Synthesis, Characterization and Urease Inhibition Studies of Transition Metal Complexes of Thioureas Bearing Ibuprofen Moiety

Abstract

Starting from ibuprofen, a non-steroidal anti-inflammatory drug, N,N'-disubstituted thiourea derivatives were synthesized by refluxing the acid chloride of ibuprofen with potassium thiocyanate followed by substituted anilines to get N-2- (4-(2-methylpropyl) phenyl)propionoyl-N´-(2´-bromophenyl) thiourea (1), N-2-(4-(2-methylpropyl)phenyl)propionoyl-N´-(2´-chlorophenyl) thiourea (2) and N-2-(4-(2-methylpropyl)phenyl)propionoyl-N´-(3´,4´-dichlorophenyl) thiourea (3).Metal complexes (4-15) of (1-3) were synthesized by refluxing it with one equivalence salts of Co (ΙΙ), Ni(ΙΙ), Pb(ΙΙ) and Cu(Ι). Structures of all the synthesized thiourea ligands and their metal complexes were determined by FTIR and 1 HNMR spectroscopy. Shift in stretching frequency in FTIR and resonance frequency in 1 HNMR spectroscopic data suggested that the ligands and metal are coordinated to afford respective metal complexes M[L] n . The synthesized compounds were tested against urease enzyme and the results were compared with standard thiourea, as positive control. Most of the investigated compounds showed potential inhibitory activity against Jack bean urease. Compound 5 was found to be the most potent urease inhibitor with IC 50 of 14.6 µM, whereas compounds 8, 11 and 12 possessed potent urease inhibition. The tested compounds can be taken as lead molecules for gastrointestinal ulcer therapy.Key words: Amides, Thioureas, Metal complexes, Ibuprofen, Urease. INTRODUCTIONUrease (urea aminohydrolase E.C. 3.5.1.5) is nickel containing metalloenzyme which belongs to the super family of amidohydrolases and phosphotriestreases, responsible for the hydrolytic decomposition of urea (Holm 1997). It was the first enzyme which crystallized from the plant source Canavalia ensiformis and was also the first protein containing nickel in the active site (Saeed et al. 2014;Saeed et al. 2013). Because of these characteristics urease is considered as a paradigm in the development of inorganic biochemistry. Urease catalyses the hydrolysis of urea in different plants, algae, fungi, and microorganisms to produce ammonia and carbamate (Mobley HL 1989). Enzyme catalysed hydrolysis-process occurred at a rate of approximately 10 14 times the rate of the unanalyzed reaction and considered as the final step of nitrogen metabolism in all living organisms. Different types of urease enzymes can be isolated from bacteria, fungi, algae and plants but enzymatic activity is same due to the occarance of the same order of amino acid (Bacanamwo M 2002;Benini S 1999). Urease activity due to infectious microorganism is the major reason for many deceases in humans such as development of infection stones, pyelonephritis, stomach and peptic ulcer, urinary catheter encrustation, and hepatic com (Gripenberg-Lerche C 2000; Mobley et al. 1995;Mobley HL 1989). To overcome these diverse types of problems, urease inhibitors have received special attention over the past few years. These inhibitors generally divided into two classes, substrate structural analogs like hydroxamic acid (Ko...

Structure and surface analyses of a newly synthesized acyl thiourea derivative along with its in silico and in vitro investigations for RNR, DNA binding, urease inhibition and radical scavenging activities

“…The compound (4) has shown highly signicant urease inhibitory efficiency with IC 50 AE SEM value of 0.0389 AE 0.0017 mM as compared to thiourea used as the standard inhibitor (18.2 AE 0.297 mM). With this least IC 50 value, compound (4) not only showed its excellent inhibitory activity towards urease enzyme in comparison to standard inhibitor but also this value was found less than that of some other thiourea derivatives reported for their potent urease inhibitory activity which include transition metal complexes of thioureas (the values for 12 complexes ranges from 14.6 AE 3.3 to 68.9 AE 4.92 mM), 56 thiourea and urea derivatives (the values for 33 derivatives ranges from 10.11 AE 0.11 to 72.99 AE 3.71 mM), 57 atenolol thiourea hybrid (the values for 23 derivatives ranges from 11.73 AE 0.28 to 212.24 AE 0.42 mM), 58 N-monoarylacetothioureas (among b1-b29, b19 was claimed excellent against both extracted urease and urease in intact cell with IC 50 values of 0.16 AE 0.05 and 3.86 AE 0.10 mM, respectively). 59 In vitro and in silico results along with comparison of the IC 50 with the reported literature, indicated compound (4) a potential candidate that can be used as template for formulating drug for the treatment of urinary tract diseases.…”

Exploring the latest trends in chemistry, structure, coordination, and diverse applications of 1-acyl-3-substituted thioureas: a comprehensive review

“…The carbonyl, thiocarbonyl and nitrogen atoms of acyl thiourea provide this moiety efficient ligating ability, therefore, various metal complexes with potential applications are a eld of interest for researchers. 74 In this section, the synthesis and structural aspects of such metal complexes are presented. N-((5-Bromopyridin-2-yl)carbamothioyl)-2-chlorobenzamide HL 1 and N-((5-bromopyridin-2-yl)carbamothioyl)furan-2carboxamide HL 2 and their metal complexes (123 and 124) with Co, Ni, and Cu were synthesized by Yes ¸ilkaynak et al by combining individual ethanolic solutions of metal and ligand in the presence of triethyl amine.…”

Recent trends in chemistry, structure, and various applications of 1-acyl-3-substituted thioureas: a detailed review

“…Because of the presence of sulphur and nitrogen atoms they act as valuable ligands and coordinate a variety of metal centers and form stable metal complexes. 41 In this section, we will discuss the recent metal complexes of thioureas along with their crystal X-ray diffraction analysis.…”