Synthesis of new series of pyrimido[4,5- b ][1,4] benzothiazines as 15-lipoxygenase inhibitors and study of their inhibi
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Med Chem Res (2013) 22:5036–5043 DOI 10.1007/s00044-013-0506-7
ORIGINAL RESEARCH
Synthesis of new series of pyrimido[4,5-b][1,4] benzothiazines as 15-lipoxygenase inhibitors and study of their inhibitory mechanism Mohsen Nikpour • Mina Mousavian • Mahdieh Davoodnejad • Maliheh Alimardani Hamid Sadeghian
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Received: 31 October 2012 / Accepted: 18 January 2013 / Published online: 6 February 2013 Ó Springer Science+Business Media New York 2013
Abstract A series of 2-substituted 4-n-propyl pyrimido[4,5b][1,4]benzothiazines were synthesized, and evaluated as soybean 15-lipoxygenase (SLO) inhibitors. Among the synthesized compounds, 2-(4-methyl piperazinyl) analog showed the best SLO inhibition activity (IC50 = 8.9 ± 0.4 lM). To rationalize the inhibitory potency variation of the compounds, computer-assisted modeling of the enzyme-inhibitor, radical scavenging evaluation, and inhibitory mechanism analyses were performed. The results showed that in 4-alkyl pyrimido[4,5-b]benzothiazines with same 2-substituent, radical scavenging potency plays a key role in lipoxygenase inhibition. Keywords Docking Radical scavenging DPPH SAR DMAB
M. Nikpour Department of Chemistry, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran M. Mousavian Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran M. Davoodnejad M. Alimardani H. Sadeghian Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran H. Sadeghian (&) Microbiology & Virology Research Center, Buali Research Institute, Mashhad University of Medical Sciences, 91967-73117 Mashhad, Iran e-mail: [email protected]
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Introduction Mammalian lipoxygenases are a series of non-hem iron containing enzymes which oxidize unsaturated fatty acids and esters into hydroperoxide derivatives (Fig. 1). The above mentioned proteins are non-homogeneous enzymes that are widely found in plants and animals, nominated mainly based on situation in which a key substrate such as arachidonic acid or other 1,4-unsaturated fatty acids is oxidized. Nowadays, among the human lipoxygenases, 15-lipoxygenase (15-LO) is introduced as a novel therapeutic target for the treatment of virus-associated asthma characterized by a Th1 immune response to inhaled allergens (Jeon et al., 2009). The effect of 15-LO inhibition on the treatment of cardiovascular and atherosclerosis diseases has been discovered. In atherosclerosis, the above mentioned enzyme significantly expresses in macrophages (Cyrus et al., 1999; Harats et al., 2002). 15-Lipoxygenase (15-LO) metabolites influence the origination and progression of prostate cancer (Kelavkar et al., 2002). The final products of arachidonic acid peroxidation by 15-LO in eosinophils have been introduced as one of the inflammation source (Feltenmark et al., 2008). Three known groups of lipoxygenase inhibitors have been reported (Charlier and Michaux, 2003): (1) Reductive inhibitors or antioxidants interact with peroxidation cycle of LO; (2) Iron chelating inhibitors; and
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