Synthesis and antimalarial activity of 3′-trifluoromethylated 1,2,4-trioxolanes and 1,2,4,5-tetraoxane based on deoxycholic acid

• Published in: Steroids Vol. 129; pp. 17 - 23
• Main Authors: Yamansarov, Emil Yu, Kazakov, Dmitri V., Medvedeva, Natal'ya I., Khusnutdinova, Elmira F., Kazakova, Oxana B., Legostaeva, Yuliya V., Ishmuratov, Gumer Yu, Huong, Le Mai, Ha, Tran Thi Hong, Huong, Do Thi, Suponitsky, Kyrill Yu
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 01.01.2018; Elsevier
• Subjects: 1,2,4,5-Tetraoxane; 1,2,4-Trioxolane; Antimalarial activity; Biochemistry & Molecular Biology; Cholic acids; Endocrinology & Metabolism; Life Sciences & Biomedicine; Science & Technology; Cholic acids; 1,2,4-Trioxolane; 1,2,4,5-Tetraoxane; Antimalarial activity; DRUG; CHOLESTEROL; OZONOLYSIS; TETRAOXANE ANTIMALARIALS; IDENTIFICATION; OZONIZATION; PEROXIDES; OZONIDES; AGENTS; DERIVATIVES
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2017.11.008

[Display omitted] •Deoxycholic acid ozonides were synthesized via the Griesbaum coozonolysis for the first time.•Two novel steroidal tetraoxanes were obtained by acid-catalyzed peroxycondensation.•Antimalarial activity was evaluated and potency for related compounds was compared. 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.