title: PASS-assisted design, synthesis and antioxidant evaluation of new butylated hydroxytoluene derivatives.
abstract: New multipotent antioxidants (MPAOs), namely 1,3,4-thiadiazoles and 1,2,4-triazoles bearing the well-known free radical scavenger butylated hydroxytoluene (BHT), were designed and synthesized using an acid-(base-) catalyzed intramolecular dehydrative cyclization reaction of the corresponding 1-acylthiosemicarbazides. The structure-activity relationship (SAR) of the designed antioxidants was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antioxidant activity using DPPH and lipid peroxidation assays verified the predictions obtained by the PASS-assisted design strategy. Compounds 4a-b, 5a-b and 6a-b showed an inhibition of stable DPPH free radicals at a 10(-4) M more than the well-known standard antioxidant BHT. Compounds with p-methoxy substituents (4b, 5b and 6b) were more active than o-methoxy substituents (4a, 5a and 6a). With an IC50 of 2.85 ± 1.09 μM, compound 6b exhibited the most promising in vitro inhibition of lipid peroxidation, inhibiting Fe(2+)-induced lipid peroxidation of essential oils derived from the egg yolk-based lipid-rich medium by 86.4%. The parameters for the drug-likeness of these BHT derivatives were also evaluated according to Lipinski's 'rule-of-five'. All of the BHT derivatives were found to violate one of Lipinski's parameters (Log P ≥ 5) even though they have been found to be soluble in protic solvents. The predictive TPSA and %ABS data allow for the conclusion that these compounds could have a good capacity for penetrating cell membranes. Therefore, these novel MPAOs containing lipophilic and hydrophilic groups can be proposed as potential antioxidants for tackling oxidative stress and lipid peroxidation processes.
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Azhar
authors.initials: A
authors.lastname: Ariffin
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Noorsaadah Abdul
authors.initials: NA
authors.lastname: Rahman
authors.affiliation: Nanotechnology & Catalysis Research Centre (NANOCAT), University of Malaya, Block 3A, Institute of Postgraduate Studies Building, Kuala Lumpur 50603, Malaysia. Electronic address: wdabdoub@um.edu.my.
authors.forename: Wageeh A
authors.initials: WA
authors.lastname: Yehye
authors.affiliation: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Abeer A
authors.initials: AA
authors.lastname: Alhadi
authors.affiliation: Division of Basic Medical Sciences (Anatomy), Faculty of Medicine, Cyberjaya University College of Medical Sciences, Cyberjaya 63000, Selangor Darul Ehsan, Malaysia.
authors.forename: Farkaad A
authors.initials: FA
authors.lastname: Kadir
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D002084:Butylated Hydroxytoluene
keywords: 1,2,4-Triazole; 1,3,4-Thiadiazole; Butylated HydroxyToluene; Multipotent antioxidant; PASS; Thiosemicarbazide