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

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

1, 1, 2,3, 2,3,4, 5, 5, 6, 6 and 7,*
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 115 bearing an aryl substituent on the central linker and fused benzopyranocoumarin derivatives 1620 and on their in vitro broad anti-DNA and RNA virus activity evaluations. The chemical identities and structure of compounds 120 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 46, 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 4-hydroxycoumarin; benzopyranocoumarin; antiviral activity; 1H/13C-NMR conformational study; X-ray diffraction
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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