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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.

Derivatives of 4-substituted 1,2-benzisothiazole-1,1-dioxide alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested in rat lens enzyme. The acetic derivatives 10, 12, and 16a-d proved to be much more potent inhibitors than the propionic derivatives 11, 13, and 17a-d. The presence of an acyl moiety on the amino group in position 4 of the acetic derivatives 16a-d led to a significant increase in activity with respect to the parent compound 14. One of the most active compounds in vitro, 10, was also evaluated in vivo as an inhibitor of glutathione lens depletion in galactosemic rats, but it did not show any activity in maintaining the rat lens glutathione level, probably due to problems of ocular bioavailability or metabolism.

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.

A number of 7-amino-2-dialkylaminoalkylpyrrolo[3,4-c] pyridin-1,3(2H)-dione derivatives were synthesized and their local anaesthetic activity was evaluated in vivo by corneal anaesthesia in rabbits. Only compounds 3,9 and 14 showed any activity, albeit lower than that of the reference drug lidocaine.

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.

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.

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.

Several N-(indol-3-ylglyoxylyl)alanine and glycine ester derivatives were prepared to evaluate the influence of the ester group size both on affinity and on activity at the benzodiazepine receptor. Moreover, indol-3-ylglyoxylic acid esters, closely related to 3-alkoxy-beta-carbolines, were synthesized and tested in vitro on the benzodiazepine receptor.

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.

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.

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.

Several N-(2-methyl or 1,2-dimethylindol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. The 2-methyl derivatives showed a lower affinity than the unmethylated analogues, and the 1,2-dimethyl derivatives practically lacked any affinity for the benzodiazepine receptor. The importance of the indole N-H group is therefore evidenced for an optimal interaction of these ligands with receptor site.

The synthesis and preliminary pharmacological evaluation of 2-aminobenzimidazole amide derivatives are reported. None of these compounds showed antilipidemic or platelet antiaggregatory activity comparable to that of drugs used in therapy.