Newer series of trioxane derivatives as potent antimalarial agents
- 196 Downloads
Among synthesized 1,2,4-trioxane derivatives, six compounds were found to be considerably potent, with better activity against resistant strain of P. falciparum than the sensitive strain. The IC50 values of the best compound with 4-hydroxyphenyl substitution were found to be 0.391 and 0.837 µg/mL against sensitive and resistant strain of P. falciparum, respectively. Results of the tested compounds were comparable with that of the standard drug, chloroquine (IC50 = 0.044 and 0.205 µg/mL against sensitive and resistant strain of P. falciparum, respectively). Docking simulation, in silico drug-likeness and ADMET studies further validated the results of in vitro antimalarial activity. 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, newly reported 1,2,4-trioxane derivative(s) 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.
KeywordsP. falciparum Resistance 1,2,4-Trioxane Falcipain 2 inhibitors Antimalarial
Authors are thankful to Bioinformatics Infrastructure Facility, Center for Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam (India) for carrying out in silico studies. Authors are also thankful to SAIF, Panjab University, Chandigarh for providing spectral data of synthesized compounds.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- Alam S, Khan F (2014) QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNAtopoisomerase IIα. Drug Des Dev Ther 8:183–195Google Scholar
- Geleta G, Ketema T (2016) Severe malaria associated with P. falciparum and P. vivax among children in Pawe Hospital, Northwest Ethiopia. Malar Res Treat 6:1–7Google Scholar
- Grover J, Kumar V, Singh V, Khemraj B, Sobhia ME, Jachak SM (2014) Synthesis, biological evaluation, molecular docking and theoretical evaluation of ADMET properties of nepodin and chrysophanol derivatives as potential cyclooxygenase (COX-1, COX-2) inhibitors. Eur J Med Chem 80:47–56CrossRefPubMedGoogle Scholar
- Khoshneviszadeh M, Shahraki O, Khoshneviszadeh M, Foroumadi A, Firuzi O, Edraki N, Nadri H, Moradi A, Shafiee A, Miri R (2016) Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities. Enzyme Inhib Med Chem 31(6):1602–1611CrossRefGoogle Scholar
- Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev 3:936–849Google Scholar
- Kyle DE, Teja-Isavadharm P, Li Q, Leo K (1998) Pharmacokinetics and pharmacodynamics of qinghaosu derivatives: how do they impact on the choice of drug and the dosage regimens? Med Trop 58:38–44Google Scholar
- Silverstein RM, Webster FX (2005) Spectrometric identification of organic compounds. Wiley Inc, New York, p 205–213Google Scholar
- World Malaria Report (2016) World Health Organization, GenevaGoogle Scholar