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Syntheses, in vitro urease inhibitory activities of urea and thiourea derivatives of tryptamine, their molecular docking and cytotoxic studies.
Bioorg Chem. 2019 03; 83:595-610.BC

Abstract

Urease is an enzyme of amidohydrolase family and is responsible for the different pathological conditions in the human body including peptic ulcers, catheter encrustation, kidney stone formation, hepatic coma, encephalopathy, and many others. Therefore, the search for potent urease inhibitors has attracted major scientific attention in recent years. Urea and thiourea derivatives of tryptamine (1-25) were synthesized via reaction of tryptamine with different substituted phenyl isocyanates/isothiocyanates. The synthetic compounds were evaluated for their urease enzyme inhibitory activity and they exhibited good inhibitory potential against urease enzyme in the range of (IC50 = 11.4 ± 0.4-24.2 ± 1.5 μM) as compared to the standard thiourea (IC50 = 21.2 ± 1.3 μM). Out of twenty-five compounds, fourteen were found to be more active than the standard. Limited structure-activity relationship suggested that the compounds with CH3, and OCH3 substituents at aryl part were the most potent derivatives. Compound 14 (IC50 = 11.4 ± 0.4 μM) with a methyl substituent at ortho position was found to be the most active member of the series. Whereas, among halogen substituted derivatives, para substituted chloro compound 16 (IC50 = 13.7 ± 0.9 μM) showed good urease inhibitory activity. These synthetic derivatives were found to be non-cytotoxic in cellular assay. Kinetic studies revealed that the compounds 11, 12, 14, 17, 21, 22, and 24 showed a non-competitive type of inhibition. In silico study identified the possible bindings interactions of potential inhibitors with the active site of enzyme. These newly identified inhibitors of urease enzyme can serve as leads for further research and development.

Authors+Show Affiliations

H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia. Electronic address: khalid.khan@iccs.edu.PCSIR Laboratories Complex, Karachi, Shahra-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan.Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21412, Saudi Arabia. Electronic address: Iqbal.choudhary@iccs.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30513472

Citation

Kanwal, , et al. "Syntheses, in Vitro Urease Inhibitory Activities of Urea and Thiourea Derivatives of Tryptamine, Their Molecular Docking and Cytotoxic Studies." Bioorganic Chemistry, vol. 83, 2019, pp. 595-610.
Kanwal , Khan M, Arshia , et al. Syntheses, in vitro urease inhibitory activities of urea and thiourea derivatives of tryptamine, their molecular docking and cytotoxic studies. Bioorg Chem. 2019;83:595-610.
Kanwal, ., Khan, M., Arshia, ., Khan, K. M., Parveen, S., Shaikh, M., Fatima, N., & Choudhary, M. I. (2019). Syntheses, in vitro urease inhibitory activities of urea and thiourea derivatives of tryptamine, their molecular docking and cytotoxic studies. Bioorganic Chemistry, 83, 595-610. https://doi.org/10.1016/j.bioorg.2018.10.070
Kanwal , et al. Syntheses, in Vitro Urease Inhibitory Activities of Urea and Thiourea Derivatives of Tryptamine, Their Molecular Docking and Cytotoxic Studies. Bioorg Chem. 2019;83:595-610. PubMed PMID: 30513472.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Syntheses, in vitro urease inhibitory activities of urea and thiourea derivatives of tryptamine, their molecular docking and cytotoxic studies. AU - Kanwal,, AU - Khan,Majid, AU - Arshia,, AU - Khan,Khalid Mohammed, AU - Parveen,Shahnaz, AU - Shaikh,Muniza, AU - Fatima,Narjis, AU - Choudhary,M Iqbal, Y1 - 2018/11/01/ PY - 2018/07/11/received PY - 2018/10/25/revised PY - 2018/10/31/accepted PY - 2018/12/5/pubmed PY - 2019/11/2/medline PY - 2018/12/5/entrez KW - Cytotoxicity KW - Docking studies KW - Gastric ulcers KW - Structure-activity relationship KW - Tryptamine derivatives KW - Urease inhibitory activity KW - Urolithiasis SP - 595 EP - 610 JF - Bioorganic chemistry JO - Bioorg Chem VL - 83 N2 - Urease is an enzyme of amidohydrolase family and is responsible for the different pathological conditions in the human body including peptic ulcers, catheter encrustation, kidney stone formation, hepatic coma, encephalopathy, and many others. Therefore, the search for potent urease inhibitors has attracted major scientific attention in recent years. Urea and thiourea derivatives of tryptamine (1-25) were synthesized via reaction of tryptamine with different substituted phenyl isocyanates/isothiocyanates. The synthetic compounds were evaluated for their urease enzyme inhibitory activity and they exhibited good inhibitory potential against urease enzyme in the range of (IC50 = 11.4 ± 0.4-24.2 ± 1.5 μM) as compared to the standard thiourea (IC50 = 21.2 ± 1.3 μM). Out of twenty-five compounds, fourteen were found to be more active than the standard. Limited structure-activity relationship suggested that the compounds with CH3, and OCH3 substituents at aryl part were the most potent derivatives. Compound 14 (IC50 = 11.4 ± 0.4 μM) with a methyl substituent at ortho position was found to be the most active member of the series. Whereas, among halogen substituted derivatives, para substituted chloro compound 16 (IC50 = 13.7 ± 0.9 μM) showed good urease inhibitory activity. These synthetic derivatives were found to be non-cytotoxic in cellular assay. Kinetic studies revealed that the compounds 11, 12, 14, 17, 21, 22, and 24 showed a non-competitive type of inhibition. In silico study identified the possible bindings interactions of potential inhibitors with the active site of enzyme. These newly identified inhibitors of urease enzyme can serve as leads for further research and development. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/30513472/Syntheses_in_vitro_urease_inhibitory_activities_of_urea_and_thiourea_derivatives_of_tryptamine_their_molecular_docking_and_cytotoxic_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(18)30698-9 DB - PRIME DP - Unbound Medicine ER -