PN-III-P2-2.1-PED-2019-3414
PROJECT CODE: PN-III-P2-2.1-PED-2019-3414, contract number 367PED ⁄ 2020
PROJECT TITLE:
Continuous-flow system bioreactor for the enzymatic kinetic resolution of novel chiral secondary heterocyclic alcohols
Bioreactor pentru rezoluția cinetică enzimatică a unor noi alcooli heterociclici secundari chirali in sistem continuu
ACRONYM: biorezol
PROJECT COORDINATOR: Politehnica University Timişoara
PROJECT DIRECTOR: Lecturer Dr. Eng. Valentin BADEA

 

PROJECT LAYOUT
Resolution (chiral separation) is an essential undertaking throughout discovery and development of biological active substances, with enantiomeric forms often possessing different biological effects. A comparison between chemical and enzymatic catalysis shows that in many cases biocatalysts are far superior in the production of chiral compounds due to their stereo-, regio- and chemoselectivity
The aim of this project is to develop, at laboratory scale, a continuous-flow system bioreactor for quantitative kinetic enzymatic resolution of racemic mixtures of novel chiral secondary heterocyclic alcohols, with potential biological activity, which will be synthesized within this project. After the synthesis of the new secondary heterocyclic alcohols (R,S)-1-(aryl/methyl)-2-[(4,5-diaryl-4H-1,2,4-triazol-3-yl)thio]ethan-1-ols as racemate, optimal conditions of enzymatic kinetic resolution will be established for each substrate, using selected microbial lipases and various reaction media. The realization of the enzymatic kinetic resolution will be done using a continuous flow bioreactor followed by the isolation and purification of the products with high enantiomeric purity. The realization of the enzymatic kinetic resolution will be done using a continuous flow bioreactor followed by the isolation and purification of the products with high enantiomeric purity. The validation of the experimental system will be accomplished through the effective obtaining of the enantiomers, whose biological activity, after assigning their absolute configuration, will be evaluated and compared with that of the racemic mixture where they come from.


PROJECT TEAM:
Project leader: Lecturer Dr. Eng. Valentin Badea
Reasearchers:
Professor Dr. Eng. Francisc Peter
Lecturer Dr. Eng. Anamaria Todea
Lecturer Dr. Eng. Iulia Maria Păușescu
Lecturer Dr. Eng. Valentin Laurențiu Ordodi
Teaching Assistant Dr. Chem. Diana Maria Aparaschivei
Research Assistant Eng. Ionuț Bîtcan

OBJECTIVE: The laboratory scale development of quantitative continuous-flow system bioreactor for the enzymatic kinetic resolution of novel chiral secondary heterocyclic alcohols racemate with potential biological activity which will be synthesized within this project, as well as choosing the enzymes with the best catalytic efficiency for this specific kinetic resolution.

The major cause of environmental pollution is due to emissions generated by burning of fossil fuels. The known crude oil reserves are going to disappear in short time and the oil crisis in recent years, together with the rising of air pollution levels has shown the need for the replacement of fossil fuels with cleaner biofuels, obtained by processing a range of organic renewable raw materials. The first step in conversion of lignocellulosic biomass to bioethanol is the pretreatment for the release of cellulose from the network formed with lignin and to increase the yield of fermentable sugars. There are many methods of pretreatment, but they are energy consumable and pollute the environment.
In this sense the project proposes an innovative approach on studies regarding biomass pretreatment and enzymatic hydrolysis of cellulose in an integrated system that can improve the exploitation of biomass components and the reuse of the biocatalyst. It is desired to provide novel biocatalysts, immobilized cellulases customized by new sol-gel entrapment techniques, used in the hydrolysis of certain types of lignocellulosic biomass. By immobilization, stability and reusability of cellulases are significantly improved, a key issue for increasing the amount of fermentable sugars and to reduce process costs.

 

STAGES
Stage 1 (2020, 2 months)- Synthesis, purification and spectroscopic characterization of intermediates used to obtain new chiral heterocyclic secondary alcohols.

Stage 2 (2021, 12 months)- Synthesis, purification and spectroscopic characterization of new heterocyclic secondary alcohols. Development of the enzymatic kinetic resolution process and elaboration of a continuous process for obtaining enantiomerically pure compounds using immobilized enzymes.

Stage 3 (2022, 10 months)- Assigning the absolute configuration by NMR spectroscopy and testing the biological activity for heterocyclic secondary alcohols.

DELIVERABLES:
Stage 1
Experimental synthesis protocol for N-(aryl)hydrazinecarbothioamide in gram amounts and spectroscopic characterization;
Experimental synthesis protocol for benzoyl(acyl)-N-arylhydrazine-1-carbothioamide in gram amounts and spectroscopic characterization;
Experimental synthesis protocol for 4-aryl-5-phenyl(alkyl)-4H-1,2,4-triazol-3-thiol in gram amounts and spectroscopic characterization;
Experimental synthesis protocol for 1-(aryl)-2-[(4-aryl-5-aryl(alkyl)-4H-1,2,4-triazol-3-yl)thio]ethan-1-one in gram amounts and spectroscopic characterization.
Stage 1 report.

Stage 2
Experimental synthesis protocol for N-(aryl)hydrazinecarbothioamide in gram amounts and spectroscopic characterization;
Experimental synthesis protocol for benzoyl(acyl)-N-arylhydrazine-1-carbothioamide in gram amounts and spectroscopic characterization;
Experimental synthesis protocol for 4-aryl-5-phenyl(alkyl)-4H-1,2,4-triazol-3-thiol in gram amounts and spectroscopic characterization;
Experimental synthesis protocol for 1-(aryl)-2-[(4-aryl-5-aryl(alkyl)-4H-1,2,4-triazol-3-yl)thio]ethan-1-one in gram amounts and spectroscopic characterization;
Experimental synthesis protocol for (R,S)-1-(aryl/methyl)-2-[(4-aryl-5-aryl(alkyl)-4H-1,2,4-triazol-3-yl) thio]ethan-1-ols in gram quantities and spectroscopic characterization;
Experimental protocol for enzymatic kinetic resolution;
Quantities of the order of grams of the immobilized enzyme with the highest activity;
Immobilized enzyme data sheet with optimal characteristics;
Laboratory methodology for the resolution of enzymatic kinetics in a continuous flow bioreactor;
Obtaining a heterocyclic secondary alcohol in gram amounts;
A paper submitted for publication in a journal;
Abstracts for two presentations at scientific conferences in the field.
Stage 2 report.

Stage 3
Obtaining a heterocyclic secondary alcohol in gram amounts;
Experimental study for assigning the absolute configuration;
Experimental protocol for assigning the absolute configuration;
Experimental protocol for the evaluation of biological activity;
A paper submitted for publication in a journal;
Stage 3 report
Final report.

 

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