Synthesis of carbazole based α-aminophosphonate derivatives: design, molecular docking and in vitro cholinesterase activity

Abstract

A series of novel carbazole based α-aminophosphonate derivatives were synthesized under solvent-free condition, characterized and evaluated for their cholinesterase inhibition, enzyme kinetic inhibition, in-vitro cell viability using N2a cells, neuroprotective studies against H₂O₂-induced stress using N2a cells and antioxidant studies using DPPH radical activity. Test compounds displayed better AChE activity (0.475 to 7.781 µM) than BuChE (3.306 to 21.32 µM). Compound 4j was most potent derivative against AChE as well as BuChE with IC₅₀=0.475 ± 0.12 µM and IC₅₀=3.306 ± 0.21 µM respectively. Kinetic inhibition studies indicate that compound 4j exhibits mixed type inhibition against both enzymes which was supported by molecular docking studies. Cell viability studies showed that compounds did not induce any cytotoxic effect against N2a cells using MTT assay. Also, compound 4j, 4 s and 4r were subjected to H₂O₂-induced stress using N2a cells and were found to be protective in nature. ADME predictions were carried out to understand the pharmacokinetics behaviour.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cholinesterase inhibitors
• enzyme kinetics
• cell viability
• molecular docking
• DPPH scavenging

Acknowledgements

One of the authors (Sarfaraz Shaikh) is thankful to DST-PURSE, New Delhi for award of research fellowship. We are also thankful to Microanalytical Laboratory, University of Mumbai for providing characterization facilities. The authors also thank Miss Heena Bhojwani and Miss Khushboo Begwani for computer-aided drug design.

Disclosure statement

The authors declare that they have no competing interests.