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Publikacije (24)

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Objective: As a further part of our chemical and biological studies in this field, we describe the preparations of the properly substituted benzylidene-bis-(4-hydroxycoumarin) derivatives 5a-h and 3-(6-oxo-(1H)-benzopyrano[4,3-b]benzopyran-7-yl)-4-hydroxycoumarin derivatives 6a-e . Methods: The synthesized compounds were screened for their in vitro antimicrobial activity against five strains of bacteria and two fungal strains using disk diffusion assay and dilution method. The way in which the substituent group’s physicochemical properties influence the antimicrobial activity is discussed in the paper. Results: The in vitro evaluation of their inhibitory properties towards five strains of Gram-positive and Gram-negative bacteria and two fungal strains indicated that the                                       4-trifluoromethylbenzylidene derivative of bis-(4-hydroxycoumarin) (compound 5c ) and                    3-(6-oxo-(1 H )-18-bromobenzopyrano[4,3-b]benzopyran-7-yl)-4-hydroxycoumarin derivative (compound 6b ) possess the most potent antibacterial activities, with MIC of 3.9 μg/mL - 7.8 μg/mL against Gram-positive bacteria. Conclusion: The compound 6b has greater antibacterial activity than the standard chloramfenicol (inhibition zone 26 mm and MIC 1.9 μg/mL) against Staphyloccocus aureus and could be considered as leading compound in the future antimicrobial drug development. Key words: Benzylidene-bis-(4-hydroxycoumarin), benzopyranocoumarin derivatives, antibacterial assays , antifungal activity.

D. Završnik, E. Veljović, Adnan Bajrović, Martina Vrankić, B. Gržeta, A. Osmanović, S. Špirtović-Halilović, Samija Muratović

Series of synthesized xanthen-3-one derivatives were analyzed for thermal characteristics by differential scanning calorimetry (DSC), as well as for crystallinity using X-ray powder diffraction. Xanthen-3-one derivatives are prepared according to the well known procedure which includes two-fold Friedel-Crafts alkylation. The aim of this research was to determine purity and crystallinity of synthesized xanthen-3-one derivatives. Thermograms of synthesized compounds showed that compounds have purity above 98%, while crystallographic analysis of powder showed that the compounds have a 10-30% crystalline form.

D. Završnik, Samija Muratović, D. Makuc, J. Plavec, M. Cetina, A. Nagl, E. De Clercq, J. Balzarini et al.

We report on the synthesis of 4-hydroxycoumarin dimers 1–15 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 16–20 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure of compounds 1–20 were deduced from their homo- and heteronuclear NMR measurements whereas the conformational properties of 5, 14 and 20 were assessed by the use of 1D difference NOE enhancements. Unequivocal proof of the stereostructure of compounds 7, 9, 16 and 18 was obtained by single crystal X-ray diffraction method. The X-ray crystal structure analysis revealed that two 4-hydroxycoumarin moieties in the 4-trifluoromethylphenyl- and 2-nitrophenyl derivatives (compounds 7 and 9, respectively) are intramolecularly hydrogen-bonded between hydroxyl and carbonyl oxygen atoms. Consequently, the compounds 7 and 9 adopt conformations in which two 4-hydroxy-coumarin moieties are anti-disposed. Antiviral activity evaluation results indicated that the 4-bromobenzylidene derivative of bis-(4-hydroxycoumarin) (compound 3) possesses inhibitory activity against HSV-1 (KOS), HSV-2 (G), vaccinia virus and HSV-1 TK- KOS (ACVr) at a concentration of 9–12 μM and at a minimum cytotoxic concentration (MCC) greater than 20 μM. Compounds 4–6, 8, and 20 were active against feline herpes virus (50% effective concentration, EC50 = 5–8.1 μM), that is at a 4-7-fold lower concentration than the MCC.

D. Završnik, Samija Muratović, Selma Spirtović, D. Softić, M. Medic-Saric

Due to exceptional reactivity of 4-hydroxycoumarin, the synthesis of new coumarin derivatives of dimer and tetramer type has been carried out. The synthesis was carried out from 4-hydroxycoumarin and various aromatic aldehydes. In this way, compounds of the dimer 3,3'-(benzilidene)bis (4-hydroxycoumarin) type, as well as of the tetramer 3,3',3'',3'''-(1,4-dimethylenphenyl)tetra (4-hydroxycoumarin) type were prepared. The newly synthesized derivatives contain different functional groups, and as such they could exhibit microbiological activity. Therefore, we tested the microbiological activity of these derivatives on various species of bacteria and fungi. The tested compounds have shown different activity in terms of growth inhibition of microorganisms. Newly synthesized derivatives exhibit antibacterial activities, manifested as growth inhibition on Gram-positive bacteria types (Bacillus, Staphylococcus), while the activity against Candida was much weaker. The same compound did not show any antimicrobial activity against two Gram-negative bacteria types (Escherichia coli, Pseudomonas aeruginosa). The compound 1 showed the best microbiological activity. The obtained results confirmed its good antibacterial and antimycotic activities against different microorganisms.

D. Završnik, Samija Muratović, Selma Špiritović, M. Medic-Saric

QSAR/QSPR (Quantitative Structure Activity (Property)Relationships) studies provide some models for a fast search of biologically active molecules, and can be used to predict biological potential for synthesizing molecules and also for non-synthesized compounds. We used topological indicesm, selected physicochemical properties and activity for a group of derivatives of 4-hydroxycoumarin. We also investigated which topological indices are the most applicable by studyng the relationship between lipophilicity and the structure of new coumarin derivatives.

Selma Spiratović, D. Završnik, Samija Muratović, M. Medic-Saric

In this work, several quantitative QSPR/QSAR models for predicting the properties and activity of new synthesized coumarins are described and evaluated.

D. Završnik, Selma Spirtović, Samija Muratović

In the QSAR (quantitative structure-activity relationship) and QSPR (quantitative structure-property-activity relationship) study physico-chemical property, lipophilicity is used, to predict bioactivity of the newly synthesized coumarin compounds. Lipophilicity is a property of a molecule which depends on and can be changed by modifications in molecular structure. The parameter of the lipophilicity, partition coefficient (log P), is commonly used in drug designing and it is a numeric characteristic of lipophilicity of the examined substance, potential drug. The synthesis of 4-arylaminocoumarins derivatives from 4-hydroxycoumarin, has been carried out. In this work we described the fragmental method of calculation of partition coefficient according to the Rekker's method, because the best correlation between calculated and experimental values log P was determined according to the Rekker model. 4-Arylaminocoumarin has negative value of log P, but substitution with alkyl or allyl groups on the position 3 increases lipofilicity. Introduction of methyl or ethyl group into position 3 increases lipofilicity, suggesting that by increasing the chain length the values of log P become higher. The influence of allyl substituent in position three increases lipophilicity similar to methyl group. The aryl supstitent decreases lipoflicity, but a general relationship among them could not be established. The results obtained in this study enable further synthesis of new coumarin derivatives and predict their biological activity and properties.

D. Završnik, Samija Muratović, Selma Spirtović

Coumarin and its derivatives are reactive compounds, suitable for many syntheses. They are used as anticoagulants, antibacterial, animistic compounds. The interest in coumarins has increased because it was found that they reduce the HIV virus activity. The synthesis of 4-arylaminocoumarin derivatives from 4-hydroxycoumarin, has been carried out, and their antimycotic effects were tested. In the QSAR (quantitative structure-activity relationship) QSPR (quantitative structure-property-activity relationship) study we have used physicochemical properties and topological indices (Balaban index J(G), Wiener index W(G), information-theoretical index I(G), and valence connectivity index (G), to predict bioactivity of the newly synthesized coumarin compounds. By using methods of molecular modelling, the relationships between structure, properties and activity of coumarin compounds have been investigated. The best QSPR models were obtained using valence connectivity index or combination indices. According Rekker's method the best correlation of calculated values log P, has been obtained with the model based on the inhibition zone (I) 4-arylaminocoumarin derivatives expressed in mm. The results obtained in this study enable further synthesis of new coumarin derivatives and predict their biological activity and properties.

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