title: Bile acid-based 1,2,4-trioxanes: synthesis and antimalarial assessment.
abstract: A new series of bile acid-based trioxanes 23a-d, 24a-d, 25a-d, 26a, 26b, and 26d have been synthesized and assessed for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. The antimalarial activity of these trioxanes showed a strong dependence on the side-chain length; shortening side-chain length lead to increase in activity. The antimalarial activity also showed even stronger dependence on the stereochemistry at C3 and C6 (C21 in Figure 5) of the trioxane moiety. Of the two diastereomers isolated of each of the trioxanes, more polar one was significantly more active than the less polar one. The more polar diastereomer of the trioxanes 26a, 26b, and 26d, were the most active compounds of the series. All these three trioxanes provided 100% protection at 24 mg/kg×4 days. In this model β-arteether provided 100% and 20% protection at 48 mg/kg×4 days and 24 mg/kg×4 days, respectively.
authors.affiliation: Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow-226001, India. chandancdri@yahoo.com
authors.forename: Chandan
authors.initials: C
authors.lastname: Singh
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hassam
authors.forename: Ved Prakash
authors.initials: VP
authors.lastname: Verma
authors.forename: Ajit Shanker
authors.initials: AS
authors.lastname: Singh
authors.forename: Niraj Krishna
authors.initials: NK
authors.lastname: Naikade
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Puri
authors.forename: Prakas R
authors.initials: PR
authors.lastname: Maulik
authors.forename: Ruchir
authors.initials: R
authors.lastname: Kant
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000737:chemistry*; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010967:Plasmodium yoelii / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared
chemical_list: C503429:1,2,4-trioxane; D000962:Antimalarials; D001647:Bile Acids and Salts; D006571:Heterocyclic Compounds