title: Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor.
abstract: The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31-27.61 μM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity.
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 UPM Serdang, Malaysia. nch_chean@hotmail.com.
authors.forename: Chean Hui
authors.initials: CH
authors.lastname: Ng
authors.affiliation: Faculty of Pharmacy, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. kamalrullah@yahoo.co.id.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rullah
authors.affiliation: Faculty of Pharmacy, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. fadhfasihi@yahoo.com.
authors.forename: Mohd Fadhlizil Fasihi Mohd
authors.initials: MF
authors.lastname: Aluwi
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 UPM Serdang, Malaysia. faridah_abas@upm.edu.my.
authors.forename: Faridah
authors.initials: F
authors.lastname: Abas
authors.affiliation: Faculty of Pharmacy, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. david_lam_98@yahoo.com.
authors.forename: Kok Wai
authors.initials: KW
authors.lastname: Lam
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 UPM Serdang, Malaysia. safinar@upm.edu.my.
authors.forename: Intan Safinar
authors.initials: IS
authors.lastname: Ismail
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 UPM Serdang, Malaysia. nrkishnan@gmail.com.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Narayanaswamy
authors.affiliation: Forest Research Institute (FRIM), Selangor Darul Ehsan, 52109 Kepong, Malaysia. fadzureena@frim.gov.my.
authors.forename: Fadzureena
authors.initials: F
authors.lastname: Jamaludin
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 UPM Serdang, Malaysia. khozirah@yahoo.com.my.
authors.forename: Khozirah
authors.initials: K
authors.lastname: Shaari
mesh_terms: D000098:Acetophenones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008084:Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D016859:Lipoxygenase Inhibitors; D008084:Lipoxygenase
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