Abstract
Among the microorganisms employed in the study, Aspergillus niger (GUFCC5443), Escherichia coli (ATCC9637), Streptomyces halstedii (CKM-2), Pseudomonas putida (NCIB9494), Cunninghamella elegans (NCIM689) and Sphingomonas paucimobilis (NCTC11030) were capable for the enantioselective conversion of racemic Carvedilol. Immobilization technique enhanced the enantioselectivity of microorganisms and thus increased the enantiomeric purity of the drug. Excellent enantiomeric ratios (E) were found in reactions catalyzed by immobilized A. niger and E. coli with values 174.44 and 104.26, respectively. Triacylglycerol lipase from Aspergillus niger was also employed in this study as a biocatalyst which resulted in the product with 83.35% enantiomeric excess (ee) and E of 11.34 while the enzyme on immobilization has yielded 99.08% ee and 216.39 E. The conversion yield (C%) of the drug by free-enzyme was 57.42%, which was enhanced by immobilization to 90.51%. Hence, our results suggest that immobilized triacylglycerol lipase from A. niger (Lipase AP6) could be an efficient biocatalyst for the enantioselective resolution of racemic Carvedilol to (S)-(−)-Carvedilol with high enantiomeric purity followed by immobilized cultures of A. niger and E. coli.
Highlights
In a chiral drug, each enantiomer has its own particular pharmacological profile
Among the employed microbial cultures only A. niger, E. coli, Streptomyces halstedii, P. putida, C. elegans and Sphingomonas paucimobilis were capable for the enantioselective resolution of racemic Carvedilol
Enantioselective Resolution of (R,S)-Carvedilol to (S)-(-)-Carvedilol by Biocatalysts putida, Streptomyces halstedii, E. coli and A. niger cultures for 10 days were shown in Fig. 2a–f, respectively
Summary
Each enantiomer has its own particular pharmacological profile. There are several advantages for single enantiomer products when compared to their racemates like more selective and comparatively simple pharmacodynamic as well as pharmacokinetic profile, potential for an improved therapeutic index and very less probability for complex drug interactions [1]. Lipases are uniquely stable in non-polar organic solvents [11] with increased catalytic activity and stereoselectivity These are readily available from various microorganisms, do not require co-factors and accept wide range of non-natural substrates [12]. Immobilization of cells and enzymes can be done by various methods like adsorption (carrier-binding), cross-linking (covalent), entrapment and membrane confinement [16] Among these methods, entrapment in calcium alginate beads is most widely used technique in pharmaceutical industry because alginate can form gels under mild conditions, and it is nontoxic, non-pathogenic, cheap and readily available [17]. Till date there has been no report on the biotransformation of racemic Carvedilol to its (S)-(-)enantiomer This drug is a suitable candidate for demonstration of biocatalytic resolution to provide a single active enantiomer compound. The present study aimed for the enantioselective resolution of racemic Carvedilol to its (S)-(-)-enantiomer using various microorganisms like Bacillus subtilis [20], Escherichia coli [21], Pseudomonas putida [22], Sphingomonas paucimobilis [23], Rhodococcus erythropolis [24], Streptomyces halstedii [25], Aspergillus niger [26], Candida parapsilosis [27], Geotrichum candidum [28], Rhizopus oryzae [29], Cunninghamella elegans [30], Cunninghamella blakesleeana [31] and an enzyme, triacylglycerol lipase from Aspergillus niger (Lipase AP6) [32], which were reported earlier for their ability to convert racemates to the eutomers (active enantiomer), enantioselectively
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