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At least 19 recordsLinked to original sources
PubMed2004

N,N-Dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines as potent factor Xa inhibitors.

A class of N,N-dialkylated 4-(4-arylsulfonylpiperazine-1-carbonyl)-benzamidines and 4-((4-arylsulfonyl)-2-oxo-piperazin-1-ylmethyl)-benzamidines has been discovered as potent factor Xa inhibitors with desirable in vitro and in vivo anticoagulant activity, but with low oral bioavailability. The 5-chloroindole and 6-chlorobenzo[b]thiophene groups are optimal as the factor Xa S1 binding elements. The strategy of incorporating a side chain on the piperazine nucleus to enhance binding affinity has been examined.

Benzamidines↗
PubMed2002

Thrombin inhibition by novel benzamidine derivatives: a free-energy perturbation study.

Thrombin is a serine protease responsible for blood coagulation. Since thrombin inhibitors appear to be effective in the treatment and prevention of thrombotic and embolic disorders, considerable attention has been focused on the structure and interactions of this enzyme. In this work, to evaluate the relative free energies of hydration and binding to thrombin for some benzamidine derivatives, we used the finite difference thermodynamic integration (FDTI) algorithm within the Discover program of MSI. By this method, two possible orders of hydration for the candidates were obtained: p-amidinophenylpyruvate > p-(2-oxo-1-propyl)benzamidine > p-methylbenzamidine > p-ethylbenzamidine > p-(1-propyl)benzamidine > benzamidine and p-amidinophenylpyruvate > p-(2-oxo-1-propyl)benzamidine > p-methylbenzamidine > p-ethylbenzamidine > benzamidine > p-(1-propyl)benzamidine. We also obtained the following order for thrombin binding: p-(2-oxo-1-propyl)benzamidine > p-ethylbenzamidine > p-(1-propyl)benzamidine > p-methylbenzamidine > benzamidine > p-amidinophenylpyruvate.

Benzamidines↗
PubMed1996

Purification of rat liver xanthine oxidase and xanthine dehydrogenase by affinity chromatography on benzamidine-sepharose.

The oxidase form of xanthine dehydrogenase (XO; EC 1.1.3.22) has been purified approximately 200-fold from rat liver extracts using a three-step process of heat treatment, ammonium sulfate precipitation, and chromatography on benzamidine-Sepharose. The purified enzyme showed only minor contamination when analyzed by gel electrophoresis under either native or sodium dodecyl sulfate (SDS)-denatured conditions and appears to be intact based on its subunit size on SDS-polyacrylamide gel electrophoresis, its N-terminal amino acid sequence, and its ability to be converted to the NAD-dependent dehydrogenase form (XD; EC 1.1.1.204) by incubation with dithiothreitol. Isoelectric focusing analysis showed that the purified enzyme consists of two major, enzymatically active isoforms with average pI values of 6.13 and 6.23 and a minor enzymatically active isoform with an average pl value of 6.07. A similar purification of XD was achieved by preincubating the partially purified oxidase with dithiothreitol prior to affinity chromatography on benzamidine-Sepharose. The effects of benzamidine on the kinetic properties of purified rat XO were characterized at pH 8 and 9 and were compared to those of bovine milk XO. Benzamidine was found to be a weak competitive inhibitor of the purified rat enzyme with Ki values of 30 and 10 mM at pH 8 and 9, respectively. In contrast, the Ki values for benzamidine with bovine XO were more than 10-fold greater. The findings presented in this study show that benzamidine is a competitive inhibitor of XO and that affinity chromatography on benzamidine-Sepharose provides a simple, rapid, and effective means of purifying both the oxidase and dehydrogenase forms of rat XO.

Aldehyde Oxidase↗
PubMed1991

N1-substituted benzamidines: synthesis, antiproteinase activity and inhibition of tumor cell growth.

We have synthesized N1-substituted benzamidines and poly-benzamidines with the aim to produce antitumor drugs retaining differential biological properties with respect to unsubstituted compounds. Antiproliferative activity on in vitro cultured human leukemic cells was exhibited by N1-substituted poly-benzamidines, while N1-substituted benzamidines were found to retain very low antitumor effects. Furthermore, our results suggest that N1-substituted benzamidines and some of poly-benzamidines exhibit low activity on trypsin and kallikrein. Taken together these data indicate that some N1-substituted poly-benzamidines could be of interest for experimental antitumor therapy, since are likely to retain low side effects due to alteration of proteinase activity.

Animals↗
PubMed1984

Benzamidine as a spectroscopic probe for the primary specificity subsite of trypsin-like serine proteinases. A case for BPTI binding to bovine beta-trypsin.

Formation and dissociation of the benzamidine:beta-trypsin adduct is accompanied by reversible spectral changes in the ultraviolet region (between 230 and 300 nm). The pH-independent difference extinction coefficient of the adduct (benzamidine:beta-trypsin complex minus the free proteinase) is 1.75 mM-1 cm-1 at 248 nm. This signal can be used in studies of inhibitor and substrate binding by rapid kinetic techniques. Therefore, following the spectral changes associated with the displacement of benzamidine from the primary specificity subsite, the kinetics of the beta-trypsin:BPTI complex formation were investigated between pH 2.9 and 7.6 (I = 0.1 M) at 21 +/- 0.5 degree C. Under all the experimental conditions the beta-trypsin:BPTI complex formation, examined by benzamidine displacement experiments, may be described in terms of a simple competition event. On the other hand, the very same reaction followed by displacement of another spectroscopic probe, proflavine, appears to involve the ternary proflavine:beta-trypsin:BPTI adduct (7). The difference between the kinetic processes of beta-trypsin:BPTI complex formation, observed by using benzamidine and proflavine as reaction indicators, suggests that the two dye molecules bind at non-coincident regions of the proteinase active center. The advantages in using benzamidine as a sensitive probe specific for the S1 subsite of the recognition center of trypsin-like proteinases, as compared to proflavine, are emphasized.

Amidines↗
PubMed1977

Benzamidine as an inhibitor of proacrosin activation in bull sperm.

Epididymal and ejaculated sperm contain a zymogen form of acrosin (acrosomal proteinase, EC 3.4.21.10) which is converted to active enzyme prior to fertilization. Benzamidine at concentrations greater than 10 mM has been shown to inhibit the conversion of proacrosin to acrosin. Based on this inhibition, a procedure was developed for extracting and quantitating the proacrosin content of bull sperm. Sperm were isolated from semen and washed by centrifugation through 1.3 M sucrose and the outer acrosomal membrane removed by homogenization. When 25 mM benzamidine was added to the semen and wash solutions, 98% or more of the acrosin activity in the sperm homogenate was present as proacrosin. Proacrosin can be extracted from the sperm homogenate by dialysis at pH 3, which solubilized the proenzyme and removed benzamidine. Benzamidine has been useful in isolating proacrosin and provides a new method for studying the activation of proacrosin in intact sperm. Neutralization of sperm extracts, after removal of benzamidine, resulted in rapid activation of proacrosin with a pH optimum of 8.5, and activation was complete within 15 min over a pH range of 7.0 to 9.5. Rapid activation also occurred during the washing of sperm in the absence of benzamidine, and this activation correlated with a swelling of the acrosomal membrane. This rapid activation appears to result from a small amount of acrosin activity consistently present in the sperm extract. These results indicate an autocatalytic conversion of proacrosin to acrosin and suggest that disruption of the acrosomal membrane may trigger this activation.

Acrosin↗
PubMed2004

Benzamides and benzamidines as specific inhibitors of epidermal growth factor receptor and v-Src protein tyrosine kinases.

The benzamides 1 and the benzamidines 2 as well as the cyclic benzamidines 3 were designed and synthesized as the mimics of 4-anilinoquinazolines for an inhibitor of EGFR tyrosine kinase. The specific inhibitions of EGFR tyrosine kinase were observed in the benzamides 1c and 1d, and the benzamidine 2a, whereas the specific inhibitions of v-Src kinase were observed in the benzamide 1j and the benzamidine 2d at a 10microg/mL concentration of compounds. The cyclic benzamidines 3a and 3b showed potent kinase inhibition of EGFR at a 1.0microg/mL concentration. According to the docking simulation using the X-ray structure of EGFR kinase domain in complex with erlotinib, the LigScore2 scoring function value of erlotinib was calculated as 5.61, whereas that of the benzamide 1c was 5.05. In a similar manner, the LigScore2 value of the cyclic benzamidine 3a was calculated as 5.10.

Benzamides↗
PubMed1992

Inhibition of human alpha-, beta- and gamma-thrombin by mono-, bis-, tris- and tetra-benzamidine structures: thermodynamic study.

The inhibitory effect of mono-, bis-, tris- and tetra-benzamidine structures (benzamidine, DAPP, TAPB and TAPP, respectively) on the catalytic properties of human alpha-, beta- and gamma-thrombin (alpha-, beta- and gamma-thrombin, respectively) was investigated (between pH 2.0 and 7.0, I = 0.1 M; T = 37.0 +/- 0.5 degrees C). The affinity of DAPP, TAPB and TAPP for alpha- and beta-thrombin is higher than that found for benzamidine association around neutrality, converging in the acidic pH limb; in contrast, benzamidine, DAPP, TAPB and TAPP show the same value of the association inhibition constant (Ki; M-1) for gamma-thrombin over the whole pH range explored. On lowering the pH from 5.5 to 3.0, the decrease in affinity for benzamidine binding to alpha-, beta- and gamma-thrombin, as well as for DAPP, TAPB and TAPP association to gamma-thrombin reflects the acidic-pK shift, upon inhibitor binding of a single ionizing group. On the other hand, values of Ki for DAPP, TAPB and TAPP binding to alpha- and beta-thrombin appear to be modulated by the acidic-pK shift, upon inhibitor association, of two equivalent proton-binding residues over the same pH range. By considering molecular models of the serine proteinase:inhibitor complexes, the observed binding behaviour of benzamidine, DAPP, TAPB and TAPP to alpha-, beta- and gamma-thrombin has been related to the inferred stereochemistry of the enzyme:inhibitor contact region(s).

Amidines↗
PubMed1991

Inhibition of bovine beta-trypsin, human alpha-thrombin and porcine pancreatic beta-kallikrein-B by benzamidine and its bis-, tris- and tetra-derivatives: thermodynamic and molecular modeling study.

The inhibitory effect of bis-, tris- and tetra-benzamidine derivatives (DAPP, TAPB and TAPP, respectively) on the catalytic properties of bovine beta-trypsin (beta-trypsin), human alpha-thrombin (alpha-thrombin) and porcine pancreatic beta-kallikrein-B (beta-kallikrein-B) was investigated (between pH 2.0 and 7.0, I = 0.1 M; T = 37.0 +/- 0.5 degrees C), and analyzed in parallel with that of benzamidine, commonly taken as a molecular inhibitor model of serine proteinases. Over the whole pH range explored, benzamidine, DAPP, TAPB and TAPP, show the same value of the association inhibition constant (Ki, M-1) for beta-trypsin; at variance, the affinity of DAPP, TAPB and TAPP for alpha-thrombin and beta-kallikrein-B is higher than that found for benzamidine association around neutrality, but tends to converge in the acidic pH limb. On lowering the pH from 5.5 to 3.0, the decrease in affinity for benzamidine binding to beta-trypsin, alpha-thrombin and beta-kallikrein-B as well as for DAPP, TAPB and TAPP association to beta-trypsin reflects the acidic-pK shift, upon inhibitor binding, of a single ionizing group. Over the same pH range, values of Ki for DAPP, TAPB and TAPP binding to alpha-thrombin and beta-kallikrein-B appear to be modulated by the acidic-pK shift, upon inhibitor association, of two equivalent proton-binding residues. Considering the X-ray three dimensional structures and the computer-generated molecular models of the serine proteinase inhibitor complexes, the observed binding behaviour of benzamidine, DAPP, TAPB and TAPP to beta-trypsin, alpha-thrombin and beta-kallikrein-B has been related to the inferred stereochemistry of the enzyme:inhibitor contact region(s).

Animals↗
PubMed1987

Effectiveness of Sepharose-bound trypsin versus liquid-phase trypsin plus benzamidine for activation of inactive renin in human plasma.

We compared the effectiveness of two techniques involving the use of the enzyme trypsin to activate inactive renin in human plasma. Both these methods were developed to optimize activation with trypsin by preventing the possible destruction of activated renin by trypsin itself. In one method, an antitryptic agent such as benzamidine is added to plasma, concomitantly with trypsin (liquid phase). In the other a low concentration of Sepharose-bound (immobilized) trypsin is used. In six plasma samples we have found that trypsin (1.5 mg/ml) activation, with or without benzamidine (0.8 mg/ml), yielded similar values of activated renin (11.0 +/- 2.7 vs. 11.3 +/- 2.3 ng/ml/hr). However, the addition of immobilized trypsin to pool plasma pretreated with trypsin plus benzamidine caused a further increase in plasma renin activity (PRA); in contrast, the addition of trypsin and benzamidine to pool plasma pretreated with immobilized trypsin caused a decrease in PRA. In 17 plasma samples from patients with essential hypertension we found that the inactive renin values were always higher after treatment with immobilized trypsin than with trypsin plus benzamidine (9.0 +/- 0.7 vs. 6.1 +/- 0.5 ng/ml/hr, P less than 0.01); moreover, there was a positive correlation between the differences in the values of inactive renin measured with the two methods and the values obtained with immobilized trypsin (r = 0.64, P less than 0.01). Therefore, the activation with immobilized trypsin is more effective than that with liquid-phase trypsin, alone or in combination with benzamidine, in converting inactive renin in human plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Amidines↗
PubMed1978

Inhibition of four human serine proteases by substituted benzamidines.

A series of substituted benzamidines has been examined for their inhibitory activity against the human serine proteases--trypsin, thrombin, plasmin, and C1s, a subunit of the first component of complement. The inhibition constants obtained for each enzyme were correlated with physical-chemical properties of the substituent group using the quantitative structure-activity relationship approach. This analysis indicated that plasmin and C1s are very similar in their interactions with substituted benzamidines. The binding of benzamidines in both enzymes was affected by electron donation from the substituent and its hydrophobicity. Thrombin-benzamidine interaction was affected only by the hydrophobicity of the substituent. Trypsin displayed a complex interaction with substituted benzamidines, and interaction was dependent on molar refractivity and molecular weight. Certain substituents deviated significantly from the interactions predicted by the analysis. These compounds, the (m- and p-amidinophenyl)pyruvic acids, when analyzed by computer modeling, suggested that direct interaction between the substituent and the enzyme surface is important in assessing the effect of substituent groups on inhibitory activity.

Amidines↗
PubMed1982

Chemistry and hypoglycemic activity of N-[[(Dialkylamino)alkoxy]phenyl]benzamidines.

A series of N-[[(dialkylamino)alkoxyl]phenyl]benzamidines was synthesized and evaluated for hypoglycemic activity in the glucose-primed rat. Structure-activity relationship indicated that N'-phenyl-N-[4-[2(diisopropylamino)-ethoxy]phenyl]benzamidine dihydrobromide (7), N'-(4-chlorophenyl)-N-[4-[2-(diisopropylamino)ethoxy]phenyl]-benzamidine dihydrochloride (31), and N'-phenyl-N-[4-[(diisopropylamino)propoxy]phenyl]benzamidine dihydrobromide (11) are some of the more interesting compounds. A comparison of these hypoglycemic agents with classical standards (tolazamide, phenformin, and buformin) in several experimental models showed that the benzamidines seem to combine in one molecule some of the biological activities of the beta-cytotrophic sulfonylureas and some of the activities of the biguanides.

Adrenalectomy↗
PubMed2003

Selective inhibition of large-to-small surfactant aggregate conversion by serine protease inhibitors of the bis-benzamidine type.

Conversion of the biophysically active large surfactant aggregate subtype (LA) of alveolar surfactant into the less surface active small surfactant aggregates (SA) occurs in vivo and is reproduced under conditions of cyclic surface area changes in vitro. A serine-active carboxyl esterase has been suggested as the responsible enzymatic activity, although the exact mechanisms underlying the conversion process are presently unclear. We investigated the influence of exogenous serine proteases and synthetic and natural serine protease inhibitors on the conversion kinetics of natural rabbit surfactant, obtained as bronchoalveolar lavage fluid (BALF). In vitro cycling of BALF was performed for various time periods in the absence or presence of increasing amounts of several serine proteases (trypsin, plasmin, thrombin, tryptase), and one natural (aprotinin) and 25 synthetic serine protease inhibitors (including regular benzamidines [group A], 3-amidinophenylalanine derivatives [group B], bis-benzamidines [group C], and analogs of naphthylsulfonyl-glycyl-4-amidinophenylalanine piperidide [group D]). LA were separated from SA by 48,000 x g centrifugation. Surface activity of the LA fraction was measured by means of the pulsating bubble surfactometer. None of the "classical" serine proteases forwarded any acceleration of the LA-to-SA conversion kinetics. Some of the serine protease inhibitors caused moderate retardation of conversion, but at the same dose range inhibited the surface tension-lowering properties of the LA fraction, which per se explained their inhibitory effect. In contrast, specific dose-dependent inhibition of the LA-to-SA transition was observed for four derivatives of the bis-benzamidine group: full blockage of conversion over 240 min of cycling was noted at doses that did not interfere with the surface activity of the LA fraction. In addition, the prototype of these bis-benzamidines, 1,4-bis-[beta-naphthylsulfonyl-(3-aminophenylalanine)]-piperazide, was found to inhibit the activity of the rabbit liver carboxylesterase ES-2 in two different synthetic substrate assays reflecting the amidase and esterase properties of carboxylesterases. These findings support the hypothesis that the LA-to-SA conversion is an enzymatically-driven process with serine-active carboxyl esterase(s) being centrally involved. Synthetic bis-benzamidine-type serine protease inhibitors may offer specific inhibition of this event.

Animals↗
PubMedDate not supplied

Inhibition of arginine gingipains (RgpB and HRgpA) with benzamidine inhibitors: zinc increases inhibitory potency.

We assayed several benzamidine derivatives for inhibition potency with HRgpA and RgpB gingipains, enzymes which are involved in the pathogenesis of gingivitis and periodontal disease. The benzamidine derivatives proved to be effective inhibitors of HRgpA and RgpB, with the best inhibitor being a bis-benzamidine with a urea linker (Ki=30 microM). The inhibition potency was increased 2-3 fold in the presence of low concentrations of zinc with the benzamidines containing a urea moiety linking the two aromatic rings. We propose an inhibition model involving a tetrahedral zinc atom coordinated with the active site Cys and His of gingipain and the urea linker in the benzamidine inhibitor. In summary, we have discovered a new series of effective inhibitors for the gingipains and found a novel way to increase inhibitor potency with the HRgpA and RgpB gingipains using zinc.

Adhesins, Bacterial↗
PubMed1992

Inhibition of human mast cell tryptase by benzamidine derivatives.

Considerable circumstantial evidence has been provided by in vitro studies that tryptase (EC 3.4.21.59), a neutral serine proteinase stored in large amounts in mast cell granules, may play an important pathogenetic role in mast cell-dependent diseases. However, a definitive role has not yet been ascribed to this trypsin-like enzyme with restricted substrate specificity as natural or synthetic inhibitors of tryptase applicable for in vivo studies are not available so far. Therefore, we have studied structure-activity relationships for inhibition of tryptase by benzamidine derivatives, compounds known to be potent inhibitors of various trypsin-like enzymes. Among the benzamidine derivatives 4-amidinophenylpyruvic acid exerts a striking inhibitory activity with a Ki of 0.71 mumol/l. Several additional inhibitors of tryptase with Ki values in the micromolar range were found among bis-benzamidines. Derivatives of N alpha-arylsulfonyl-omega-amidinophenyl-alpha-aminoalkylcarboxylic acids are only weak inhibitors of tryptase, although members of this group are potent and selective inhibitors of several other trypsin-like enzymes. Comparison of the inhibition of tryptase and trypsin revealed that the affinities of the benzamidine derivatives to both proteinases are closely correlated (correlation coefficient r = 0.702; n = 37; p < 0.001). These results demonstrate that 4-amidinophenylpyruvic acid may be useful as a pharmacologic tool for the investigation of the (patho)physiological role of tryptase. In addition, benzamidine derivatives may be applicable to probe the active site topography of tryptase isoenzymes.

Benzamidines↗
PubMed2003

Inhibitors of benzamidine type influence the virulence properties of Porphyromonas gingivalis strains.

Synthetic inhibitors of benzamidine type have been found to have inhibiting effects on arginine specific cysteine proteinases of P. gingivalis. The purpose of our study was to assess the effects of these inhibitors on the virulence properties of two P. gingivalis strains, the reference strain ATCC 33277 and JH16-1, a clinical isolate obtained from a patient with severe periodontitis. The inhibitors tested were pentamidine, benzamidine, three bis-benzamidine derivatives with a pentamidine-related structure, one bis-benzamidine derivative with another structure, and one arginine derivative as a negative control, each in the concentrations of 2 microM and 20 microM. As virulence criteria the following parameters were determined: arginine-specific amidolytic activity, growth inhibition, hemagglutination of sheep erythrocytes, adherence to KB cells and immuno-phagocytosis including intracellular killing. Pentamidine and the bis-benzamidine derivatives with pentamidine-related structure showed the most remarkable effects on reduction of amidolytic activity by 35%, growth inhibition and reduced hemagglutination. Except for the arginine derivative all other inhibitors tested enhanced the phagocytosis capacities of granulocytes. No clear influence of the inhibitors on adherence of P. gingivalis to KB cells was seen. Although in vitro effects of the synthetic inhibitors of cysteine proteinases on virulence of P. gingivalis were observed further in vitro tests concerning immunomodulatory effects should be done before these substances are used for therapy in clinically controlled studies.

Animals↗
PubMed1993

Biotransformation of benzamidine and benzamidoxime in vivo.

After administration of benzamidine (1) or benzamidoxime (2), respectively, to rats and rabbits, plasma from rats and rabbits as well as urine from rats were examined for the presence of benzamidoxime (2) or benzamidine (1). Some of the samples were worked-up directly and the others after enzymatic pretreatment with beta-glucuronidase or arylsulfatase, respectively. HPLC analysis was employed for the detection of the metabolites. After administration of 1, an in vivo N-hydroxylation of an amidine to an amidoxime was demonstrated for the first time. The metabolite 2 could only be detected after enzymatic cleavage of the glucuronide or sulfate, respectively, and only in plasma at a low concentration. After administration of benzamidoxime (2), on the other hand, benzamidine (1) was detected in very high concentrations in all biological samples. Benzamidine was present in the free state but indications for glucuronidization and sulfatation were also detectable. These investigations suggest that the benzamidoxime (2) formed by an in vivo N-hydroxylation undergoes ready retro-reduction but that further transformations of the metabolite 2, such as conjugation to a glucuronide or a sulfate, respectively, prevent complete back reaction. Furthermore, benzamide (3) could be detected as a transformation product in urine after administration of either 1 or 2.

Animals↗