Benzylidene-bis-(4-Hydroxycoumarin) and Benzopyrano-Coumarin Derivatives: Synthesis, 1H/13C-NMR Conformational and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations

doi:10.3390/molecules16076023

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Molecules 2011, 16(7), 6023-6040; doi:10.3390/molecules16076023

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Benzylidene-bis-(4-Hydroxycoumarin) and Benzopyrano-Coumarin Derivatives: Synthesis, ¹H/¹³C-NMR Conformational and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations

Davorka Završnik¹, Samija Muratović¹, Damjan Makuc^2,3, Janez Plavec^2,3,4, Mario Cetina⁵, Ante Nagl⁵, Erik De Clercq⁶, Jan Balzarini⁶ and Mladen Mintas^7,*

¹ Faculty of Pharmacy, University of Sarajevo, Čekaluša 90, Sarajevo BA-71000, Bosnia and Hercegovina ² Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana SI-1000, Slovenia ³ EN-FIST Centre of Excellence, Dunajska 156, Ljubljana SI-1000, Slovenia ⁴ Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva cesta 5, Ljubljana SI-1000, Slovenia ⁵ Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovića 28a, Zagreb HR-10000, Croatia ⁶ Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium ⁷ Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, Zagreb HR-10000, Croatia

* Author to whom correspondence should be addressed.

Received: 13 June 2011; in revised form: 6 July 2011 / Accepted: 12 July 2011 / Published: 19 July 2011

(This article belongs to the Special Issue Antivirals)

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Abstract: 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 (ACV^r) 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.

Keywords: 4-hydroxycoumarin; benzopyranocoumarin; antiviral activity; ¹H/¹³C-NMR conformational study; X-ray diffraction

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MDPI and ACS Style

Završnik, D.; Muratović, S.; Makuc, D.; Plavec, J.; Cetina, M.; Nagl, A.; Clercq, E.D.; Balzarini, J.; Mintas, M. Benzylidene-bis-(4-Hydroxycoumarin) and Benzopyrano-Coumarin Derivatives: Synthesis, ¹H/¹³C-NMR Conformational and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations. Molecules 2011, 16, 6023-6040.

AMA Style

Završnik D, Muratović S, Makuc D, Plavec J, Cetina M, Nagl A, Clercq ED, Balzarini J, Mintas M. Benzylidene-bis-(4-Hydroxycoumarin) and Benzopyrano-Coumarin Derivatives: Synthesis, ¹H/¹³C-NMR Conformational and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations. Molecules. 2011; 16(7):6023-6040.

Chicago/Turabian Style

Završnik, Davorka; Muratović, Samija; Makuc, Damjan; Plavec, Janez; Cetina, Mario; Nagl, Ante; Clercq, Erik De; Balzarini, Jan; Mintas, Mladen. 2011. "Benzylidene-bis-(4-Hydroxycoumarin) and Benzopyrano-Coumarin Derivatives: Synthesis, ¹H/¹³C-NMR Conformational and X-ray Crystal Structure Studies and In Vitro Antiviral Activity Evaluations." Molecules 16, no. 7: 6023-6040.

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