Research Article STRUCTURE-ACTIVITY RELATIONSHIP STUDY: SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL INVESTIGATION OF SCHIFF BASES DERIVED FROM 2-AMINOPHENOL AND 4- HALOACETOPHENONES MUHAMMAD ASLAM 1,2 , ITRAT ANIS 2 , NIGHAT AFZA 1* , AJAZ HUSSAIN 3 , LUBNA IQBAL 1 , JAMSHED IQBAL 4 , ZAITOON ILYAS 4 , 1 SAMINA IQBAL, ASIF HANIF CHAUDHRY 5 AND MUHAMMAD NIAZ 1 1 Pakistan Council of Scientific and Industrial Research, Karachi-75280, Pakistan, 2 Department of Chemistry, University of Karachi, Karachi-75270, Pakistan, 3 Department of Chemistry, Government College University, Faisalabad-38040, Pakistan, 4 Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology Abbottabad-22060, Pakistan, 5GARL, GSP, Islamabad, Pakistan. Email: hocprc@yahoo.com Received: 01 August 2012, Revised and Accepted: 22 August 2012 ABSTRACT Two biologically active Schiff bases (imines) 4-5 were synthesized by the reaction of 2-aminophenol 1 with 4-chloroacetophenone 2 or 4- hydroxyacetophenone 3 in the presence of conc. H2SO4. The characterization of Schiff bases were carried out by using spectroscopic techniques including IR, 1 H-NMR, EI-MS along with elemental analyses. The Schiff bases were checked for biological screening and found that the compound with -OH group to be more biologically active than the compound with halo (-X) group. The Schiff base 5 is a potent antioxidant agent as well as α- glucosidase inhibitor. The Schiff bases 4-5 also have excellent antibacterial activity for strains; Bacillus subtilis, Staphylococcus aureus, Escherichia coli while moderate for Salmonella typhi and Pseudomonas aeruginosa, against gentamicin as standard drug. Keywords: Schiff Base, Structure-Activity Relationship, Potent Antioxidant Agent, α-Glucosidase Inhibitor, Lipoxygenase Inhibition Activity, Urease Inhibition Activity. INTRODUCTION Many Schiff bases are known to be medicinally important and used to design medicinal compounds 1 . Schiff bases are the compounds which possess an azomethine linkage (Fig. 1) and are found to attribute various pharmacological activities like antibacterial 2 , antifungal 3 , antimalarial 4 , antimicrobial 5 , antiviral 6 , anticancer 7 , antitubercular 8 and antiinflammatory activity. They also serve as a back bone for the synthesis of various heterocyclic compounds. The use of schiff bases as acid base indicators has also been observed. In this connection, sulfanilamide was condensed with p-dimethylaminobenzaldehyde and it was found that the reagent solution showed a reproducible change in its color upon the addition of base and acid 9 . A large number of reports on the preparation and reaction applications of such compounds are published every year 10 . As a result, a new series from this class of compounds (i.e. hydrazones) is utilized in metal coordination chemistry for the formation of metal complexes 11 . The enantioselective cyclopropanation of styrenes is carried out by using Schiff bases and their metal complexes 12 . The imine groups (-RC=N-) are usually achieved by the condensation of active carbonyl compounds with primary mono and diamine in methanol or any other suitable solvent. In addition to that, a large variety of transition metal complexes based on hydrazones have been prepared due to the involvement of hydrazone chemistry in the coordination complexes and their increased biological significance 13 . These complexes can behave as electroluminescent materials like schiff base complexes of Zn (II) which are being used these days 14 . It was found that the preparation of potentiometric sensors for determining cations and anions involves the use of Schiff bases as carrier compounds 15 . The use of schiff bases as corrosion inhibitors for mild steel and similarly copper, zinc and aluminum has also been observed 16 . Moreover, interesting photophysical properties are exhibited by Schiff base compounds and their complexes17. Schiff bases are also employed as protective groups in organic synthesis for amino groups18. Antioxidant A number of activated oxygen forms are produced during metabolism and include reactive oxygen species (ROS), like non free radical species such as H2O2, free radicals such as anion radicals (O2-), hydroxyl radical (OH•) and singlet oxygen (1O2) species19, and etiology and pathophysiology of human aging is associated with these species20 and is the major reason of, cancer, Alzheimer’s disease, coronary heart disease21, cataracts and inflammation, neurodegenerative disorders, and atherosclerosis22. Antioxidants are the species which protect human body from oxidation by reacting with active oxygen species. Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are among the most commonly used antioxidants. Urease The study of enzyme inhibition is the most significant area of pharmaceutical research because a number of useful drug discoveries for a variety of physiological conditions were based on such studies. The activity of enzymes is blocked by the interaction of various enzyme inhibitors. The potent antiulcer drugs are based upon enzyme inhibitors in recent days. Sardonically, the first crystallized enzyme was urease but no clear picture of its mechanism of action was reported in literature. The broad classification of urease inhibitors includes two categories such as: (i) Inhibitors directed by active site (substrate-like), (ii) Inhibitors directed by mechanism. Only few inhibitors having binding mode analogous to urea can inhibit urease due to its high substrate (urea) specificity. The enzyme-inhibitor complex is stabilized by various non-covalent interactions like hydrogen bonding and hydrophobic interactions of inhibitors with the enzyme. The functional groups having electronegative atoms like nitrogen, oxygen and sulfur etc. are among the reported functional groups which serve as bidentate in most of the cases and tridentate in few cases, or as ligand-chelator to form distorted octahedral complexes with nickel ion in the enzyme. The presence of bulky groups in the the pharmacophore causes a decrease in the activity of inhibitors and the absence of bulky groups results in easy entry of urease inhibitors into the substrate binding pockets of enzyme. Moreover, the lack of bulky groups also decreases the chances of unfavourable steric interaction of inhibitor with the amino acid residues of enzyme23. Lipoxygenase A family of non-haeme iron-containing dioxygenases, called lipoxygenases (LOXs) which have been considered to serve a major role in the pathophysiology of several inflammatory and allergic diseases, are the key enzymes involved in the biosynthesis of leukotrienes. The oxygenation catalyzed by LOXs produces some moities like hydroperoxyeicosatetraenoic acids (HPETE), hydroxyeicosatetraenoic acids (HETE), leukotrienes and lipoxins , which are apparently taking part in rheumatoid arthritis, psoriasis, asthmatic responses and glomerular nephritis24.