Original article Structure based drug design, synthesis and evaluation of 4-(benzyloxy)-1- phenylbut-2-yn-1-ol derivatives as 5-lipoxygenase inhibitors Nimmanapalli P. Reddy a , T. Chandramohan Reddy a , Polamarasetty Aparoy a , Chandrani Achari a , P. Ramu Sridhar b , Pallu Reddanna a, * a School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India b School of Chemistry, University of Hyderabad, Hyderabad 500 046, India article info Article history: Received 8 July 2011 Received in revised form 13 October 2011 Accepted 1 November 2011 Available online 10 November 2011 Keywords: 4-(Benzyloxy)-1-phenylbut-2-yn-1-ol derivatives 5-LOX Site point connection method In silico prediction Carcinoma cell line Acute lung injury abstract A group of 4-(benzyloxy)-1-phenylbut-2-yn-1-ol derivatives were designed using Site point connection method, synthesized and evaluated for their 5-Lipoxygenase (5-LOX) inhibitory activity. Hydrophobic site points in 5-LOX were considered for the study and substitutions were planned such that 4k will have strong hydrophobic group in the corresponding site point. Biological results supported the in silico prediction with compound 4k exhibiting good inhibition with IC 50 value of 8 mM against 5-LOX. The compounds 4j and 4k showed potent cytotoxic effects against various cancer cell lines (COLO-205, MDA- MB-231 and HepG2) but with no effect on normal cell line (HaCaT). The overall trend showed 4k as the most potent compound. Further studies demonstrated the protective effect of 4k in mouse Acute Lung Injury (ALI) model induced by lipopolysaccharide (LPS). Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Leukotrienes (LTs) are potent lipid mediators of inflammation [1]. The first step for LT biosynthesis requires 5-lipoxygenase (5- LOX), which, in the presence of 5-LOX-activating protein (FLAP), converts arachidonic acid into LTA 4 [2]. LTs have been implicated as inflammatory mediators in experimental models of acute lung injury (ALI) [3,4] and are known to contribute to the pathophysi- ology of osteoarthritis, asthma and other cancers including pros- tate, lung, breast and colon [5]. They were found to be elevated in pulmonary edema fluid obtained from patients with human acute respiratory distress syndrome (ARDS) [6]. MK886, a 5-LOX inhibitor has been shown to improve lung function by decreasing inflam- matory parameters including LTB 4 induced by mechanical venti- lation in a piglet model of airway lavage [7]. Recently, it has been shown that 5-LOX (ALOX5) is a critical regulator for leukemia cancer stem cells (LSCS) in chronic myeloid leukemia (CML) [8]. With an increase in reports illustrating the role of 5-LOX in various pathological conditions there is a growing demand for the development of potential and novel 5-LOX inhibitors [5]. In this study we focused on the development of 5-LOX inhibitors and their role in ALI. ALI is a significant cause of morbidity and mortality in critically ill patients. Histologically, ALI in humans is characterized by a severe acute inflammatory response in the lungs and neutrophilic alveolitis [9,10]. Inflammatory stimuli from microbial pathogens, such as endotoxin [lipopolysaccharide (LPS)], are well recognized for their ability to induce pulmonary inflammation and experi- mental administration of LPS, both systemically and intratracheally, has been used to induce pulmonary inflammation in animal models of ALI [11e 13], characterized by activation of alveolar macrophages, infiltration of neutrophils, lung edema and production of inflam- matory mediators that resemble the inflammation and ALI seen in ARDS [14]. However, despite decades of research, few therapeutic strategies for clinical ARDS have emerged and current specific options for treatment are limited [15e17]. Studies suggest a causal role for 5-LOX and LTs in LPS-induced ALI [18,19]. It has been re- ported that mediators including LTB 4 , are considered to be the major causes of ALI because of their strong effect on neutrophil activation and migration [20]. The increase in studies illustrating the role of 5-LOX in various diseases has increased interest in the development of * Corresponding author. Tel.: þ91 40 23134542; fax: þ91 40 23010745. E-mail addresses: prsl@uohyd.ernet.in, preddanna@yahoo.com (P. Reddanna). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.11.003 European Journal of Medicinal Chemistry 47 (2012) 351e359