R. R. Akhmedzhanov

Amide- and urea-based synthetic anticonvulsants, antihypoxics, and inducers of the hepatic monooxygenase system. VII. Effect of benzhydrylureas on the cytochrome P-450-dependent liver monooxygenase system

54. D. M. Sedlock, R. A. Dobson, D. M. Deuel, et al., Antimicrob. Agents Chemother., 34, No. 4, 568-575 (1990). 55. S. Segeu, A. Barrilai, N. Rosen, and E. Rubinstein, Antimicrob. Agents Chemother., Abstract No. 385 (1988). 56. S. Segeu, A. Barrilai, N. Rosen, et al., Arch. Intern. Med., 149, No. 6, 1314-1316 (1989). 57. C. Siporin, et al. (eds.), The New Generation of Quinolones, New York-London (1990). 58. J. T. Smith and C. S. Levin, The Quinolones, V. T. Andriole (ed.), London (1988). 59. M. Soliati, D. Basetti, B. Datto!i, et al., Congress of Chemotherapy, Tokyo, pp. 1797!798 (1985). 60. R. Stahlman, Drugs Today, 24, 529-536 (1988). 61. R. W. Strunk, J. C. Gratz, R. Moserati, and W. M. Schell, Antimicrob. Agents Chemother., 28, 428-432 (1985). 62. P. van der Auwera, P. Grenier, Y. Glupczynki, and D. Picard, J. Antimicrob. Chemother., 2~, 209-219 (1989). 63. J. Vanderdouckt, A. Hellebrand, and R. Cordier, Curr. Ther. Res., 43, 82-91 (1988). 64. A. Vellucci, G. Bernardini, A. M. Battaglia, and P. Battaglia, Int. J. Clin. Pharmacol. Ther. Toxicol, 25, 279-281 (1987). 65. M. R. Wentland, The New Generation of Quinolones, C. Siporin, et al. (eds.), New York, Basel (1990), pp. 1-45. 66. W. J. A. Wijnands, A. J. A. Van Griethuysen, T. B. Vree, et al., J. Antimicrob. Chemother., i_88, 719-727 (1986). 67. W. J. A. Wijnands, T. B. Bree, A. M. Baars, et al., J. Antimicrob. Chemother., 21, 67-77 (1988). 68. L. S. Young, Ann. Intern. Med., 106, 144-146 (1987).

Quantitative relationships between structure and dissociation constants of enzyme - substrate complexes of microsomal cytochrome p-450 with derivatives of urea, diphenyl, diphenylmethane, and carbamide-containing heterocycles

Cytochrome P-450 is a key component in the monooxygenase system of liver, which is responsible for the metabolism of many xenobiotics [1]. The cytochrome P-450 dependent monooxygenase system serves a universal chemical receptor and chemical analyzer sensitive to a wide circle of compounds [2, 3]. Interaction of a substance with P-450 ferricytochrome, leading to the formation of an enzyme substrate complex, is the first stage in the process of oxidation of this substance. The formation and character of the enzyme substrate complexes can be studied by spectroscopic methods, for example, by monitoring the differential absorption spectra [4, 5]. The mechanisms of interaction in these complexes can be elucidated by studying the quantitative structureactivity relationships (QSAR), in particular, using the dissociation constant K s of the substratecytochrome P--450 complex as the measure of biological activity. In the previous works [6-8] , we used spectroscopic techniques to determine the K s values for the complexes of phenobarbital-induced microsomal cytochrome P-450 with some substrates reported [9] as activators of the liver monooxygenase system in rat liver. As is known, the shape of the differential absorption spectra of these complexes can be used to classify all ligands as belonging to subsmites of types I and H [ 10]. In this work, we have analyzed data on the K s values for cytochrome P-450 complexes with 15 substrates of type I and 37 substrates of type II. As a result, quantitative relationships offering high predicting ability were established between the structure and dissociation constants of these complexes.

Amide- and urea-based synthetic anticonvulsants, antihypoxics, and inducers of the hepatic monooxygenase system. VIII. Effect of benzhydrylureas and m-chlorobenzhydrylureas on the rat liver monooxygenase system

Studies of the enzyme-inducing properties of a series of benzhydrylureas have established that the most active compounds are benzhydrylurea (I) and its m-chloro-substituted derivative (II), which produce pronounced reductions in the duration of hexobarbital sleep in mice, with parallel increases in the microsomal hemoprotein content [2]. Cytochrome P450 induction of the phenobarbital type was proposed to occur in mice receiving I and II. We report here our further studies on the effects of these compounds on the monooxygenase system of rat liver.

Enzyme-substrate complexes between diphenyl derivatives and microsomal cytochrome P-450. Electronic absorption spectra and dissociation constants

It was reported that some diphenyl derivatives may act as cytochrome P-450 inductors. These include polychlorinated diphenyls (possessing properties of inductors of the phenobarbital or methylcholanthrene type) [ 1 3 ] and aminodiphenyls [4]. Previously we have demonstrated that some substituted diphenyls, such as dibenzazepinone and diphenic acid anilides, also possess the properties of the phenobarbital-like inductors [5 7]. In this context, it was of interest to study the degree of affinity of these substances with respect to microsomal cytochrome P-450 because some published data are indicative of a relationship between the enzyme-inducing properties of the compounds and their ability to form complexes with microsomal hemoproteins [8, 9]. The purpose of this work was to investigate the differential electronic absorption spectra measured in the course of titration of a suspension of liver microsomes with solutions of compounds I VII. We have also determined the apparent dissociation constants K, of a series of enzymesubstrate complexes of the following types.

Synthetic anticonvulsants, antihypoxics, and liver monooxygenase system inducers based on amides and urea. XI. Synthesis of alkyl- and arylalkylureas and their effects on the liver monooxygenase system

During studies on the search for and synthesis of new compounds able to induce the liver cytochrome--P-450-dependent monooxygenase system, we have produced a series of urea derivatives (I-XVIII) and we have evaluated their enzyme-inducing activities using the hexobarbital sleep test. Alkyland arylalkylureas I-XVIII were prepared by combining the corresponding alkyland arylalkylamines with nitrourea in aqueous solution as described in [1]. The yields, physicochemical properties, and spectral characteristics (IR, 1H, and 13 C NMR) of compounds I-XVIII are given in Tables 1-3, and their enzyme-inducing activities are shown in Table 4.

Enzyme — Substrate Complexes of Cytochrome P-450 with Some Biologically Active Compounds Studied by Electronic Absorption Spectroscopy

well-known drugs. In this study, we determined the K S values for a group of such drugs, including diazepam (I), nozepam (II), chloramphenicol (III), phenacetin (IV), anesthesin (V), lidocaine (VI), and 2-benzylacetanilide (VII) (cliche) (the bioconversion of which proceeds with the participation of some isoforms of cytochrome P-450 [5]), as well as of two compounds, N-trifluoroacetylbenzhydrylamine (VIII) and N-benzhydryl-N -trifluoroacetylurea (IX), possessing anticonvulsant activity [6, 7]. The pK S values for compounds I – IX were calculated using QSAR relationships [8] derived by the method of frontal polyhedra (FP) [9, 10]. A comparative analysis of the experimental and calculated values, together with analogous data obtained previously for some derivatives of diphenylamine, benzimidazole, benzotriazole, and phenoxazine [4], allowed us to evaluate the ability of the FP method to predict the dissociation constants of the enzyme – substrate complexes of microsomal cytochrome P-450.

Complexes of microsomal cytochrome P-450 with imidazole, benzotriazole, phenoxazine, and diphenylamine derivatives studied by electronic absorption spectroscopy

Previously [1 3], we reported on the spectral properties of complexes of a large group of heterocyclic and acyclic nitrogen-containing compounds with cytochrome P-450 of liver microsomes. It was demonstrated that the formation of complexes leads to changes in the shape of the differential electronic absorption spectra of the compounds, by which the substance s studied can be divided into two groups-substrates of types I a n d H [4, 5]. It was suggested [3] that the interaction of cytochrome P-450 with ligands corresponding to types I o r / / i s determined by the degree of electron-pair localization on the nitrogen atom of the ligand depending, in particular, on the number of carbonyl neighbors. In this work, we have experimentally determined the dissociation constants K s of complexes formed by the phenobarbital-induced microsomal cytochrome P-450 of rat liver with derivatives of heterocyclic a m i n e s benzimidazole, benzotriazole, and phenoxazine as well as with the diphenylamine derivatives containing no carbonyl groups. The derivatives included N-unsubstituted amines and their N-allyl and N-propenyl substituted analogs (series I IV). In series I, we have additionally studied 2-(o-fluorophenyl)benzimidazole. The absence of some N-allyl and N-propenyl derivatives and t rans isomers in the series studied is explained by the difficulties in isolating these compounds in pure form [6]. Compounds Ia, Ila, IIIb, IIIc, and IVa exhibited competitive complexation with the well-known cytochrome P-450 substrates aniline and hexenal.

Inducers of the phenobarbital type (a review)

Over 30 years ago, Conney suggested the possibility of clinical application o f inducers of the monooxygenase system of the liver (MOSL) [1]. Among numerous compounds with enzyme-inducing properties, inducers of the phenobarbital type (PB inducers) are currently attracting major attention. They are used to correct the antitoxic function of the liver in its various pathologies, and as homeostatic modulators [2]. In addition to increasing the rate of metabolism of a large range ofsubstrates, the PB inducers considerably less often, in comparison with other inducers of the methylcholanthrene type (MC type), cause the toxification of xenobiotics and their acquisition of mutagenic, carcinogenic, and teratogenic properties. This is apparently associated with the fact that the substrates whose metabolism is accelerated with induction of the PB type do not include many xenobiotics whose toxicity substantially grows upon microsomal biotransformation in the liver, e.g., because of K-region formation [3]. The prospects for new PB-type inducers depend primarily on the degree of their specificity for various species. Thus, 1,4-bis(3,5-dichloro-2-pyridyloxy)benzene is effective for the MOSL of mice, but is inactive in rats; whereas 2,4,6-triphenyl1,3-dioxane induces the MOSL in rats, but not in mice [4]. Phenobarbital is a standard PB inducer having no specificity for various species. The present review presents the results of analyzing the structure activity relation for PB-type inducers with the aim of singling out the most general structural criteria encompassing all known inducers of this type.

Synthetic anticonvulsants, antihypoxics, and liver monooxygenase system inducers based on amides and urea. VI. Synthesis and search for liver monooxygenase system inducers among compounds containing the benzhydryl group

i. A. A. Bakibaev, L. G. Tignibidina, V. D. Filimonov, et al., Khim. Farm. Zh., No. 5, 31-35 (1991). 2. A. A. Bakibaev, V. D. Filimonov, V. K. Gorshkova, et al., Khim. Farm. Zh., No. 4, 34-36 (1993) . 3. E. V. M o n t s e v i c h y u t e g r i n g e n e , P a t . F i x i o l . , No. 4, 71-78 (1964) . 4. A. G. Pechenkin, L. G. Tingibidina, V. K. Gorshkova, et al., Khim. Farm. Zh., No. 5, 57-59 (1979). 5. V. D. Filimonov, A. A. Bakibaev, A. V. Pustovoitov, et al., Khim. Farm. Zh., No. 5, 540-545 (1988). 6. M. J. O r l o f f , H. L. Wi l l iams, and C. C. P f e i f e r , Proc. Soc. Exp. B io l . (N .Y . ) , 70, 254257 (1949). 7. E. A. Swinyard, W. C. Brown, and L. S. Goodman, J. Pharmacol. Exp. Ther., 106, 319-330 (1952).

Synthetic anticonvulsants, antehypoxants, and inducers of the hepatic monooxygenase system based on amides and ureas

A number of N-acyl derivatives of benzhydrylamine were previously synthesized and their anticonvulsant properties studied [2]. Several highly active compounds were found among these. It is known [3] that the trifluoroacetyl group frequently intensifies the biological effect of compounds. We therefore carried out the synthesis of N-(trifluoroacetyl)-N-(benzhydryl)amines I-X and established their anticonvulsant and antihypoxic properties and also their effect on the cytochrome P-450-dependent hepatic monooxygenase system. Trifluoroacetamides I-X were synthesized by reaction of benzhydrylamines (which in turn were obtained by the method we have described previously [2]) with trifluoroacetic anhydride in benzene at room temperature in good yield (75-86%).