title: Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies.
abstract: In this study 36 new compounds were synthesized by condensing barbituric acid or thiobarbituric acid and respective anilines (bearing different substituents) in the presence of triethyl orthoformate in good yields. In vitro urease inhibition studies against jack bean urease revealed that barbituric acid derived compounds (1-9 and 19-27) were found to exhibit low to moderate activity however thiobarbituric acid derived compounds (10-18 and 28-36) showed significant inhibition activity at low micro-molar concentrations. Among the synthesized compounds, compounds (15), (12), (10), (36), (16) and (35) showed excellent urease inhibition with IC50 values 8.53 ± 0.027, 8.93 ± 0.027, 12.96 ± 0.13, 15 ± 0.098, 18.9 ± 0.027 and 19.7 ± 0.63 μM, respectively, even better than the reference compound thiourea (IC50 = 21 ± 0.011). The compound (11) exhibited comparable activity to the standard with IC50 value 21.83 ± 0.19 μM. In silico molecular docking studies for most active compounds (10), (12), (15), (16), (35) and (36) and two inactive compounds (3) and (6) were performed to predict the binding patterns.
authors.affiliation: Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan. Electronic address: lecorganic@yahoo.com.
authors.forename: Abdul
authors.initials: A
authors.lastname: Rauf
authors.affiliation: Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan; Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore 54000, Pakistan.
authors.forename: Sohail
authors.initials: S
authors.lastname: Shahzad
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.affiliation: Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore 54000, Pakistan. Electronic address: drmyar@ciitlahore.edu.pk.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Yar
authors.affiliation: Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
authors.forename: Faiz
authors.initials: F
authors.lastname: Ahmed
authors.affiliation: Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
authors.forename: Nazar
authors.initials: N
authors.lastname: Hussain
authors.affiliation: Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak 26300, Kuantan, Pahang, Malaysia.
authors.forename: Muhammad Nadeem
authors.initials: MN
authors.lastname: Akhtar
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Ajmal
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Jończyk
mesh_terms: D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013858:Thiobarbiturates / Q000138:chemical synthesis* / Q000737:chemistry*; D014510:Urease / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D013858:Thiobarbiturates; D014510:Urease; C029684:thiobarbituric acid
keywords: Barbituric; In silico; Jack bean; Thiobarbituric; Triethyl orthoformate; Urease