Carbohydrazones as new class of carbonic anhydrase inhibitors: Synthesis, kinetics, and ligand docking studies

Sarosh Iqbal; Muhammad Saleem; M Kamran Azim; Muhammad Taha; Uzma Salar; Khalid Mohammed Khan; Shahnaz Perveen; M Iqbal Choudhary

doi:10.1016/j.bioorg.2017.03.014

Carbohydrazones as new class of carbonic anhydrase inhibitors: Synthesis, kinetics, and ligand docking studies

Bioorg Chem. 2017 Jun:72:89-101. doi: 10.1016/j.bioorg.2017.03.014. Epub 2017 Mar 30.

Authors

Sarosh Iqbal¹, Muhammad Saleem², M Kamran Azim³, Muhammad Taha⁴, Uzma Salar³, Khalid Mohammed Khan⁵, Shahnaz Perveen⁶, M Iqbal Choudhary⁷

Affiliations

¹ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Chemistry, Government College University Faisalabad, 38000, Pakistan.
² H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Chemistry, University of Education Lahore, Campus Dera Ghazi Khan, Punjab, Pakistan.
³ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁴ Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, 42300, Malaysia; Faculty of Applied Science, Universiti Teknologi MARA, Shah Alam, 40450 Selangor D. E., Malaysia.
⁵ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: khalid.khan@iccs.edu.
⁶ PCSIR Laboratories Complex Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan.
⁷ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 214412, Saudi Arabia. Electronic address: iqbal.choudhary@iccs.edu.

PMID: 28390994
DOI: 10.1016/j.bioorg.2017.03.014

Abstract

Discovery and development of carbonic anhydrase inhibitors is crucial for their clinical use as antiepileptic, diurectic and antiglaucoma agents. Keeping this in mind, we have synthesized carbohydrazones 1-27 and evaluated them for their in vitro carbonic anhydrase inhibitory potential. Out of twenty-seven compounds, compounds 1 (IC₅₀=1.33±0.01µM), 2 (IC₅₀=1.85±0.24µM), 3 (IC₅₀=1.37±0.06µM), and 9 (IC₅₀=1.46±0.12µM) have showed carbonic anhydrase inhibition better than the standard drug zonisamide (IC₅₀=1.86±0.03µM). Moreover, compounds 4 (IC₅₀=2.32±0.04µM), 5 (IC₅₀=3.96±0.35µM), 7 (IC₅₀=2.33±0.02µM), and 8 (IC₅₀=2.67±0.01µM) showed good inhibitory activity. Cheminformatic analysis has shown that compounds 1 and 2 possess lead-like properties. In addition, kinetic and molecular docking studies were also performed to investigate the binding interaction between carbohydrazones and carbonic anhydrase enzyme. This study has identified a novel and potent class of carbonic anhydrase inhibitors with the potential to be investigated further.

Keywords: Carbohydrazones; Carbonic anhydrase II inhibitors; Cheminformatic analysis; Kinetic studies; Ligand docking; bis-Schiff bases.

Publication types

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

MeSH terms

Animals
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Cattle
Dose-Response Relationship, Drug
Hydrazones / chemical synthesis
Hydrazones / chemistry
Hydrazones / pharmacology*
Kinetics
Ligands
Molecular Docking Simulation*
Molecular Structure
Structure-Activity Relationship

Substances

Carbonic Anhydrase Inhibitors
Hydrazones
Ligands
Carbonic Anhydrases