Synthesis, Characterization and Evaluation of the Antimicrobial and Herbicidal Activities of Some Transition Metal Ions Complexes with the Tranexamic Acid.

New tranexamic acid (TXA) complexes of ferric(III), cobalt(II), nickel(II), copper(II) and zirconium(IV) were synthesized and characterized by elemental analysis (CHN), conductimetric (Λ), magnetic susceptibility investigations (µeff), Fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H-NMR), ultraviolet visible (UV-vis.), optical band gap energy (Eg) and thermal studies (TG/DTG and DTA). TXA complexes were established in 1 : 2 (metal: ligand) stoichiometric ratio according to CHN data. Based on FT-IR and 1H-NMR data the disappeared of the carboxylic proton supported the deprotonating of TXA and linked to metal ions via the carboxylate group's oxygen atom as a bidentate ligand. UV-visible spectra and magnetic moment demonstrated that all chelates have geometric octahedral structures. Eg values indicated that our complexes are more electro conductive. DTA revealed presence of water molecules in inner and outer spheres of the complexes. DTA results showed that endothermic and exothermic peaks were identified in the degradation mechanisms. The ligand and metal complexes were investigated for their antimicrobial and herbicidal efficacy. The Co(II) and Ni(II) complexes showed antimicrobial activity against some tested species. The obtained results showed a promising herbicidal effect of TXA ligand and its metal complexes particularly copper and zirconium against the three tested plants.

[Preparation of tranexamic acid-loaded porous starch and evaluation of its hemostatic ability].

This study was aimed to develop a new generation of ideal hemostatic powder which can be safely, effectively and easily used mainly to first aid anterior to hospital by the synergistic effect of physical and chemical hemostatic mechanisms. The tranexamic acid(TA)-loaded porous starch(PS) (TAPS) was prepared by using PS as carrier and TA as loaded drug component. The absorption property of TAPS was evaluated by water absorption; the hemostatic ability of TAPS was evaluated by test in vitro and in vivo, the blood coagulation time of TAPS was detected by using Lee-white method. The experiment was divided into 3 groups: blank control group, Yunnan Baiyao group and TAPS group, each group with 10 blood samples in vitro test; the 27 SD rats were used to test in vivo, and randomly were divided into 3 groups: PS,Yunnan Baiyao and TAPS, each group consisted of 9 rats for establishing the animal model of liver trauma and detecting the complete hemostasis time. The results showed that the water absorption of PS did not be affected by TA when dose of TA loaded in PS was <0.02 g/g PS. There was no statistic difference in blood coagulation time between TAPS and PS groups(P > 0.05). The complete hemostatic time of TAPS for trauma of left lobe liver was 236.67 ± 55.00 seconds, which was shorter than that of Yunnan Baiyao (340.00 ± 73.48 seconds) and PS (396.67 ± 68.37 seconds) (P < 0.05 and P < 0.01, respectively). It is concluded that PS can load TA and play the hemostatic effect through releasing TA; the TA loading <0.02 g/g PS did not affect the water absorption and pro-coagulation properties. The TA can enhance the hemostatic efficacy of PS, the hemostatic property of TAPS is derived from synergism of physical and chemical hemostatic mechanisms.

Design, synthesis and in vitro kinetic study of tranexamic acid prodrugs for the treatment of bleeding conditions.

Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several maleamic acid amide derivatives four tranexamic acid prodrugs were designed. The DFT results on the acid catalyzed hydrolysis revealed that the reaction rate-limiting step is determined on the nature of the amine leaving group. When the amine leaving group was a primary amine or tranexamic acid moiety, the tetrahedral intermediate collapse was the rate-limiting step, whereas in the cases by which the amine leaving group was aciclovir or cefuroxime the rate-limiting step was the tetrahedral intermediate formation. The linear correlation between the calculated DFT and experimental rates for N-methylmaleamic acids 1-7 provided a credible basis for designing tranexamic acid prodrugs that have the potential to release the parent drug in a sustained release fashion. For example, based on the calculated B3LYP/6-31G(d,p) rates the predicted t1/2 (a time needed for 50 % of the prodrug to be converted into drug) values for tranexamic acid prodrugs ProD 1-ProD 4 at pH 2 were 556 h [50.5 h as calculated by B3LYP/311+G(d,p)] and 6.2 h as calculated by GGA: MPW1K), 253 h, 70 s and 1.7 h, respectively. Kinetic study on the interconversion of the newly synthesized tranexamic acid prodrug ProD 1 revealed that the t1/2 for its conversion to the parent drug was largely affected by the pH of the medium. The experimental t1/2 values in 1 N HCl, buffer pH 2 and buffer pH 5 were 54 min, 23.9 and 270 h, respectively.

Gd-complexes of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-1,4,7,10-tetraacetic acid (DOTA) conjugates of tranexamates as a new class of blood-pool magnetic resonance imaging contrast agents.

Gd-complexes of the type [Gd(L)(H(2)O)]·xH(2)O (5a-c), where L is DOTA conjugates of tranexamic acid (4a) and tranexamic esters (4b,c), have been prepared as a new class of MRI blood-pool contrast agents (BPCAs). Thermodynamic stability (K(GdL)) and pharmacokinetic inertness of 5 compare well with or better than those of analogous MRI contrasting agents (CAs) such as Gd-DOTA and Gd-DTPA-BMA. Their R(1)-relaxivities are significantly higher than those of any of the clinically used MRI CAs. T(1)-weighted MR images of mice administered by 5c demonstrate high blood-pool effect with simultaneous contrast enhancement in liver. The structural uniqueness of 5c lies in the fact that it adopts macrocyclic DOTA instead of acyclic DTPA. In addition, 5c is nonionic and makes no resort to aromatic substituent(s) in the chelate backbone for the blood-pool enhancement. The nature of hepatobiliary uptake demonstrated by 5c may be explained in terms of lipophilicity of tranexamate in the chelate (4c). The cell cytotoxicity test shows no toxicity found with 5, suggesting their use as a practical MRI BPCAs.

Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers.

The purpose of this work was to develop a novel approach to transdermal permeation enhancer design, based on utilizing some favorable properties of their metabolites. As an example of this concept, a series of carbamic acid salts of tranexamic acid (TXA) esters was synthesized, because TXA was previously shown to improve skin barrier homeostasis. Enhancement activities of 1% TXA derivatives dispersed in both hydrophilic and lipophilic vehicles were evaluated in vitro using human skin and theophylline as a model drug. Dispersed in an aqueous donor vehicle, the dodecyl ester showed the enhancement ratio (ER) of 4.3+/-0.9, which is almost 2 times higher than that of 1-dodecylazepan-2-one (Azone; 2.2+/-0.7). From an isopropyl-myristate suspension, the decyl ester was the most effective enhancer (4.9+/-1.4), while Azone was inactive. Decomposition of the carbamate in a slightly acidic environment was shown by FTIR; hydrolysis of the pertinent ester by porcine esterase was monitored by TLC and HPLC. Biodegradable enhancers of this type could mediate easier and faster recovery of the skin barrier after transdermal delivery through the action of the released TXA.

Design of plasma kallikrein inhibitors: functional and structural requirements of plasma kallikrein inhibitors.

The synthetic plasma kallikrein (PK) inhibitor trans-4-aminomethylcyclohexanecarbonylphenylalanine-4-carboxyme thylanilide (PKSI-527) consists of three parts. Each part was replaced by analogues in an attempt to improve the potency and the selectivity of PKSI-527. Among the peptides examined, trans-4-aminomethylcyclohexanecarbonylphenylalanine-4-carboxyan ilide (peptide 16) inhibited PK with a high selectivity and an IC50 value of 2.7 microM, being as potent as PKSI-527.

Development of active center-directed plasmin and plasma kallikrein inhibitors and studies on the structure-inhibitory activity relationship.

The molecule of trans-4-aminomethylcyclohexanecarbonylphenylalanine 4-carboxymethylanilide (8), which is a potent and selective inhibitor of plasma kallikrein, can be divided into three parts (P1, P1' and P2'), each of which contains one of the rings. In order to study the role of each part in the manifestation of potent and selective inhibitory activity and the relationship between the structure and inhibitory activities toward plasmin, plasma kallikrein, urokinase and thrombin, each part was substituted with various other moieties to give many kinds of analogs and their inhibitory activities against the above enzymes were examined. Among them, trans-4-aminomethylcyclohexanecarbonyl-O-2-bromobenzyloxycarbon yltyrosine 4-acetylanilide (12) inhibited plasmin and plasma kallikrein with IC50 values of 2.3 x 10(-7) M and 3.7 x 10(-7) M, and K(i) values of 1.2 x 10(-7) M and 1.3 x 10(-7) M, respectively.

Synthesis of trans-4-aminomethylcyclohexanecarbonyl-L- and -D-phenylalanine-4-carboxymethylanilide and examination of their inhibitory activity against plasma kallikrein.

Based on studies of structure-activity relationship, trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanine-4-carbox ymethylanilide (Tra-Phe-APAA) was designed as a selective plasma kallikrein inhibitor and synthesized. Tra-Phe-APAA inhibited plasma kallikrein with a Ki value of 0.81 microM, while it inhibited glandular kallikrein, plasmin, urokinase, factor Xa and thrombin with Ki values of greater than 500, 390, 200, greater than 500, and greater than 500 microM, respectively. However, its stereoisomer, Tra-D-Phe-APPA did not exhibit any detectable inhibitory activity against the above enzymes.

[The synthesis of 4'-(2-carboxyethyl)phenyl trans-4-aminomethyl cyclohexane carboxylate hydrochloride (cetraxate hydrochloride) by means of enzymatic debenzylation].

Cetraxate hydrochloride (1) (antiulcer agent) has been industrially produced by the chemical protective method of p-hydroxy propionic acid derivatives. Screening of enzymes which quantitatively hydrolyzed cetraxate benzyl ester hydrochloride (2) into 1 was undertaken to establish a novel enzymatic method of production of 1. It was found that the enzyme activity for debenzylation of 2 is contained in cellulase enzymes originated from Aspergillus sp. Lower alkyl groups or phenyl groups of p-hydroxy propionic acid derivatives are likewise selectively hydrolyzed by the cellulase enzyme. This enzymatic synthetic method is very useful for the industrial preparation of 1.

Tranexamic acid derivatives with enhanced absorption.

Derivatives of the antifibrinolytic drug tranexamic acid [trans-4-(aminomethyl)cyclohexanecarboxylic acid] containing one or two tranexamic acid moieties were synthesized. Most of the derivatives have good stability in acidic and neutral solutions but are easily hydrolyzed in plasma. By measuring the amount of tranexamic acid excreted in the urine after an oral dose, relative absorptions of a number of derivatives in the rat were estimated. Most of the derivatives showed greater absorption than tranexamic acid itself. 1-[(Ethoxycarbonyl)oxy]ethyl trans-4-(amino-methyl)cyclohexanecarboxylate hydrochloride was chosen for studies in man.