INHIBITION OF UREASE ENZYME ACTIVITY BY UREA AND THIOUREA DERIVATIVES OF DIPEPTIDES CONJUGATED 2, 3-DICHLOROPHENYL PIPERAZINE
Keywords:Amino acids, Piperazine, Conjugation, Ureathiourea, Urease inhibitors
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 ÂµM) more potent than the reference standard, 21.0Â±0.11 ÂµM.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.Â
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