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Year : 2019  |  Volume : 12  |  Issue : 5  |  Page : 195-203

Antimalarial activity of a novel series of artemisinin-derived 1, 2, 3-triazole dimers

1 ICMR-Regional Medical Research Centre, N.E., Dibrugarh-786 001, Assam, India
2 CSIR-North-East Institute of Science and Technology, Jorhat-785 001, Assam, India
3 Digboi College, Chemistry Department, Tinsukia-786 171, Assam, India
4 ICMR-Regional Medical Research Centre, N.E., Dibrugarh-786 001; Pratiksha Institute of Pharmaceutical Scinces, Panikheti, Guwahati -781 026, Assam, India
5 Cotton University, Zoology Department, Guwahati-781 001, Assam, India
6 ICMR-Regional Medical Research Centre, N.E., Dibrugarh-786 001, Assam; ICMR-National Institute for Research in Environmental Health, Bhopal-462 001, Madhya Pradesh, India

Correspondence Address:
Dr. Anil Prakash
ICMR-National Institute For Research in Environmental Health (Indian Council of Medical Research) Kamla Nehru Hospital Building Gandhi Medical College Campus Bhopal-462 001, Madhya Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1995-7645.259240

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Objective: To obtain suitable artimisinin-based drug candidates with high antimalarial activity. Methods: Three different reaction schemes were used to synthesize a total of 15 artemisinin-based compounds. The first synthetic scheme involved the synthesis of diazido aliphatic and aromatic compounds from commercially available dihalides and azido derivatives of artemisinin. The second scheme consisted of the reaction of dibromoaliphatic compounds with sodium azide in dimethylformamide which yielded the desired compounds. Artemisinin-based compounds on treatment with sodium azide and bromotrimethylsilane in dichloromethane produced the most potent compound GB-2. Another potent compound GB-1 was synthesized from artemisinin by treatment with alcohols in the presence of Aberlyst-15 in anhydrous dichloromethane. The third scheme involved the Huisgen 1,3-dipolar cycloaddition between the synthesized aliphatic and aromatic diazides and two alkyne derivatives of artemisinin to obtain the desired artemisinin dimers with average yields. Results: The best in vitro antiplasmodial activity was shown by the compound GB-2 registering IC50 value 0.066 μg/mL against chloroquine-sensitive and 0.865 μg/mL against chloroquine-resistant strains of Plasmodium falciparum. It suppressed 59.0% parasitaemia in vivo of rodent malaria parasite Plasmodium berghei in Swiss albino model at 50 μg/kg body weight dosage. Molecular docking interactions of Plasmodium falciparum ATP6 (PfATP6) protein revealed strong bonding of GB-2 with Thr255 residue which is likely to be the reason for excellent antimalarial activity of this compound. Conclusion: Two compounds GB-1 and GB-2 exhibited excellent in vitro antiplasmodial activity and fair in vivo antimalarial activity. Of the two, GB-2 showed better activity which could be attributed to its strong bonding interactions with Thr255 as evidenced from the molecular docking study. Study helped in identifying artemisinin analogues possessing good antimalarial properties and further research in structural alterations of the selected molecules should be carried out which may result in obtaining potent drug candidates against the malarial parasite.

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