s30

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AN EIYBRID MOLECULE AS POTENTLAL CARDIOVASCULAR DRUG S. Lanai, E. Lumschi, A. Sac&l, E. Abignente, M. Gallitelli Diprtimento di Chimica Fannaceutica e Tossicoiogice, Via D. Montesano, 49, 8013 I Napoii, Italia.

Sometimes, the use of a therapeutic agent alone in the treatment of a desease may be limited by side effects caused by its own action. Then, combination of drugs with different phannaco-therapeutic effects are feasible. Combination drug therapy can be applied either using concomttant administration of hvo or more single active drags or by drugs in which the single active agents are cotnblned in one molecuie so coiled hybrid moiecuies. Hybrid drugs are comtimted of different phammmphoric groups which are directiy linked to each other or vie spacer. The advantage of hybrid drugs over lixed-ratio drug combination in one dosage fotm would be that hybrtd drugs are sdrerbed, distributed, metabolized and extracted at one rate, implying that the concentration of the dmg during the entire course remains in Mance.

Cardiovascular des%ses involve several distinct disorders such as arrhythmia. angina pectoris, mngestive heart failure or hypettension, so we have synthetized an hybrid molecuic based on a caiciutn channel biccker and a angiotensin ii converting enzyme (ACE)-inhibitor as tdfedipine and wptopril.

These type of cardiovascuiar agents, as single drug, can be applied as both antiarrhythmics. antianginais and antihypertensivc drugs. Pharmacological asseys on our combination drug therapy in a single dosage fan have been proven to be swcesstid in cardiovasadar disorders

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MAGNETIC RESONANCE IMAGING (MRI): A NON-INVASIVE TECHNIQUE TO EVALUATE THE EFFICACY OF ANTiEACTERlAL TREATMENTS IN THE MODEL OF THIGH INFECTION. PCristofori, ALanzoni. E.Di Modugno, CLadel, 5 Niwlato, ??P.Marzola Glaxo Wellcome S.p.A. Medicines Research Centre. Verona, Italy *Laboratorio di Risonanza Magnetica Sperimentale. lsthuto di Anatomia Umana, Universita’ degli Studi di Verona, Italy

Thigh infection provides a sensitive experimental model to evaluate the effectiveness of an antimlcrobial and measure drug/pathogen interactions. The aim of this study was to evaluate the suitabllity of Magnetic Resonance Imaging (MRI) as a technique for studying a murine model of thioh infection and the effiwcv of antibacterial treatment. Mice were Gfected under ltght anesthesia’ by intramuscular injection of methicillin susceptible S. aweus, grown in broth to logarithmic phase. lmlpenem/cilastatin or vanwmycin were administered subcutaneously to groups of infected mice; infected untreated animals ware the control group. The progfessk~n of infection was monitored at different timepoints (I,24 or 48 hours aher Infection) using MRI, haematology. bacterial counts, macroscopic and microscopic investigations. MRI was acquired using a Sisw 200/300 lmager spectrometer operating at 4.7T. Tl- and T2- weighted Spin Echo Images were acquired. T2- weighted images provided a sensitive record of the progression of infection and the different effects of antibacterial treatments. A good correlation with the bacterial and anatomo-pathological profiles was observed. Compared to histopathological and micmbtological techniques, MRI makes it possible lo follow the chmnologiil evolution of the lesion in the same animal, lowering interindividual vartabtlity as well as redwing the number of animals used and the amount of antibiotic. Results of this study show that MRI pmvldes a very useful tool to monitor jg&g the efficacy of antibacterial agents. In conclusion, In the drug discovery process MRI is a powetiul non-invasive technique which makes it oossible: to evaluate the effectiveness of new chemical entities in a localised infection and to monttor the progression of infedion not only in the thigh but throughout the body.

THE MODELING OF THIAZOLIDONE-4 DERIVATIVES WITH ANTI-INFLAMMATORY ACTIVITY B. Zimenkovsky’, 0. Viadziminka’, R. Lesvk’, 1. Nektegayevc, V. Sokoiskyb, V. Soiyanykb, S. Goiota’ ‘Department of Pharmaceuticai, Organic and Bioorganic Chemistry, bDepartment of Pharmacology, Zsboratoty of Industrial Toxicology, Lviv State Medical University, P&a&a 69,299OiO Lviv-IO, Ukraine

In order to create the more effective NSAlDs and establish the “structure-activity” relationships we have synthesized and carried out the pharmaw-logical research of the large group of new thiazolidone- 4 derivatives (more than 200 substances) [1,2,3].The anti- infiammatory activity has been studied by rat’s paw edema test. The results of ph armacoiogical research aiiow us to formulate the main principles of the direct modeling the thiazolidone-4 derivatives with anti-inflammatory activity. The most effective sub&u&s and thetr positions in molecule can be represented in the table. It is important to note, that substituent in position 5 of thinzolidine cycle (X) has the

We also ha1

: on anti-inflammatory action. -,

I-hydroxyhenzyiidene, Hz, -CH(COOKat)(CH$tCOOKat

(n=i,2; Kat=Na, K)

~~~~~,

separated the group of high-act t .ivt

CA

2-or 3- hydroxy- phenyi AO

N x> :low

with higher activity than diciofenac sodium, phenazone, aspirin. (11 Lesyk R et al. Form Uumal, S-6,64-68 (19%) (in Ulminim) [2] Lesyk R. et ai. Sci’. Phmm.. l-2, 101 (1997) [3] Lesyk R. et al. Vm. No& DOS/., l-2,4-8 (1998) (in Ukrainian)

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THIAZOLIDONES-4 AS THE POTENTIAL CHOLERETICS R. Lesvk’, 0. Viadzimirska’, 1. Nektegayev’, 0. Vovk’, R. Siuniger’ ‘Deuarttuent of Phatmaceutical. Oroanic and Bioorrtanic Chemisttv, %boratoty of Industrial Toxiioiogy, Lviv -State Medi&i University, Pekarska 69, 290010 Lviv-10, Ukraine

The analisys of fitndamentai research in the region of choleretic substances showed that heterocyclic suifodetivatives with phenoitc hydroxyl or methoxy group and large molecular mass could be the potential choieretics. That’s why the search for substances with choleretic activity among the thiazolidone-4 derivatives was the aim of our research. Earlier obtained results (I,31 showed that thiazolidones-4 displayed the highest choieretic activity with 3-oxy- 4-methoxybenzylidene substituent in position 5 and 3-hydroxy- phenyl substituents in position 3 of thiazolidine cycle. Proceeding our research we synthesized i2-arylidene-I-thia-3,lOdiazathree- cyciic[4-9;2-lO]dodecene-2-arene-4_ones-I I (I), diatyiidene deriva- tives of 3-amino-2-thionethiaiidone-4 (II) and derivatives of 3- dicarboxyaikylthiazoiidones-4 (III).

R, = 3-OH, R2 = H; R, = 3-OCHs, RI =4-OH; R, = 3-OC~HI, 4-OH The choler&c activity of the synthesized substances has been studied in the acute experiments with white rats by fist&-free method [2]. The obtained results gave the opportunity to make some conclusions about structure-choieretic acttvity reiationshtps and separate the potential choieretics. [i] Lesyk R. et al. vim. Nauk Dosl., l-2,4-8 (1998) (in Ukrainian) [2] Lilvinchuk M et al. Pharm. and Toxico/..6,674-676 (1979) (in Russian) 131 Vladzimirska 0. et ai so Pharm.. 1-2. 117 (1997)