A. F. Ismagilova

Complex Compounds of Glycyrrhizic Acid with Antimicrobial Drugs

A promising direction in the development of new effective drugs is the synthesis of molecular complexes, for example, with cyclodextrins, which can protect parent substances from premature metabolic decay and provide for their transmembrane transport [1]. Previously, we suggested using 18 -glycyrrhizic acid (GA, I) as a complex-forming agent for the synthesis of new transport forms of the well-known drugs (nonsteroidal antiinflammatory agents, prostaglandins, uracils, etc.) and other biologically active substances [2 – 7]. In continuation of our work in the R&D of new GA-based preparations, we have synthesized a series of new molecular 1 : 1 complexes (II – XI) between antimicrobial drugs and GA (92 2 %) [8]

Synthesis and Antitumor Activity of Complex Compounds of β-Glycyrrhizic Acid with Antitumor Drugs

A promising way of creating new highly effective drugs is the synthesis of molecular complexes which can protect parent substances from premature metabolic decay and provide for their controlled release. A premise in our approach was that the complex-forming agent must contain both a hydrophilic component (binding the main parent substance) and a hydrophobic component (responsible for the drug transport). Previously, we demonstrated that the molecular complexes of -glycyrrhizic acid (I) with prostaglandins and nonsteroidal antiinflammatory drugs are characterized by reduced toxicity and increased therapeutic breadth as compared to those of the components [1 – 6]. The main disadvantage of the well-known antitumor drugs 5-fluorouracil (II), ftorafur (III), rubomycin (IV), and their analogs is high toxicity [7 – 9]. We have synthesized a series of complex compounds involving acid I and drugs II – V in 1 : 1 ratio. The molecular complexes of I with fluorouracil were obtained in a water – ethanol medium at ~50°C, and the complexes with anthracycline antibiotics, in ethanol at room temperature. All compounds were characterized by IR and UV spectra. The UV spectra of complexes I II and I III exhibit intense absorption maxima in the region of 250 – 260 nm, related to the total absorption of conjugated ketone and fluoropyrimidine chromophore groups. The UV spectra of complexes I IV and I V display intense maxima in the region characteristic of aromatic chromophores (234 – 235 nm) and new maxima related to anthracycline groups (470 – 530 nm). As can be seen from the data in Table 1, the complexes of I with compounds II – IV are less toxic than the initial antitumor drugs. According to the results of preliminary experiments, the molecular complex of acid I with drug III exhibits antitumor action with respect to Pliss lymphosarcoma, melanoma B-16, and Guerin’s carcinoma (Table 2).

Synthesis of Glycyrrhizic Acid from Glycyrram and Pharmaciological Characterization of the Product

Glycyrrhizic acid (I) is an active component of licorice root extract obtained from plants of the Glycyrrhiza glabra L. and Glycyrrhiza uralensis Fisher species. The derivatives of acid I possess a broad spectrum of pharmacological properties, including antiinflammatory, antiulcer, antiallergic, antidote, antiviral, and some other types of activity [1]. Glycyrrhizic acid and its salts were recommended for the treatment of various forms of skin and liver cancer [2, 3] and are successfully used in the form of Stronger Neo-Minophagen C (SNMC) preparation for the therapy of patients with AIDS and hepatitis B [4, 5]. A purified glycoside component enters into the drug Clatraprostin (a veterinary preparation) and is used in the new medicinal forms of nonsteroidal antiinflammatory drugs and some other preparations [6, 7]. Previously [8] we proposed a method of obtaining purified glycyrrhizic acid (84 – 89%) from a commercial dry licorice root extract containing 26 – 28% of glycosides (available from the Urals Licorice Plant). Another commercial raw material that can be used for the synthesis of glycyrrhizic acid is glycyrram – a monoammonium salt of glycyrrhizic acid (available from the Chimkentbiofarm corporation). Glycyrram is an antiinflammatory drug used for the treatment of bronchial asthma, eczemas, and allergic dermatitis [9]. For the synthesis of pure glycyrrhizic acid from a commercial monoammonium salt, Volan and Dumazert [10] recrystallized the commercial product from acetic acid (AcOH) and ethanol, after which the purified glycoside was converted into a tripotassium salt (3K-salt) (II). Finally, salt II was converted into glycyrrhizic acid by acidification with an aqueous H 2 SO 4 solution. I: R = R = H, II: R = R = K, III: R = K, R = H.

Synthesis and wound-healing and antiulcer activity of a chitosan-rhodium(III) complex

The experiments were performed with chitosan prepared from FarEast crab shells (P = 1100; deacetylation degree, 75%; particle size, 0 .250-0 .315mm). A polysaccharide metal complex was synthesized at room temperature in an aqueous medium (pH 7). To a weighed amount of the ligand was added with stirring an aqueous RhC13 solution so as to provide for a 6 : 1 molar ratio of the elemental chitosan chain units to metal. After a 2-h reaction, the adduct (complex) was washed with water and acetone and dried in vacumn. The IR absorption spectra were measured on a Specord M-80 spectrophotomeer (Germany) using samples pelletized with KBr. The content of rhodium in the complex was determined by elemental analyses (Table l) and by analysis of the products of complex decomposition with tin chloride [ 15].

Synthesis and immunotropic activity of pyrimidine derivatives. Part. IV. Synthesis and immunotropic and antiinflammatory activity of pyrimidine acyclonucleosides

Compounds I V (Table 1) were obtained by interaction of 6-methyluracil or 5-hydroxy-6-methylumcil with epichlorohydrin (ECI-I) in the presence of catalytic amounts of potassium carbonate in DMF at 7 0 80~ [ 4 9]. It was established that alkylation of 6-methyluracil by ECH leads to the formation, in addition to compound I, of 1-(2-hydroxy-3-chloropropyl)-6-methyluracil (I1) at a yield of 8%. The proposed positions of substituents were confirmed by the UV spectroscopic data: pH 1, L~n = 245 nm, Lmax = 257 nm; pH 7, ~min = 245 mat, Xmax = 260 nm; pH 12,. L~, = 247 nm, Xm~x = 265 rim. Insignificant variation of the absorption maximum in the UV spectrum of compound 1I, observed when the pH value is changed from 1 to 12, is indicative of the substitution at position I.

Isomerization of glycyrrhizic acid. Antiulcer activity

The 18]3-GA isomer, extracted from the root of licorice (Glycyrrhiza glabra L. and Glycyrrhiza uralensis F.) [3], as well as its 18ct-GA counterpart exhibit a broad spectrum of pharmacological activity, producing antiinflammatory, antiallergic, antiviral, expectorant, antitumor, and antiulcer effects [ 4 10]. The two GA isomers possess close physicochemical compositions, but trans-GA differs from the cis isomer by higher solubility in water, higher stability of the

Synthesis and Pharmacological Characterization of New Acyclonucleoside Derivatives

The target pyrimidine acyclonucleosides III – VI were obtained using interactions of 1,3-bis(2-hydroxy-3-chloropropyl)uracil (I) and 1,3-bis(2-hydroxy-3-chloropropyl)-6methyluracil (II) with levomycetin or piperidine. The proposed structures of the synthesized compounds were confirmed and their purity was checked by elemental analyses and by the data of IR, UV, and NMR (H and C) spectroscopy. The IR spectra of all compounds display absorption bands in the region of 1670 – 1715 cm – 1 characteristic of uracil derivatives. Compounds II and IV exhibit characteristic absorption at 690 cm – 1 ( CCl), while the bands at 1060 – 1270 cm – 1 are indicative of the presence of a tertiary nitrogen atom. The absorption bands at 3300 – 3600 cm – 1 are due to the stretching vibrations of OH bonds; the bands at 840 – 890 cm – 1 belong to the stretching vibrations in 1,4-disubstituted aromatic ring ( para position); and the bands at 1450, 1530, 1570, and 3100 cm – 1 are also characteristic of the aromatic ring.

Synthesis and local anesthetic activity of α-amino-2-(2-cyclopentenyl)acetanilides

Aminoacetic acid alkylanilide hydrochlorides are known to possess pronounced local anesthetic properties. A convenient initial reagent for the synthesis of cycloalkenyl analogs of these compounds is offered by 2-cyclopentenylaniline, which can be synthesized by the Claisen rearrangement [1]. With the purpose of expanding the circle of potential local anesthetics belonging to this group of arylamines, we have synthesized and characterized a series of cyclopentenylacetanilides. First, the interaction of 2-cyclopentenylaniline (I) with chloroacetyl chloride in the presence of K2CO3 on heating in benzene or toluene led to a high yield of N-(2-chloroacetyl)2-(2-cyclopenten-t@)aniline (II). The subsequent condensation of anilide (II) with secondary amines led to aminoacetic acid anilides (IIla-IIId). The latter compounds were converted into hydrochlorides (IVa-IVd) and pharmacologically tested.

ANTIINFLAMMATORY AND ANTIULCER PROPERTIES OF NEWLY SYNTHESIZED ESTERS OF GLYCYRRHIZIC ACID

The main disadvantage inherent in common antiinflammatory drugs of both steroidal and nonsteroidal types (ortopher~ indomethacin, acetylsalicylic acid, prednisolone, etc.) is the irritating action upon the gastrointestinal tract [1 -3]. The search for new antiinflammatory drugs free of this side effect is a currently important task. Glycyrrhizic acid (I) and its derivatives are known to possess both antiinflammatory and antiulcer activity [4 9]. In continuation of a series of works aimed at the search for the new biologically active derivatives of glycyrrhyzic acid, we have synthesized several new esters (acylates I I I -V) by modifying the hydroxy groups in the hydrocarbon f r a ~ e n t of the molecule [10]. The purpose of this work was to characterize the new compounds with respect to their antiinflammatory and antiulcer activity. As is seen from Table 1, all the compounds studied in this work exhibit antiinflammatory activity with respect to the model of carrageenan-induced inflammation. The maximum activity was observed for pentacinnamate IIIc introduced at a dose of 50 or 100 mg/kg. Pentanitrobenzoate IV was active only at a dose of 100 mg/kg. The antiinflammatory effect of compounds IIIc and IV is more pronounced than that of compound I and comparable to the effect ofniglizin. Salicylate IIIa introduced at a dose of 25 or 50 mg/kg and methoxycirmamate IIId (50 mg/kg) inhibited the growth of the inflammation edema similarly to compound I. Acetylsalicylate IIIb showed a significant antiinflammatory activity only at a dose of 50 rag/kg. 2,4-Dinitrobenzoate Va at a dose of 25 mg/kg produces an antiinflammatory effect comparable to that of I, while isonicotinate Vb is of low efficiency. All the compounds studied in this work also exhibited antiinflammatory activity with respect to formalin-induced inflammation. The effect is comparable to that of compound I and is more pronounced than the action ofnigtizin (Table 2). Tests on the experimental model of utters induced by indomethacin showed that all the compounds protect the mu-

Antiinflammatory and antiulcer properties of 3-O-(β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside) derivatives of steroidal alcohols

Glycyrrhizic acid and its aglycon-glycyrrhetic ac id are found as components in the root extracts from licorice plants of the Glycyrrhizia glabria and Glycyrrhizia uralensis species. Glycyrrhizic acid and its derivatives are known to possess a broad spectrum of pharmacological activity (antiinflammatory, antiulcer, immunomodulating, and antiviral) and are of interest in medical practice [1 -5] . In the previous works we have demonstrated that glycyrrhizic acid derivatives exhibit a high antiinflammatory activity, produce no irritation of the mucous membrane of the stomach, and are efficient antiulcer agents [6, 7].