Research Articles

2019  |  Vol: 5(1)  |  Issue: 1(January-February)  |
In vitro antimalarial evaluation and molecular docking analysis of Mannich base curcumin analogues against the artemisinin target PfATP6

Kabita Gogoi1, Dipak Chetia2, Nabin Chandra Barua3, Neelutpal Gogoi2, Chandrajit Dohutia4*

1Regional Medical Research Centre NE (Indian Council of Medical Research), Dibrugarh 786001, India

2Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh 786004, India

3CSIR-NEIST, NH 37, Pulibor, Jorhat, Assam 785006 India

4Pratiksha Insititute of Pharmaceutical Sciences, Chandrapur Road, Guwahati 781026 India

*Address for Corresponding author

Dr. Chandrajit Dohutia

Pratiksha Insititute of Pharmaceutical Sciences, Chandrapur Road, Guwahati 781026 India


Objective: The aim was to design twenty Mannich bases of curcumin based on their structural analogy to curcumin, dock them against the Plasmodium falciparum ATP6 (PfATP6) gene and based on their binding energies with the protein, select, synthesize and evaluate them for their in vitro antimalarial activity. Methods and Results: Compounds were designed and docked onto the active site of PfATP6 to determine their binding affinities with the protein. The selected compounds were synthesized using the Mannich reaction and their antimalarial activity was evaluated in vitro against chloroquine-sensitive 3D7 strain and mutant RKL2 strain of P. falciparum. The compounds CDM3 (-3.11 Kcal/mol, 4.11 µg/ml against 3D7 and 10.89 µg/ml against RKL2 strains) and CDM1 (-4.11 Kcal/mol, 4.09 µg/ml against 3D7 and 8.2 µg/ml against RKL2 strains) showed the best binding energies and antimalarial activity with IC50 values comparable to that of curcumin (-4.95 Kcal/mol, 2.13 µg/ml, 5.59 µg/ml) but less than that of chloroquine (0.7 µg/ml against 3D7 and 1.4 µg/ml against RKL2 strains). Conclusion: Mannich base curcumin derivatives showed substantial antimalarial activity compared to curcumin and showed proper binding energies with the PfATP6 protein through hydrophobic binding interactions. The major binding point was found to be with the residue Lys1213 which could be the reason for the antimalarial activity of the compounds and the site could be exploited for further antimalarial drug targeting. The study provided a detailed insight into the necessary structural modifications to be made in the curcumin molecule to create more potent drug candidates for rationale-based antimalarial drug design and development.

Keywords: Malaria, Mannich base, Curcumin, PfATP6, Molecular docking

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