Novel 1,3-diarylpyrazole acrylamides: synthesis, antiplatelet activity screening, and in silico evaluation studies
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Med Chem Res DOI 10.1007/s00044-013-0580-x
ORIGINAL RESEARCH
Novel 1,3-diarylpyrazole acrylamides: synthesis, antiplatelet activity screening, and in silico evaluation studies Sultan Nacak Baytas • Nazan Inceler • Yesim Ozkan • Serdar Unlu • M. Fethi Sahin
Received: 8 November 2012 / Accepted: 11 March 2013 Ó Springer Science+Business Media New York 2013
Abstract (E)-3-[3-(pyridin-4-yl)-1-phenyl-1H-pyrazole4-yl]acryl amides were evaluated for their antiplatelet activities. Compounds 4o and 4r were found as active derivatives showing a potent inhibitory activity on the arachidonic acid-induced aggregation, with IC50 of 20.2 and 30.3 lM, respectively. Compounds 4j, 4k, and 4u presented significant inhibitor effect on collagen-induced platelet aggregation (73.1, 82.5, and 86.7 %, respectively). All synthesized compounds demonstrated good drug-likeness and drug-score values in silico evaluations. Keywords Antiplatelet activity 1,3-Diarylpyrazoles Acryl amides Arachidonic acid Collagen
Introduction Cardiovascular diseases are responsible for the largest number of natural deaths worldwide. Cardiac conditions involving thrombotic disorders include acute myocardial infarction, valvular heart disease, unstable angina, and atrial fibrillation (Yusuf et al., 2001). Platelet adhesion and S. N. Baytas (&) N. Inceler S. Unlu M. Fethi Sahin Division of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06330 Ankara, Turkey e-mail: [email protected] Y. Ozkan Department of Biochemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey Present Address: S. Unlu FARGEM (Pharmaceutical Research and Development Center) Inc., Sancaklar Mevkii, 81100 Du¨zce, Turkey
aggregation are key events in homeostasis and thrombosis (clot formation). Hyperactivity of platelets increases the risk of various vascular diseases, such as unstable angina, acute myocardial infarction, transient ischemic attacks, stroke, and complications following percutaneous coronary intervention (Fuster et al., 1992; Davis and Thomas, 1985; Trip et al., 1990; Jackson and Schoenwaelder, 2003). Thus, antiplatelet therapy is a basic tool in the prevention and treatment of atherothrombotic diseases. In injured vessels, blood aggregation is generated as a physiological defense reaction by releasing biologically active compounds such as adenosine diphosphate (ADP), thrombin, and prostaglandin endoperoxide. Agonists such as thrombin, arachidonic acid (AA), thromboxane A2 (TxA2), platelet-activating factor (PAF), and collagen are able to induce platelet aggregation. Among these agonists, AA is one of the most powerful agonists for platelet activation (Fuster et al., 1992; Arita and Hansaki, 1989; Needleman et al., 1986). Currently, different antiplatelet agents such as ticlopidine, clopidogrel, glycoprotein IIb/IIIa inhibitors, and acetylsalicylic acid (ASA) are available for clinical use. However, they have certain disadvantages such as notable side effects (i.e., gastric erosion, agranulocytosi
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