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  3. Syntheses, in vitro urease inhibitory activities of urea and thiourea derivatives of tryptamine, their molecular docking and cytotoxic studies

Syntheses, in vitro urease inhibitory activities of urea and thiourea derivatives of tryptamine, their molecular docking and cytotoxic studies

  • Bioorg Chem. 2019 Mar:83:595-610. doi: 10.1016/j.bioorg.2018.10.070.
Kanwal 1,  Majid Khan 1,  Arshia 1,  Khalid Mohammed Khan 2,  Shahnaz Parveen 3,  Muniza Shaikh 4,  Narjis Fatima 1,  M Iqbal Choudhary 5
Affiliations

Affiliations

  • 1 H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
  • 2 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.
  • 3 PCSIR Laboratories Complex, Karachi, Shahra-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan.
  • 4 Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
  • 5 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.
PMID: 30513472 DOI: 10.1016/j.bioorg.2018.10.070
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.

Keywords

Cytotoxicity; Docking studies; Gastric ulcers; Structure-activity relationship; Tryptamine derivatives; Urease inhibitory activity; Urolithiasis.

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