Resolution, absolute configuration and antifilarial activity of coumarinyl amino alcohols
摘要:
The resolution of racemic coumarinyl amino alcohols 5-10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-L-proline (S)-11. Direct esterification of rac-5-10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5-10 and (R)-(-)-5-10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(-)-9 and (S)-(+)-10, (R)-(-)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action. (C) 2017 Elsevier Ltd. All rights reserved.
Resolution, absolute configuration and antifilarial activity of coumarinyl amino alcohols
摘要:
The resolution of racemic coumarinyl amino alcohols 5-10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-L-proline (S)-11. Direct esterification of rac-5-10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5-10 and (R)-(-)-5-10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(-)-9 and (S)-(+)-10, (R)-(-)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action. (C) 2017 Elsevier Ltd. All rights reserved.
A series of 4-oxycoumarin derivatives was synthesized, characterized and evaluated in vitro and in vivo for antifilarial activity against the human lymphatic filarial parasite, Brugia malayi. A majority of the compounds studied showed potent in vitro activity with low IC50 values in the micro molar (mu M) range (0.014-1.73 and 0.0056-0.43) against adult worms and microfilariae, respectively. Compounds 8 and 9 were identified to be the most promising antifilarial candidate molecules exhibiting activity in the nanomolar (nM) range. The IC50 values for compound 8 were 14 nM and 5.6 nM while for compound 9 were 94 nM and 13 nM, respectively, for adult worm and microfilaria. These two compounds also displayed promising adulticidal activity (74.9 +/- 4.8% and 69.4 +/- 2.8%, respectively) in the primary rodent (jird) screen. This study also serves as a starting point for investigating structure-activity relationship with different amino substituents. (C) 2015 Elsevier Masson SAS. All rights reserved.
New syntheses on the basis of 4-hydroxy-2H-chromen-2-ones
作者:A. A. Avetisyan、A. G. Alvandzhyan、K. S. Avetisyan
DOI:10.1134/s1070428009070161
日期:2009.7
Alkylation of 4-hydroxy-2H-chromen-2-ones with 2-chloromethyloxirane in acetone in the presence of potassium carbonate gave 4-(2,3-epoxypropoxy)-2H-chromen-2-ones which were treated with various amines to obtain the corresponding 4-(3-amino-2-hydroxypropoxy)-2H-chromen-2-ones, and the latter were acylated at the hydroxy group with benzoyl chloride.