Jack Bean Urease Inhibitors, and Antioxidant Activity Based on Palmitic acid Derived 1-acyl-3- Arylthioureas: Synthesis, Kinetic Mechanism and Molecular Docking Studies

Abstract

A series of acylthioureas was synthesized and their inhibitory effects on the DPPH and jack bean urease were evaluated. The results showed that all of the synthesized compounds exhibited significant jack bean urease inhibitory activities. Especially, 1-(4-chlorophenyl)-3 palmitoylthiourea 5a bearing 4-chloro substituted phenyl ring exhibited the most potent tyrosinase inhibitory activity with an IC₅₀ value 0.0170 μM compared to the IC₅₀ value of 4.720 μM of thiourea used as standard. The inhibition mechanism analyzed by Lineweaver–Burk plots revealed that the type of inhibition of compound 5a on tyrosinase was noncompetitive. The docking study against jack bean urease enzyme was also performed to determine the binding affinity of the compounds. The compounds 4c and 4e showed the highest binding affinity with the active binding site of tyrosinase. The initial structure activity relationships (SARs) analysis suggested that further development of such compounds might be of interest. The statistics of our results endorses that all compounds and particularly 5a may serve as a structural template for the design and development of novel urease inhibitors [Graphical Abstract].

Graphical Abstract

Key words

antioxidant - Jack bean Urease - synthesis - acylthioureas - molecular docking - kinetic mechanism

• References

• 1 Upadhyay LSB. Urease inhibitors: A review. Indian. J. Biotechnol 2012; 11: 381-388
• 2 Han Y, Huo GF, Sun J. et al. Axle length-and solvent-controlled construction of (pseudo)[1] rotaxanes from mono-thiourea-functionalised pillar [5] arene derivatives. Supramol Chem 2017; 29: 547-552
• 3 Horta LP, Mota YC, Barbosa GM. et al. Urease Inhibitors of Agricultural Interest Inspired by Structures of Plant Phenolic Aldehydes. J. Brazilian. Chem. Soc 2016; 27: 1512-1519
• 4 Khan KM, Iqbal S, Lodhi MA. et al. Biscoumarin: New class of urease inhibitors; economical synthesis and activity Bioorg. Med. Chem 2004; 12: 1963-1968
• 5 Arfan M, Ali M, Ahmad H. et al. Urease inhibitors from Hypericum oblongifolium WALL. J. Enzym. Inhibit. Med. Chem 2010; 25: 296-299
• 6 Amtul Z, Rasheed M, Choudhary MI. et al. Kinetics of novel competitive inhibitors of urease enzymes by a focused library of oxadiazoles/thiadiazoles and triazoles. Biochem. Biophys. Res. Commun 2004; 319: 1053-1063
• 7 Khan KM, Ullah Z, Lodhi MA. et al. Successful computer guided planned synthesis of (4R)-thiazolidine carboxylic acid and its 2-substituted analogues as urease inhibitors. Mol. Divers 2006; 10: 223-231
• 8 Amtul Z, Siddiqui RA, Choudhary MI. Chemistry and mechanism of urease inhibition. Curr. Med. Chem 2002; 9: 1323-1348
• 9 Aslam MAS, Mahmood SU, Shahid M. et al. Synthesis, biological assay in vitro and molecular docking studies of new Schiff base derivatives as potential urease inhibitors. Eur. J. Med. Chem 2011; 46: 5473-5479
• 10 Saeed A, Zaib S, Pervez A. et al. Synthesis, molecular docking studies, and in vitro screening of sulfanilamide-thiourea hybrids as antimicrobial and urease inhibitors. Med. Chem. Res 2013; 22: 3653-3662
• 11 Saeed A, Khan MS, Rafique H. Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors. Bioorg. Chem 2014; 52: 1-7
• 12 Saeed A, Imran A, Channar PA. 2-(Hetero (aryl) methylene) hydrazine-1-carbothioamides as Potent Urease Inhibitors. Chem. Bio. Drug. Design 2015; 85: 225-230
• 13 Saeed A, Flörke U, Erben MF. A review on the chemistry, coordination, structure and biological properties of 1-(acyl/aroyl)-3-(substituted) thioureas. J. Sulf. Chem 2014; 35: 318-355
• 14 Zaib S, Saeed A, Stolte K. et al. New aminobenzenesulfonamide–thiourea conjugates: Synthesis and carbonic anhydrase inhibition and docking studies. Eur.J. Med. Chem 2014; 78: 140-150
• 15 Saeed A, Khurshid A, Jasinski JP. et al. Competing intramolecular N H⋯ O C hydrogen bonds and extended intermolecular network in 1-(4-chlorobenzoyl)-3-(2-methyl-4-oxopentan-2-yl) thiourea analyzed by experimental and theoretical methods. Chem. Phy 2014; 431: 39-46
• 16 Saeed A, Erben MF, Bolte M. Synthesis, structural and vibrational properties of 1-(adamantane-1-carbonyl)-3-halophenyl thioureas. Spectro. Acta Part A: Mol. Biomol. Spectro 2013; 102: 408-413
• 17 Saeed A, Khera RA, Abbas N. et al. Synthesis, characterization, crystal structures, and antibacterial activity of some new 1-(3, 4, 5-trimethoxybenzoyl)-3-aryl thioureasreas. Turk. J. Chem 2010; 34: 335-346
• 18 Raza R, Saeed A, Lecka J. et al. Identification of small molecule sulfonic acids as ecto-5’-Nucleotidase inhibitors. Med Chem 2012; 8: 1133-1139
• 19 Schroeder DC. Chem. Rev 1955; 55: 181-228
• 20 Saeed A, Shah MS, Larik FA. et al. Synthesis, computational studies and biological evaluation of new 1-acetyl-3-aryl thiourea derivatives as potent cholinesterase inhibitors. Med. Chem. Res 2017; 1-12
• 21 Madarász Á, Dósa Z, Varga S. et al. Thiourea derivatives as brønsted acid organocatalysts. ACS Catalysis 2016; 6: 4379-4387
• 22 Sahu S, Rani PS, Patel S. et al. Oxidation of thiourea and substituted thioureas: A review. J. Sulf. Chem 2011; 32: 171-197
• 23 Loto CA, Loto RT, Popoola API. Corrosion inhibition of thiourea and thiadiazole derivatives: A review. J. Mat. Environ. Sci 2012; 3: 885-894
• 24 Larik FA, Saeed A, Channar PA. et al. New 1-octanoyl-3-aryl thiourea derivatives: Solvent-free synthesis, characterization and multi-target biological activities. Bangladesh. J. Pharmacol 2016; 11: 894-902
• 25 Saeed A, Qamar R, Fattah TA. et al. Recent developments in chemistry, coordination, structure and biological aspects of 1-(acyl/aroyl)-3-(substituted) thioureas. Res. Chem. Intermed 2016; 1-41
• 26 Hussain R, Abbas Q, Hassan M. et al. Isolation, characterization, and in silico, in vitro and in vivo antiulcer studies of isoimperatorin crystallized from Ostericum koreanum. Pharma. Bio 2017; 55: 218-226
• 27 Zaman A, Rafiq M, Seo SY. et al. Synthesis, kinetic mechanism and docking studies of vanillin derivatives as inhibitors of mushroom tyrosinase. Bioorg. Med. Chem 2015; 23: 5870-5880
• 28 Weatherburn MW. Enzymic method for urea in urine. Anal. Chem 1967; 39: 971-974
• 29 Reddy CVK, Sreeramulu D, Raghunath M. Antioxidant activity of fresh and dry fruits commonly consumed in India. Food. Res. Int. 2010; 43: 285-288
• 30 Pettersen EF, Goddard TD, Huang CC. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem 2004; 25: 1605-1612
• 31 Chen VB, Arendall 3rd WB, Headd JJ. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr 2010; 66: 12-21
• 32 Gasteiger E, Hoogland C, Gattiker A. et al. In Walker JM. (ed) The Proteomics Protocols Handbook. Humana Press; 2015: 571-607
• 33 D. Studio. Discovery. “version 2.1.” Accelrys: San Diego, CA. 2008;
• 34 Willard L, Ranjan A, Zhang H. et al. VADAR: A web server for quantitative evaluation of protein structure quality. Nucleic Acids Res 2003; 31: 3316-3319
• 35 Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Mol. Biol 2015; 1263: 243-250
• 36 Wallace AC, Laskowski RA, Thornton JM. PDBsum: A Web-based database of summaries and analyses of all PDB structures, LIGPLOT. Protein Eng. 1996; 8: 127-134
• 37 Ghose AK, Herbertz T, Hudkins RL. et al. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem Neurosci 2012; 3: 50-68
• 38 Tian S, Wang J, Li Y. et al. The application of in silico drug-likeness predictions in pharmaceutical research. Adv. Drug. Deli Rev 2015; 86: 2-10
• 39 Selick HE, Beresford AP, Tarbit MH. The emerging importance of predictive ADME simulation in drug discovery. Drug Discov Today. 2002; 7: 109-116
• 40 Morris GM, Green LG, Radić Z. et al. Automated docking with protein flexibility in the design of femtomolar “click chemistry” inhibitors of acetylcholinesterase. J. Chem. Inf. Model. 2013; 53: 898-906