Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis

Madiha Kazmi; Imtiaz Khan; Ajmal Khan; Sobia Ahsan Halim; Aamer Saeed; Saifullah Mehsud; Ahmed Al-Harrasi; Aliya Ibrar

doi:10.1016/j.bmc.2019.115123

Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis

Bioorg Med Chem. 2019 Nov 15;27(22):115123. doi: 10.1016/j.bmc.2019.115123. Epub 2019 Sep 16.

Authors

Madiha Kazmi¹, Imtiaz Khan², Ajmal Khan³, Sobia Ahsan Halim³, Aamer Saeed⁴, Saifullah Mehsud⁵, Ahmed Al-Harrasi⁶, Aliya Ibrar⁷

Affiliations

¹ Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan; Department of Chemistry, University of Gujrat, Rawalpindi Sub-campus, Satellite Town, Rawalpindi, Pakistan.
² School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom; Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.
³ Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Oman.
⁴ Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address: aamersaeed@yahoo.com.
⁵ Department of Chemistry, Abbottabad University of Science and Technology, Havelian, Abbottabad, Pakistan.
⁶ Natural and Medical Sciences Research Center, University of Nizwa, P.O Box 33, Postal Code 616, Birkat Al Mauz, Nizwa, Oman. Electronic address: aharrasi@unizwa.edu.om.
⁷ Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan; Department of Chemistry, Abbottabad University of Science and Technology, Havelian, Abbottabad, Pakistan. Electronic address: jadoonquaidian@gmail.com.

PMID: 31623971
DOI: 10.1016/j.bmc.2019.115123

Abstract

Although a diverse range of chemical entities offering striking therapeutic potential against urease enzyme has been reported, the key challenges (toxicity and safety) associated with these inhibitors create a large unmet medical need to unveil new, potent and safe inhibitors of urease enzyme. In this pursuit, the present study demonstrates the successful synthesis of carbazole-chalcone hybrids (4a-n) in good yields. The evaluation of the preliminary in vitro biological results showed that selected members of the investigated library of hybrid compounds possess excellent urease inhibitory efficacy. In particular, compounds 4c and 4k were the most potent inhibitors with lowest IC₅₀ values of 8.93 ± 0.21 and 6.88 ± 0.42 μM, respectively. Molecular docking analysis of the most potent inhibitor 4k suggests that the compound is fitted neatly at the active site interface and mediates interaction with both nickel atoms present in the active site. Several other obvious interactions including metal-carbonyl contact, hydrogen bonding and hydrophobic interactions were also observed, playing a crucial part in the stabilization of 4k in the active site of urease.

Keywords: Carbazole; Chalcone; Enzyme inhibition; Hybrid scaffold; Structural diversity; Urease.

Publication types

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

MeSH terms

Carbazoles / chemical synthesis*
Carbazoles / chemistry*
Chalcones / chemical synthesis*
Chalcones / chemistry*
Molecular Docking Simulation
Structure-Activity Relationship
Urease / antagonists & inhibitors*

Substances

Carbazoles
Chalcones
carbazole
Urease