Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors

Chemistry Central Journal

Assem Barakat⁴  Abdullah Mohammed Al-Majid⁵  Gehad Lotfy³  Fiza Arshad²  Sammer Yousuf²  M. Iqbal Choudhary¹  Sajda Ashraf¹  Zaheer Ul-Haq¹ 

[1] Dr. Panjwani Center for Molecular Medicine and Drug Research, 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

[3] Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt

[4] Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia, Alexandria 21321, Egypt

[5] Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia

关键词: MD simulation and molecular docking;    Urolitheasis;    Urease enzyme;    Zwitterions;    Barbituric acid;   

Others  :  1233355
DOI  :  10.1186/s13065-015-0140-1

 received in 2015-07-23, accepted in 2015-11-01,  发布年份 2015

【 摘 要 】

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 (IC ₅₀  = 17.6 ± 0.23 µM) and 5l (IC ₅₀  = 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 (IC ₅₀  = 21.2 ± 1.3 µM). Whereas, compounds 4a–b, 4d–e, 4g–h, 4j–4r, 4x, 4z, 5b, 5e, 5k, 5n–5q having IC ₅₀values 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.

【 授权许可】

   
2015 Barakat et al.

【 图 表 】

Fig.1.

Fig.2.

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