Design, synthesis, and SAR study of isopropoxy allylbenzene derivatives as 15-lipoxygenase inhibitors

Document Type: Original Article

Authors

1 Department of Biology, Faculty of Science, Payame Noor University, Mashhad, Iran

2 Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Biology, Faculty of Science, Payame Noor university, Tehran, Iran

4 Department of Pharmaceutics, Faculty of Pharmacy, University of Al-Zahraa for Women, Karbala, Iraq

5 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Allylbenzenes have been recently developed as inhibitors of lipoxygenases. They decrease peroxidation activity via mimicking 1,4-unsaturated bonds of fatty acids by their allyl portion. We designed and synthesized new derivatives of allyl benzenes (6a-f) with isopropoxy and amide substituents at ortho and meta positions towards allyl group, respectively. The inhibitory potency of the synthetized allylbenzenes against soybean 15-lipoxygenase (SLO) and subsequently structure-activity relationships was assessed.
Materials and Methods: 3-allyl-4-isopropoxybenzenamine (5) as starting material was synthesized by coupling of 4-nitropheol with allyl bromide, performing Claisen rearrangement and finally reduction of the nitro moiety. Final products 6a-f were prepared via amidation of 5 with the desired acyl chloride.
Results: Among the compounds, N-(3-allyl-4-isopropoxyphenyl)adamantan carboxamide (6f) potentially showed best inhibition (IC50 = 1.35 µM) while 6a with cyclopropyl carboxamide moiety was the weakest inhibitor and 6e with phenyl carboxamide moiety showed no effect. Energy minimized 3D structures of the compounds were docked into the active site pocket of SLO. For the aliphatic amides, docking results showed compatibility between inhibitory potency and average Ki of the cluster conformers, in which their allyl moiety oriented towards SLO iron core. For the aliphatic analogs, by enlargement of the amide moiety size the inhibitory potency was increased.
Conclusion: Docking results showed that orientation of the amide and allyl moieties of the inhibitors in the active site pocket is the major factor in inhibitory potency variation. Based on the mentioned orientation, for cycloaliphatic amides, by enlargement of the amide moiety both inhibition potency and calculated binding energy increases.

Keywords


1. Kuhn H, Borngraber S. Mammalian 15-lipoxygenases. Enzymatic properties and biological implications. Adv Exp Med Biol 1999; 447:5-28.
2. His LC, Wilson LC, Eling TE. Opposing effects of 15-lipoxygenase-1 and-2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma. J Biol Chem 2002; 277:40549-40556.
3. KuÈhn H, Barnett J, Grunberger D, Beacker P, Chow J, Nguyen B, et al. Overexpression, purification and characterization of human recombinant 15-lipoxygenase. J Biochim Biophys Acta 1993; 1169:80-89.
4. KuÈhn H, Thiele BJ, Ostareck-Lederer A, Stender H, Suzuki H, Yoshimoto T. Bacterial expression, purification and partial characterization of recombinant rabbit reticulocyte 15-lipoxygenase. J Biochim Biophys Acta 1993; 1168:73-78.
5. Alavi SJ, Sadeghian H, Seyedi SM, Salimi A, Eshghi H. A novel class of human 15-LOX-1 inhibitors based on 3-hydroxycoumarin. Chem Bio Drug Des 2018; 91:1125-1132.
6. Jabbari A, Davood Nejad M, Alimardani M, Assadieskandar A, Sadeghian A, Safradi H, et al. Synthesis and SAR studies of 3-allyl-4-prenyloxyaniline amides as potent 15-lipoxygenase inhibitors. J Bioorg Med Chem 2012; 20:5518-5526.
7. Sadeghian H, Jabbari A. 15-Lipoxygenase inhibitors: a patent review. Expert Opin Ther Pat 2016; 26:65-88.
8. Van Leyen K, Kim HY, Lee SR, Jin G, Arai K, Lo EH. Biacalein and 12/15- lipoxygenase in the ischemic brain. Stroke 2006; 37:3014-3018.
9. Mytilineou C, Kramer BC, Yabut JA. Glutathion depletion and oxidative stress. Parkinsonism. Relat. Disord. 2002; 8: 385-387.
10. Sadeghian H, Seyedi M, Attaran N, Jabbari A, Jafari Z. Synthesis and SAR comparative studies of 2-allyl4-methoxy-1-alkoxybenzenes as 15-lipoxygenase inhibitors. J Enzyme Inhib Med Chem 2011; 26:238-244.
11. Seyedi M, Jafari Z, Attaran N, Sadeghian H, Saberi MR, Riazi MM. Design, synthesis and SAR studies of 4-allyoxyaniline amides as potent 15-lipoxygensae inhibitors. Bioorg Med Chem 2009; 17:1614-1622.
12. Sadeghian H, Seyedi SM, Saberi MR, Arghiani Z, Riazi M. Design and synthesis eugenol derivatives, as potent 15-lipoxygenase inhibitors.  Bioorg Med Chem 2008; 16:890-901.
13. Sadeghian H, Attaran N, Jafari Z, Saberi MR, Seyedi, SM., Eshghi H., et al. Design and synthesis of 4-methoxyphenylacetic acid esters as 15-lipoxygenase inhibitors and SAR comparative studies of them. Bioorg Med Chem 2009; 17:2327-2335.
14. Iranshahi M, Jabbari A, Orafaie A, Mehri R, Zeraatkar S, Ahmadi T, et al. Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors. Eur J Med Chem 2012; 57:134-142.
15. Nikpour M, Mousavian M, Davoodnejad M, Alimardani M, Sadeghian H. Synthesis of new series of pyrimido[4,5-b][1,4] benzothiazines as 15-lipoxygenase inhibitors and study of their inhibitory mechanism. Med Chem Res 2013; 22:5036-5043.