RelationshipABSTRACT
The preparation of 5-substituted 1-aryl-4,5-dihydro-1H-pyrazolo[4,3- c][1,8] naphthyridines by reaction of 5-substituted 3-hydroxymethylene-2,3-dihydro-1,8-naphthyridin-4(1H)-ones with various phenylhydrazines is described. The benzodiazepine binding activity of these compounds was evaluated in vitro. Only the 5-methyl substituted derivatives showed affinity for the benzodiazepine receptor, with K1 values ranging from 2.9 to 0.195 microM for the para-phenyl substituted compounds. A hypothesis of interaction of these ligands with the receptor site is reported.
Subject(s)
Naphthyridines/chemical synthesis , Receptors, GABA-A/metabolism , Animals , Cattle , Ligands , Naphthyridines/metabolism , Structure-Activity RelationshipABSTRACT
Recently, several derivatives, in which tryptamine, tyramine, and dopamine moieties are linked to the indole nucleus by an oxalyl bridge, were tested for their affinity and efficacy at the benzodiazepine receptor (BzR). To better define the structure-activity relationships (SAR) several phenylethylamine derivatives were also synthesized and tested for their affinity at the BzR. Compounds bearing a protic group on the aromatic system of the side chain show a pharmacological profile of inverse agonist, while the products lacking this group behave as partial agonist. We now report the affinity data at the BzR of new compounds in which the distance between the phenyl ring and the amide group of the side chain has been changed. The benzylamine derivatives showed a good affinity at the BzR, generally higher than that of the phenylethylamine derivatives. In this series the pharmacological profile showed to be opposite to that of the corresponding phenylethylamine derivatives, since the compounds substituted with protic groups on the phenyl ring behaved as partial agonists. Moreover, a probable interaction with the receptor site is hypothesized.
Subject(s)
Indoles/chemical synthesis , Receptors, GABA-A/drug effects , Animals , Cattle , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , In Vitro Techniques , Indoles/metabolism , Indoles/pharmacology , Receptors, GABA-A/metabolism , Structure-Activity Relationship , gamma-Aminobutyric Acid/metabolismABSTRACT
Several N-(indol-3-ylglyoxylyl)dipeptide derivatives 1-12 were synthesized and tested for their affinity at the benzodiazepine receptor in bovine cortical membranes. They proved to bind with low or no affinity at the receptor site. It was hypothesized that this result was not due to the steric hindrance of the dipeptide side chain, but to the establishment of intramolecular hydrogen bonds involving the indole N-H and/or the glyoxylyl C = O(2). Conformational analysis indicated that coiled conformations, with intramolecular hydrogen bonds, were energetically more favoured than the staggered, completely unfolded ones. Therefore, the low or no affinity of these compounds should be attributed to the unavailability of the N-H and/or C = O(2) groups for the binding, again confirming that both these groups are necessary for interaction with the receptor.
Subject(s)
Dipeptides/chemical synthesis , Dipeptides/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Receptors, GABA-A/drug effects , Animals , Binding Sites , Cattle , Dipeptides/chemistry , Flunitrazepam/metabolism , Indoles/chemistry , Receptors, GABA-A/metabolism , Structure-Activity RelationshipABSTRACT
Several 1-alkyl or 1-aralkyl substituted 2-aminobenzimidazole derivatives, bearing an acetic or acetohydroxamic group at 3-position, were synthesized. Some of these products were tested for their antiinflammatory and analgesic properties. These compounds exhibited an antiinflammatory activity lower than that of reference drug Indomethacin. Compound 2e showed the highest efficacy, but not in a dose-related manner. Only compounds 3a and 16 exhibited some analgesic activity, but at a very high dose.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Benzimidazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzimidazoles/pharmacology , Benzoquinones , Carrageenan , Edema/chemically induced , Edema/prevention & control , Male , Mice , Pain/chemically induced , Pain/prevention & control , Rats , Rats, Sprague-DawleyABSTRACT
Several derivatives, in which tryptamine, tyramine, and dopamine moieties are linked to the indole nucleus by an oxalyl bridge, were tested for their ability to displace the specific binding of [3H]flunitrazepam from bovine brain membranes. GABA ratio and in vivo tests for the most potent compounds showed they behave as inverse agonists at the benzodiazepine receptor (BzR). To better define the structure-activity relationship (SAR) of this kind of ligand, several phenylethylamine derivatives were synthesized to evaluate their affinity to BzR. Some of these derivatives (17, 21, 24, 26, and 30) were found to exhibit high affinity (Ki = 0.51-0.085 microM) for BzR and possessed a partial agonist activity, although their chemical structure is closely related to tryptamine 2-6, tyramine 7-11, and dopamine 12-16 derivatives. A different interaction of these ligands to the receptor site is hypothesized. Moreover, all the prepared 1-methyl derivatives exhibited very low binding affinity to BzR.
Subject(s)
Dopamine/analogs & derivatives , Indoles/metabolism , Receptors, GABA-A/metabolism , Tryptamines/chemistry , Tyramine/analogs & derivatives , Animals , Anticonvulsants , Binding, Competitive , Cattle , Cell Membrane/metabolism , Cerebral Cortex/metabolism , Convulsants , Flunitrazepam/metabolism , Indoles/chemical synthesis , Indoles/pharmacology , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
The synthesis of some 2-aminobenzimidazole and indole amide derivatives containing a 2,6-dichloroaniline moiety is described. The preparation of a theophylline derivative is also reported. All the compounds tested showed no appreciable antihypertensive activity on spontaneously hypertensive rats.
Subject(s)
Antihypertensive Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Indoles/chemical synthesis , Animals , Benzimidazoles/pharmacology , Blood Pressure/drug effects , Clonidine/pharmacology , Hypertension/physiopathology , Indoles/pharmacology , Male , Rats , Rats, Inbred SHRABSTRACT
The synthesis of some amidic derivatives, obtained by condensation of various 5-substituted indoleglyoxylchlorides with physiologically important amines as tyramine, tryptamine and 5-aminouracil, is described. The preparation of one glycolyl derivative is also reported. Study of analgesic and antiinflammatory properties has shown only a feeble activity of these compounds.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Glyoxylates/chemical synthesis , Indoles/chemical synthesis , Animals , Carrageenan , Chemical Phenomena , Chemistry , Edema/drug therapy , Glyoxylates/pharmacology , Indoles/pharmacology , Male , Mice , Rats , Rats, Inbred Strains , Reaction Time/drug effectsABSTRACT
Several 4H-pyrido[1,2-a]pyrimidine derivatives with a basic substituent in the 2-position have been synthesized. All the compounds tested showed no appreciable antihypertensive activity.
Subject(s)
Antihypertensive Agents/chemical synthesis , Pyrimidinones/chemical synthesis , Animals , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Heart Rate/drug effects , Male , Minoxidil/pharmacology , Pyrimidinones/pharmacology , Rats , Rats, Inbred SHRABSTRACT
Several 1,8-naphthyridine derivatives have been synthesized and pharmacologically investigated. Some of them exhibited a marked antihypertensive activity on spontaneously hypertensive rats.
Subject(s)
Antihypertensive Agents/chemical synthesis , Naphthyridines/chemical synthesis , Adrenergic alpha-Antagonists , Adrenergic beta-Antagonists , Animals , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Male , Naphthyridines/pharmacology , Rats , Rats, Inbred SHR , Rats, Inbred StrainsABSTRACT
Some 3-amino- and 3-hydroxy-8-halosubstituted 6H-indolo[2,3-b] [1,8]naphthyridines were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. All prepared compounds were more active than the corresponding 8-unsubstituted derivatives. Moreover, among these compounds the 8-chloroindolonaphthyridines were clearly the most potent.