Amidine Compounds Research Articles

Characterization of a Novel DNA Minor-Groove Complex

Many dicationic amidine compounds bind in the DNA minor groove and have excellent biological activity against a range of infectious diseases. Para-substituted aromatic diamidines such as furamidine, which is currently being tested against trypanosomiasis in humans, and berenil, which is used in animals, are typical examples of this class. Recently, a meta-substituted diamidine, CGP 40215A, has been found to have excellent antitrypanosomal activity. The compound has a linear, conjugated linking group that can be protonated under physiological conditions when the compound interacts with DNA. Structural and molecular dynamics analysis of the DNA complex indicated an unusual AT-specific complex that involved water-mediated H-bonds between one amidine of the compound and DNA bases at the floor of the minor groove. To investigate this unique system in more detail DNase I footprinting, surface plasmon resonance biosensor techniques, linear dichroism, circular dichroism, ultraviolet-visible spectroscopy, and additional molecular dynamics simulations have been conducted. Spectrophotometric titrations of CGP 40215A binding to poly(dAT) 2 have characteristics of DNA-binding-induced spectral changes as well as effects due to binding-induced protonation of the compound linker. Both footprinting and surface plasmon resonance results show that this compound has a high affinity for AT-rich sequences of DNA but very weak binding to GC sequences. The dissociation kinetics of the CGP 40215A–DNA complex are much slower than with similar diamidines such as berenil. The linear dichroism results support a minor-groove complex for the compound in AT DNA sequences. Molecular dynamics studies complement the structural analysis and provide a clear picture of the importance of water in mediating the dynamic interactions between the ligand and the DNA bases in the minor groove.

Synthesis and characterisation of aluminium and magnesium complexes supported by pendant oxalic amidinate ligands

Two pendant oxalic amidine compounds [C6H5NC{NH(CH2)2OMe}–C{NH(CH2)2OMe}NC6H5] (1) (oxam(OMe)2H2) and [C6H5NC{NH(CH2)2NMe2}–C{NH(CH2)2NMe2}NC6H5] (2) (oxam(NMe2)2H2) are described. Reactions of 1 or 2 with two molar equivalents of AlMe3 in toluene give the bimetallic complexes [(Me2)Al(oxam(OMe)2)Al(Me2)] (3) and [(Me2)Al(oxam(NMe2)2)Al(Me2)] (4), respectively. Treatment of 1 or 2 with two molar equivalents of MeMgBr in THF affords the bimetallic complexes [(Br)(THF)Mg(oxam(OMe)2)Mg(THF)(Br)] (5) and [(Br)(THF)Mg(oxam(NMe2)2)Mg(THF)(Br)] (6) respectively. The crystal and molecular structures are reported for compounds 1, 2, 3, 5 and 6.

Design and synthesis of factor Xa inhibitors and their prodrugs

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency ( 14, IC 50=0.028 μM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.

Anti-Pneumocystis activities of aromatic diamidoxime prodrugs.

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

The anti-bacterial activity of acaricides in relation to streptothricosis.

The anti-bacterial activity of 13 commercially available acaricides, in use in the Caribbean, was tested against Dermatophilus congolensis, an actinomycete involved in streptothricosis of cattle, sheep and goats in the tropics. Acaricides used included organochloride, organophosphorus, carbamate, pyrethroid and amidine compounds. Each acaricide was tested at a typical working dilution used by the farmers, at 25 degrees C and 37 degrees C, in the presence or absence of 15 percent newborn calf serum as a fouling agent. Fouling of acaricides was found to have a marked inhibitory effect on its anti-bacterial activity. Vapona and Cattle Washing Detergent were found to be more active against Dermatophilus congolensis than the other acaricides tested.

Inhibition of monoamine oxidase by the pesticide chlordimeform and related compounds.

CHLORDIMEFORM is a formamidine acaricide and insecticide used to control phytophagous mites, cattle ticks and certain lepidopterous insects. Because of its unique spectrum of biological activity with regard to selectivity, chlordimeform may be the forerunner of a new class of agricultural chemicals. Although its mechanism of action is unknown, Knowles and Roulston1, studying the action of chlordimeform and related compounds on the southern cattle tick, suggested that inhibition of monoamine oxidase (MAO) could be involved. This hypothesis was based on observations of ticks poisoned with formamidine compounds and on the known ability of amidine compounds, such as propamidine and pentamidine, to inhibit MAO from mammals2. We have observed that symptoms manifested by rats poisoned by chlordimeform and demethylchlordimeform are similar to those elicited by sympathomimetic agents including known MAO inhibitors (unpublished results of F. R. Johannsen and C. O. K.). Thus, it seemed appropriate to examine chlordimeform and related compounds as potential inhibitors of rat liver MAO in vitro.

Hydrophobic interactions in the trypsin active center. The sensitivity of the hydrophobic binding site to side chain modifications in competitive inhibitors of the amidinium type

An investigation was carried out with model compounds designed to allow the study of the effects of small substituents (methyl groups), uncharged isosteres, methyl substitution on the benzamidinium nucleus, and extension of the aromatic side chain, on the binding properties of the hydrophobic binding site of the trypsin active center. Formamidine-HCl, guanidine-HCl, methylguanidine sulfate, meta- and para-toluamidines, as well as beta-naphthamidine-HCl were shown to be competitive inhibitors of trypsin. The methyl group contributes about −0.45 Kcal/mole to the free-energy of binding to the active center of the enzyme. If the methyl group is meta- or para- to the aromatic ring of benzamidine, there is a slight decrease in binding as compared to benzamidine itself, probably due to steric hindrance. In the amidine compounds, exchanging the phenyl ring of benzamidine for the naphthyl ring of beta-naphthamidine results in no alteration in the free-energy of binding. The results are discussed in terms of their usefulness in the design of compounds suitable for the labeling of the hydrophobic binding site of the trypsin active center.

The Preparation of Some Imidazoline and Amidine Compounds

Considering the amidines as the “open” model of a drug and the imidazolines as the “closed” model, a series of alkyl esters and amides of p- (2-imidazolin-2-yl) benzoic acid were prepared. The analogous esters and amides in the amidine series were previously shown to have marked local anesthetic activity. A series of esters of p-amidinobenzoic acid, containing alkyl groups in the amidine portion of the molecule, also were prepared.