title: Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors.
abstract: BACKGROUND
  Discovery of potent inhibitors of urease (jack bean) enzyme is the first step in the development of drugs against diseases caused by ureolytic enzyme.
  
  
  RESULTS
  Thirty-two derivatives of barbituric acid as zwitterionic adducts of diethyl ammonium salts were synthesized. All synthesized compounds (4a-z and 5a-s) were screened for their in vitro inhibition potential against urease enzyme (jack bean urease). The compounds 4i (IC50 = 17.6 ± 0.23 µM) and 5l (IC50 = 17.2 ± 0.44 µM) were found to be the most active members of the series, and showed several fold more urease inhibition activity than the standard compound thiourea (IC50 = 21.2 ± 1.3 µM). Whereas, compounds 4a-b, 4d-e, 4g-h, 4j-4r, 4x, 4z, 5b, 5e, 5k, 5n-5q having IC50 values in the range of 22.7 ± 0.20 µM-43.8 ± 0.33 µM, were also found as potent urease inhibitors. Furthermore, Molecular Dynamics simulation and molecular docking studies were carried out to analyze the binding mode of barbituric acid derivatives using MOE. During MD simulation enol form is found to be more stable over its keto form due to their coordination with catalytic Nickel ion of Urease. Additionally, structural-activity relationship using automated docking method was applied where the compounds with high biological activity are deeply buried within the binding pocket of urease. As multiple hydrophilic crucial interactions with Ala169, KCX219, Asp362 and Ala366 stabilize the compound within the binding site, thus contributing greater activity.
  
  
  CONCLUSIONS
  This research study is useful for the discovery of economically, efficient viable new drug against infectious diseases.Graphical abstract:STD. Thiourea (IC50 = 21.2 ± 1.3 µM).
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451 Saudi Arabia.|Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria, 21321 Egypt.
authors.forename: Assem
authors.initials: A
authors.lastname: Barakat
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451 Saudi Arabia.
authors.forename: Abdullah Mohammed
authors.initials: AM
authors.lastname: Al-Majid
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
authors.forename: Gehad
authors.initials: G
authors.lastname: Lotfy
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Fiza
authors.initials: F
authors.lastname: Arshad
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Sammer
authors.initials: S
authors.lastname: Yousuf
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Sajda
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
keywords: Barbituric acid; MD simulation and molecular docking; Urease enzyme; Urolitheasis; Zwitterions