BACKGROUND: Currently, used oral antiplatelet drugs are both limited and associated with the risk of treatment failure/resistance. Research in this area is hence highly desired. A series of xanthene-3-ones derivatives, we had synthesized, showed us that these derivatives had antiplatelet activity. As far as we know, no research on the effects of xanthen-3-ones in this area has been done. OBJECTIVE: The aim was to study the antiplatelet potential of a series of synthesised 9-phenylxanthene- 3-ones and to find the ideal structural feature(s) for antiplatelet potential and determine the mechanism of action. METHODS: The compounds were synthesized from 1,2,4-triacetoxybenzene and various benzaldehydes. The reaction proceeded smoothly under acidic alcoholic conditions, furnishing the desired products in good yields. The compounds were first screened in whole human blood where platelet aggregation was induced by arachidonic acid. Further analysis was targeted at search of the mechanism of action. RESULTS: Initial screening showed that a majority of the synthesized derivatives had substantial antiplatelet potential. None of the compounds were able to block cyclooxygenase 1 or thromboxane synthase. The mechanism appeared to be based on antagonism of thromboxane effects. The most potent compound 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxy-xanthene-3-one had better potential to block collagen induced platelet aggregation than clinically used acetylsalicylic acid. CONCLUSION: The last mentioned derivative is promising for further in vivo testing.

Department of Pharmaceutical Botany and Ecology Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Pharmaceutical Chemistry Faculty of Pharmacy in Sarajevo University of Sarajevo Cekalusa 90 71000 Sarajevo Bosnia and Herzegovina

Department of Pharmacognosy Faculty of Pharmacy in Sarajevo University of Sarajevo Cekalusa 90 71000 Sarajevo Bosnia and Herzegovina

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Physiology and Pharmacology Vittorio Erspamer Sapienza University of Rome Piazzale Aldo Moro 5 00185 Rome Italy

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$a Applová, Lenka $u Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. $7 xx0277670

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$a 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxy-xanthene-3-one is a Potentially Novel Antiplatelet Drug which Antagonizes the Effect of Thromboxane A2 / $c L. Applova, E. Veljovic, S. Muratovic, J. Karlickova, K. Macakova, D. Zavrsnik, L. Saso, K. Duric, P. Mladenka,

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$a BACKGROUND: Currently, used oral antiplatelet drugs are both limited and associated with the risk of treatment failure/resistance. Research in this area is hence highly desired. A series of xanthene-3-ones derivatives, we had synthesized, showed us that these derivatives had antiplatelet activity. As far as we know, no research on the effects of xanthen-3-ones in this area has been done. OBJECTIVE: The aim was to study the antiplatelet potential of a series of synthesised 9-phenylxanthene- 3-ones and to find the ideal structural feature(s) for antiplatelet potential and determine the mechanism of action. METHODS: The compounds were synthesized from 1,2,4-triacetoxybenzene and various benzaldehydes. The reaction proceeded smoothly under acidic alcoholic conditions, furnishing the desired products in good yields. The compounds were first screened in whole human blood where platelet aggregation was induced by arachidonic acid. Further analysis was targeted at search of the mechanism of action. RESULTS: Initial screening showed that a majority of the synthesized derivatives had substantial antiplatelet potential. None of the compounds were able to block cyclooxygenase 1 or thromboxane synthase. The mechanism appeared to be based on antagonism of thromboxane effects. The most potent compound 9-(4'-dimethylaminophenyl)-2,6,7-trihydroxy-xanthene-3-one had better potential to block collagen induced platelet aggregation than clinically used acetylsalicylic acid. CONCLUSION: The last mentioned derivative is promising for further in vivo testing.

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$a Veljovic, Elma $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy in Sarajevo, University of Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina.

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$a Muratovic, Samija $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy in Sarajevo, University of Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina.

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$a Karlickova, Jana $u Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.

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$a Macakova, Katerina $u Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.

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$a Zavrsnik, Davorka $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy in Sarajevo, University of Sarajevo, Cekalusa 90, 71000 Sarajevo, Bosnia and Herzegovina.

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$a Saso, Luciano $u Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.

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$a Duric, Kemal $u Department of Pharmacognosy, Faculty of Pharmacy in Sarajevo, University of Sarajevo, Cekalusa 90, 71000 Sarajevo. Bosnia and Herzegovina.

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$a Mladenka, Premysl $u Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.

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