Novel series of 1,2,4-trioxane derivatives as antimalarial agents

Abstract

Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC₅₀ values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.

Keywords:

• P. falciparum
• resistance
• trioxane derivatives
• falcipain 2 inhibitors
• antimalarial

Acknowledgements

The authors are thankful to Bioinformatics Infrastructure Facility, Centre for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam (India) for carrying out in silico studies. The authors extend their sincere thanks to SAIF, NEHU, Shillong and SAIF, Panjab University, Chandigarh for providing spectral data of synthesised compounds. Authors gratefully thank the Director, National Institute of Malaria Research (ICMR), New Delhi for providing necessary facilities to carry out in vitro antimalarial screening of synthesized compounds.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

UGC10.13039/501100001501One of the authors is grateful to UGC, New Delhi, India, for the financial support in the form of Senior Research Fellowship (F/2015-16/NFO-17-OBC-TRI-33908).