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Electrochemical Synthesis of Novel 1,3-Indandione Derivatives and Evaluation of Their Antiplatelet Aggregation Activities

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Electrochemical Synthesis of Novel 1,3-Indandione Derivatives and Evaluation of Their Antiplatelet Aggregation Activities Iranian Journal of Pharmaceutical Research (2013), 12 (supplement): 91-103 Copyright © 2013 by School of Pharmacy Received: September 2012 Shaheed Beheshti University of Medical Sciences and Health Services Accepted: February 2013 Original Article Electrochemical Synthesis of Novel 1,3-Indandione Derivatives and Evaluation of Their Antiplatelet Aggregation Activities Salimeh Amidia, Farzad Kobarfardab*, Abdolmajid Bayandori Moghaddamc Kimia Tabiba and Zohreh Soleymania aDepartment of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. bPhytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. cDepartment of Engineering Science, College of Engineering, University of Tehran, P.O. Box 11155-4563, Tehran, Iran. Abstract Electrochemical oxidation of some selected catechol derivatives, using cyclic voltammetry, in the presence of different 2-aryl-1,3-indandiones as nucleophiles, resulted in electrochemical synthesis of new 1,3- indandione derivatives in an undivided cell in good yield and purity. A Michael addition mechanism was proposed for the formation of the analogs based on the reaction conditions which were provided in electrochemical cell. The in-vitro antiplatelet and anticoagulant activity of these compounds was evaluated, using arachidonic acid (AA) and adenosine diphosphate (ADP) as the platelet aggregation inducers. The results show that the incorporation of catechol ring in 1,3-indandione nucleus leads to the emergence of antiplatelet aggregation activity in these compounds. The compounds may exert their antiaggregation activity by interfering with the arachidonic acid pathway. Keywords:Electrochemical synthesis; 1,3-Indandione; Platelet aggregation inhibition. Introduction anticoagulants and platelet aggregation inhibitors is frequently used in high risk patients in order Stroke and cardiovascular diseases are the to achieve more efficient clinical results (4-5). major reasons of morbidity and mortality in the However, these medications exhibit some side world (21.9% of total death) which are mainly effects such as aspirin-related gastrointestinal caused by thrombus formation and platelet ulcers, allergy and bleeding or warfarin-induced activation (1). skin necrosis (3, 6). Furthermore, the efficacy of Antiplatelet agents such as aspirin these drugs is not still satisfactory. Therefore, (acetylsalicylic acid), clopidogrel or ticlopidine medicinal chemists are still trying to find new and anticoagulants such as warfarin are currently drug candidates in this therapeutic area (7). two predominant groups of orally consumable Quercetin (I) is a naturally occurring flavonoid drugs in standard therapeutic protocols for structurally related to coumarins with a catechol prophylaxis and treatment of venous thrombosis ring at its position 2 of coumarin scaffold (Figure and reducing the risk of recurrent myocardial 1). It was also shown to be effective inhibitor of infarction (2-3). Combination therapy with platelets aggregation in dogs and monkeys (8). Catechol (II) is a diphenolic derivative * Corresponding author: which could be electrochemically converted E-mail:[email protected] to 1,2-benzoquinone by a reversible two- Amidi S et al. / IJPR (2013), 12 (supplement): 91-103 OH O OH O O O OH HO O OCH3 OH OH O O O OH Quercetin (I) Catechol (II) 1,3- Indandione (III) Phenindione (IV) Anisindione (V) Cl OH O OH O O O O O O 4-Hydroxycoumarin (VI) Chlorophacinone (VII) Brodifacoum (VIII) Br Figure 1. Chemical structures of quercetin, catechol, 1,3-Indandione and coumarin derivatives. electron, two-proton oxidation (Figure 2). The formation of 2-substituted indandione. electrochemically generated o-benzoquinones 1,3-Indandione derivatives such as are quite reactive intermediates which in a phenindione (IV) and anisindione (V) are a group proper condition can be attacked by a variety of of anticoagulants with anti vitamin K activity nucleophiles and undergo various reactions such similar to 4-hydroxycoumarins (VI) (Figure 1). as Michael addition. Catechols are known to have antiplatelet Electrochemical methods are considered aggregation activity due to their prominent redox as green methods for the synthesis of organic power. Kitagawa et al, (9) have reported the compounds and our goal in the present study inhibitory effect of polyhydric phenols against was to use these methods for preparation of a arachidonic acid-induced aggregation of rabbit few novel catechol containing structures with platelets and they found catechol as the most potential antiplatelet aggregation activity. potent non-substituted dihydric phenols. 1,3-Indandiones (III) were selected as In fact, it has been reported that various the compounds with nucleophilic carbon. phenolic compounds such as quercetin inhibit 1,3-Indandione is an aromatic β-diketone. In platelet cyclooxygenase (10). the solid state it occurs as a diketone while in Dolmella et al. (11) have proposed a three- solution, it is partially enolized and the enolate dimensional (3D) biophore model that explains anion exhibits significant delocalization and the the requirements for efficient indandione and highest electron density is on the second carbon. coumarin derivatives. They have suggested two If catechol is oxidized to o-benzoquinone domains in the structure of these derivatives: a in the presence of indandione derivatives, a recognition domain which consists of a phenyl Michael addition reaction will occur between ring plus two negatively charged oxygens indandione and o-benzoquinone resulting to the (recognition flag), and an activity domain which OH O -2 e - 2 H OH O Catechol (II) 1, 2 - benzoquinone (IX) Figure 2. Electrochemical conversion of catechol to 1,2-benzoquinone. 92 Electrochemical Synthesis of Novel 1,3-Indandione Derivatives Figure 3. Main parameters of the biophore model. V is excluded volume (11). starts half way between the two oxygens on a purity of the products, easy process and better short aliphatic chain and consists of a second control over the reaction process. They are also phenyl ring attached to the terminal atom of considered as green chemical synthesis methods the chain (Figure 3). Indandione and coumarin (16-17). derivatives, with a bulky lipophilic side chain Here, we used a simple one-pot at activity domain such as chlorophacinone electrochemical synthesis for preparing the (VII) and brodifacoum (VIII), enjoy more proposed indandione derivatives and the potency due to establishing an additional drug- antiplatelet aggregation activities of these new receptor interaction by this extra anchoring compounds were evaluated. group (Figure 1) (11). According to the previously reported methods Our goal in this study was incorporating for the synthesis of compound 15a-b (15-16), we a catechol ring to the structure of indandione described here a facile one pot electrochemical derivatives in the activity domain of Dolmella’s method for the synthesis of new indandione model. The catechol ring is assumed to increase derivatives (16a-b, 17a-b, 18a-b, 19a-b). the resemblance of these compounds to quercetin The key reactions involved the and they are thus expected to show antiplatelet electrooxidation of catechol derivatives aggregation activity. (compouds12-14) in the presence of indandiones Different methods have been used for the (7-11) as nucleophiles. Compounds 7-11 are synthesis of 1,3-indandione derivatives with 1,3-diketones with an acidic methylene group substitution at position 2. Beringer et al. (12) at position 2, which is easily converted to their and Matano et al. (13) reported phenylation of corresponding enolate ions (7i – 11i). These 1,3-Indandione with diaryliodonium salts and can act as nucleophile in Michael addition α-alkenylation of β-dicarbonyl compounds with reaction and add to the beta carbon of an α,β- alkenyltriarylbismuthonium salts, respectively. unsaturated system. Compounds 12-14 could be The Friedel-Crafts methods were also reported for electrochemically oxidized to its corresponding the derivatization of 1,3-indandione at position 2 quinonic form (12i-14i). When the oxidation (14). In addition to these conventional methods, process takes place in the presence of 7-11, the the electrochemical synthesis has also been used methylene group of compounds 7-11 can attack for preparation of indandione derivatives with the quinonic ring in a Michael type addition catechol or 2,3-dimethylhydroquinone ring on reaction. The quinine ring could then be reduced their position 2 (15-17). The main advantages electrochemically, using a cyclic voltammetric of the electrochemical methods lie in their high process, to regenerate the reduced form of 93 Amidi S et al. / IJPR (2013), 12 (supplement): 91-103 OH OH R2 R3 12-14 -2e, -2H O O O O R 1 -H R1 +H R2 O O R 7-11 7i-11i 3 12i-14i HO OH OH O O O R2 R2 R3 H R3 O O 15a-c 16a-c 15ia-ic 16ia-ic 17a-c R1 18a-c 17ia-ic 19a-c 18ia-ic R1 19ia-ic The overall reaction : HO OH 3 4 O OH O 2 5 OH R2 1 6 R1 -2e, -2H R R2 3 O R3 15a-c O 7-11 12-14 16a-c 17a-c 18a-c R1 19a-c R1 R2 R3 R = H 7 1 12 R2 = H R3= H 15a H H H R = F 15b H CH3 H 8 1 13 R2 = CH3 R3= H 9 R = Cl 15c H H COOH 1 14 R2 = H R3= COOH 10 R1 = Br 16a F H H 11 R1 = OCH3 16b F CH3 H 16c F H COOH 17a Cl H H 17b Cl CH3 H 17c Cl H COOH 18a Br H H 18b Br CH3 H 18c Br H COOH 19a OCH3 H H 19b OCH3 CH3 H 19c OCH3 H COOH Figure 4. Mechanism of Michael addition reaction occurred in electrochemical cell. 94 Electrochemical Synthesis of Novel 1,3-Indandione Derivatives O O NaOC2H5 O R R H C2H5OH O Reflux O R : H, F, Cl, Br, OCH3 R : H, F, Cl, Br, OCH3 1 2-6 7-11 Figure 5. Synthesis route of 1,3-indandiones 7-11. catechol ring (Figure 4). on a 500 MHz Bruker spectrometer and the Compounds 7-11 were prepared by chemical shifts were expressed in δ (ppm) condensation of phthalide (1) with appropriate using TMS (tetramethylsilane) as an internal benzaldehydes (2-6), in the presence of sodium standard.
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