Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency

Abstract

A series of hybrid antiprotozoal compounds with quinine-triazolyl scaffold were prepared by copper catalyzed Huisgen 1,3-dipolar cycloaddition via O-mesylation with mesyl chloride followed by azide displacement. The synthesized azide derivative was made to react with various aromatic and aliphatic alkynes. The triazolyl-linked quinine scaffolds were synthesized under solvent-free mechanochemical ball milling conditions. Products (6a-s) were screened for in-vitro antimalarial and antileishmanial activity. Screening results indicated that out of the synthesized series of 19 products, compounds 6d, 6h, 6l, 6m, and 6n showed significant antimalarial (P. falciparum) and antileishmanial activities (L. donavani) with IC50 values 0.28, 0.28, 0.25, 0.33, 0.76 µM and 8.26, 4.4, 1.78, 3.95, and 4.06 µM, respectively. Further toxicological analysis established the Median lethal dose (LD50), No observed adverse effect level (NOAEL) and human equivalent dose (HED) of the most potent compounds by acute and sub acute toxicity studies performed in rodent animal model. The studies revealed that compounds (6d, 6h, 6l and 6m) did not reveal any toxic manifestation at dose 1000 mg/Kg and from which the corresponding HED was calculated to be 13.84 mg/kg.