Synthesis and antimalarial activity of 3′-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxane based on deoxycholic acid
| Autor: | Yuliya V. Legostaeva, Gumer Yu. Ishmuratov, Emil Yu. Yamansarov, Tran Thi Hong Ha, E. F. Khusnutdinova, Kyrill Yu. Suponitsky, Le Mai Huong, Natalya I. Medvedeva, Oxana B. Kazakova, D. T. Huong, Dmitri V. Kazakov |
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| Rok vydání: | 2018 |
| Předmět: |
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Molecular Plasmodium falciparum Clinical Biochemistry Molecular Conformation Stereoisomerism Chemistry Techniques Synthetic Methylation 01 natural sciences Biochemistry Medicinal chemistry Antimalarials Structure-Activity Relationship chemistry.chemical_compound Endocrinology Acetone Structure–activity relationship Tetraoxanes Furans Molecular Biology Pharmacology 010405 organic chemistry Organic Chemistry Deoxycholic acid Cholic acid Diastereomer 0104 chemical sciences Hexane 010404 medicinal & biomolecular chemistry chemistry Deoxycholic Acid |
| Zdroj: | Steroids. 129:17-23 |
| ISSN: | 0039-128X |
| DOI: | 10.1016/j.steroids.2017.11.008 |
| Popis: | A series of new steroidal peroxides - 3'-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes based on deoxycholic acid were prepared via the reactions of the Griesbaum coozonolysis and peroxycondensation, respectively. 1,2,4-Trioxolanes were synthesized by the interaction of methyl O-methyl-3-oximino-12α-acetoxy-deoxycholate with CF3C(O)CH3 or CF3C(O)Ph and O3 as the mixtures of four possible stereoisomers at ratios of 1:2:2:1 and in yields of 50% and 38%, respectively. The major diastereomer of methyl 12α-acetoxy-5β-cholan-24-oate-3-spiro-5'-(3'-methyl-3'-trifluoromethyl-1',2',4'-trioxolane) was isolated via crystallization of a mixture of stereoisomers from hexane and its (3S,3'R)-configuration was determined using X-ray crystallographic analysis. Peroxycondensation of methyl 3-bishydroperoxy-12α-acetoxy-deoxycholate with CF3C(O)CH3 or acetone led to 1,2,4,5-tetraoxanes in yields of 44% and 37%, respectively. Antimalarial activity of these new steroidal peroxides was evaluated in vitro against the chloroquine-sensitive (CQS) T96 and chloroquine-resistant (CQR) K1 strains of Plasmodium falciparum. Deoxycholic acid 3'-trifluoromethylated 1,2,4,5-tetraoxane demonstrated a good IC50 value against CQR-strain (IC50 (K1) = 7.6 nM) of P. falciparum. Tetraoxane with the acetone subunit demonstrated the best results among all tested peroxides with an IC50 value of 3 nM against the CQ-resistant K1 strain. In general, 1,2,4-trioxolanes of deoxycholic acid are less active than 1,2,4,5-tetraoxanes. |
| Databáze: | OpenAIRE |
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