INHIBITION OF UREASE ENZYME ACTIVITY BY UREA AND THIOUREA DERIVATIVES OF DIPEPTIDES CONJUGATED 2, 3-DICHLOROPHENYL PIPERAZINE


D. M. Suyoga Vardhan, H. K. Kumara, H. Pavan Kumar, D. Channe Gowda

Abstract


Objective: Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs used in a variety of physiological conditions. In search of novel urease enzyme inhibitors, four dipeptides were synthesized, conjugated to 2,3-dichlorophenyl piperazine analogue and converted into urea/thiourea derivatives.

Methods: The peptides were synthesized by solution phase method and conjugated to 2,3-dichlorophenyl piperazine (PZN) using 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDCI)/hydroxybenzotriazole (HOBt) as a coupling agent and N-methylmorpholine (NMM) as a base. The tert-butyloxycarbonyl (Boc) group was removed using trifluoroacetic acid (TFA), neutralized with NMM and converted to urea and thiourea derivatives using substituted phenyl isocyanates and isothiocyanates respectively.

Results: Most of the synthesized analogues were found to be good inhibitors of urease enzyme activity. The conjugates of thiourea with F and Cl substituents at meta or para positions showed predominant urease inhibitory activity. The analogue 23 was nearly 10 fold (2 µM) more potent than the reference standard, 21.0±0.11 µM.

Conclusion: The reported activity was correlated with some of the literature reported urease inhibitors and found that our compound 23 was more potent than the existing ones. 

 


Keywords


Amino acids, Piperazine, Conjugation, Urea/thiourea, Urease inhibitors

| PDF | HTML |

References


Mobley HLT, Island MD, Hausinger RP. Molecular biology of microbial ureases. Microbiol Rev 1995;59:451-80.

Mobley HLT, Island MD, Hausinger RP. Microbial ureases: significance, regulation and molecular characterization. Microbiol Rev 1989;53:85-102.

Samtoy, DeBeukelaer BM. Ammonia encephalopathy secondary to urinary tract infection with proteuis mirabilis. Pediatrics 1980;65:294-7.

Betkas H, Ceylan S, Demisbas N, Alpay-Karaoglu S, Sokmen BB. Antimicrobial and anti-urease activities of newly synthesized morpholine derivatives containing an azole nucleus. Med Chem Res 2013;22:3629-39.

Khan I, Ali S, Hameed S, Rama NH, Hussain MT, Wadood A, et al. Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Eur J Med Chem 2010;45:5200-7.

Mao WJ, Lv PC, Shi L, Lee HQ, Zhu HL. Synthesis, molecular docking and biological evaluation of metronidazole derivatives as potent Helicobacter pylori urease inhibitors. Bioorg Med Chem 2009;17:7531-6.

Khan KM, Saify ZS, Lodhi MA, Buttz N, Perveen S, Maharvi GM, et al. Piperidines: a new class of urease inhibitors. Nat Prod Res 2006;20:523-8.

Khan KM, Ali M, Wadood A, Zaheer Ul Haq, Khan M, Lodhi MA, et al. Molecular modeling-based antioxidant arylidene barbiturates as urease inhibitors. J Mol Graphics Modell 2011;30:153-6.

You ZL, Xian DM, Zhang M, Cheng XS, Li XF. Synthesis, biological evaluation and molecular docking studies of 2,5-substituted-1,4-benzoquinone as novel urease inhibitors. Bioorg Med Chem 2012;20:4889-94.

Upadhyaya RS, Kulkarni GM, Vasireddy NR, Vandavasi JK, Dixit SS, Sharma V, et al. Design, synthesis and biological evaluation of novel triazole, urea and thiourea derivatives of quinoline against Mycobacterium tuberculosis. Bioorg Med Chem 2009;17:4681-92.

Suresha GP, Suhas R, Kapfo W, Gowda DC. Urea/thiourea derivatives of quinazolinone lysine conjugates: synthesis and structure-activity relationships of a new series of antimicrobials. Eur J Med Chem 2011;46:2530-40.

Faidallah HM, Khan KA, Asiri AM. Synthesis and biological evaluation of new 3,5-di(trifluoromethyl)-1,2,4-triazole-sulfonylurea and thiourea derivatives as antidiabetic and antimicrobial agents. J Fluorine Chem 2011;132:870-7.

Venkatachalam TK, Maob C, Uckun FM. Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds. Bioorg Med Chem 2004;12:4275-84.

Sunduru ZN, Srivastava K, Rajakumar S, Ouri SK, Saxena JK, Chauhan PMS. Synthesis of novel thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline as potent antimalarials. Bioorg Med Chem Lett 2009;19:2570-3.

Zhi-Jian C, Ya Na C, Chun Na Xu, Shan-Shan Zhao, Qui-Yue Cao, Shao-Sang Qian, et al. Synthesis, crystal structures, molecular docking, and in vitro biological activities evaluation of transition metal complexes with 4-(3,4-dichlorophenyl) piperazine-1-carboxylic acid. J Mol Struct 2016;1117:293-9.

ABD-El-Aziz AS, Abdelghani AA, El-Sadany SK, Overy DP, Kerr RG. Antimicrobial and anticancer activities of organoiron melamine dendrimers capped with piperazine moieties. Eur Polym J 2016;82:307-23.

Silva DPB, Florentino IF, Oliveria LP, Lino RC, Galdino PM, Menegetti R, et al. Antinociceptive and anti-inflammatory activities of 4-[(1-phenyl-1H-pyrazol-4-yl) methyl] 1-piperazine carboxylic acid ethyl ester: a new piperazine derivative. Pharmacol Biochem Behav 2015;137:86-92.

Wynn RL. New antiplatelet and anticoagulant drugs. Gen Dent 2012;60:8-11.

Barman A, Shivaprakash S, Latha D, Reddy GC. Acute toxicity study of (z)-1-benzhydryl-4-cinnamylpiperazines in swiss albino mice. Asian J Pharm Clin Res 2015;8:223-4.

Suresha GP, Suhas R, Wethroe K, Gowda DC. Urea/thiourea derivatives derivatives of quinazolinone-lysine conjugates: synthesis and structure activity relationships of a new series of antimicrobials. Eur J Med Chem 2011;46:2530-40.

Shantharam CS, Suyoga Vardhan DM, Suhas R, Sridhara MB, Channe Gowda D. Inhibition of protein glycation by urea and thiourea derivatives of glycine/proline conjugated benzisoxazole analogue-synthesis and structure activity studies. Eur J Med Chem 2013;60:325-32.

Suyoga Vardhan DM, Shantharam CS, Suhas R, Sridhra MB, Channe Gowda D. Synthesis and SAR studies of urea and thiourea derivatives of Gly/Pro conjugated to piperazine analogue as potential AGE inhibitors. Protein Peptde Lett 2013;20:888-97.

Suhas R, Chandrashekar S, Gowda DC. Synthesis of ureido and thioureido derivatives of peptides conjugated heterocycles–a new class of promising antimicrobials. Eur J Med Chem 2012;48:179-91.

Gowda BKK, Prasad HS, Rangappa KS, Gowda DC. Hydrophobicity dependence of oxidation of tetrapeptides of elastin sequences with Mn(III): synthesis, characterization, kinetics and mechanistic study. Int J Chem Kinet 2002;34:39-48.

Prasad KU, Iqbal MA, Urry DW. Utilization of 1-hydroxy benzotriazole in mixed anhydride coupling reactions. Int J Pept Protein Res 1985;25:408-13.

Y Oshiro, S Tokushima, Sata and Itana. U. S. Patent; 1991;5,006,528.

Weatherburn MW. Phenol-hypochlorite reaction for determination of ammonia. Anal Chem 1967;39:971-4.

Khan I, Ali S, Hamed S, Rama NH, Hussain MT, Wadood A, et al. Synthesis, antioxidant activities and urease inhibition of some new 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Eur J Med Chem 2010;45:5200-7.

Zambelli B, Musiani F, Benini S, Ciurli S. Chemistry of Ni2+in urease: sensing, trafficking and catalysis. Acc Chem Res 2011;44:520-30.




About this article

Title

INHIBITION OF UREASE ENZYME ACTIVITY BY UREA AND THIOUREA DERIVATIVES OF DIPEPTIDES CONJUGATED 2, 3-DICHLOROPHENYL PIPERAZINE

Keywords

Amino acids, Piperazine, Conjugation, Urea/thiourea, Urease inhibitors

DOI

10.22159/ijpps.2017v9i9.19425

Date

13-07-2017

Additional Links

Manuscript Submission

Journal

International Journal of Pharmacy and Pharmaceutical Sciences
Vol 9, Issue 9, 2017 Page: 92-99

Online ISSN

0975-1491

Statistics

48 Views | 26 Downloads

Authors & Affiliations

D. M. Suyoga Vardhan
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore – 570 006, Karnataka, India

H. K. Kumara
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore – 570 006, Karnataka, India

H. Pavan Kumar
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore – 570 006, Karnataka, India

D. Channe Gowda
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore – 570 006, Karnataka, India
India


Article Tools



Refbacks

  • There are currently no refbacks.