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Approaches Toward the Inhibition of Mycobacterium tuberculosis enzyme MshC using Substrate Analogues and Natural Products

Patel, Krishnakant
http://rave.ohiolink.edu/etdc/view?acc_num=toledo151327611162838

Abstract Details

2017, Doctor of Philosophy, University of Toledo, Chemistry.
Tuberculosis (TB), an airborne infectious disease caused by bacillus Mycobacterium tuberculosis (Mtb), is the second largest cause of death in humans from an infection only after human immunodeficiency virus (HIV). As per the Global Tuberculosis Report 2015 an overwhelming 10 million new cases were reported. Due to the emergence of the multi-drug resistant (MDR) and extremely-drug resistant (XDR) strains, the current drugs in the market are rendered ineffective. In order to combat the disease, there is a need to identify new drugs and drug targets. In our attempt to address the problem, we designed the synthesis of substrate analogues and tetrahydroisoquinolines (THIQ) as potential inhibitors for the Mtb enzyme Mycothiol ligase (MshC). We also attempted the synthesis of Mycothiol (MSH); substrate for the enzyme Mycothiol-S-transferase (MST). In the first project, we report the synthesis of substrate analogues, as potential inhibitors, for the Mycothiol cysteine ligase (MshC) enzyme. MshC is a key enzyme in the mycothiol (MSH) biosynthesis and a promising target for developing new anti-mycobacterial compounds. The target molecules were synthesized employing a Schmidt glycosylation strategy using an enantiomerically pure inositol acceptor and 2-deoxy trichloroacetimidate glycosyl donors with glycosylation yields greater than 70% and overall yields >5%. The inositol acceptor was obtained via chiral resolution of (±)-myo-inositol. In the second project, we attempted the synthesis of Mycothiol (MSH), also known as Acetyl Cysteine Glucosamine Inositol. MSH is the substrate for the enzyme MST and a key low-molecular weight thiol in most actinomycetes assisting in their survival. In the process of achieving the target, we encountered difficulties in the removal of benzyl protecting group which in general is easily removed via catalytic hydrogenation and other metal based reactions. In the third project, we focused on the synthesis of tetrahydroisoquinoline (THIQ) derivatives. The THIQ skeleton is encountered in many drug molecules and metabolites and thus considered as one of the most biologically relevant heterocyclic molecule. Previous methods reported in the literature for the synthesis of THIQs involve the use of chiral catalysts, metal catalysts, chiral ligands, asymmetric reduction, oxidation, enzymatic or chiral resolution to obtain stereoselective C-1 substituted THIQ derivatives. We report the use of Asymmetric Strecker and Pictet-Spengler reactions to attain the main core for the derivatives with good stereoselective for the penultimate cyclization reaction, compared to the reports in the literature.
Peter Andreana (Committee Chair)
Steven Sucheck (Committee Member)
Donald Ronning (Committee Member)
L. M Viranga Tillekeratne (Committee Member)
126 p.
Chemistry; Organic Chemistry
MshC; Mycobacterium tuberculosis; Mycothiol; Pictet-Spengler; Tetrahydroisoquinoline

Recommended Citations

Citations

  • Patel, K. (2017). Approaches Toward the Inhibition of Mycobacterium tuberculosis enzyme MshC using Substrate Analogues and Natural Products [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo151327611162838

    APA Style (7th edition)

  • Patel, Krishnakant. Approaches Toward the Inhibition of Mycobacterium tuberculosis enzyme MshC using Substrate Analogues and Natural Products. 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo151327611162838.

    MLA Style (8th edition)

  • Patel, Krishnakant. "Approaches Toward the Inhibition of Mycobacterium tuberculosis enzyme MshC using Substrate Analogues and Natural Products." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo151327611162838

    Chicago Manual of Style (17th edition)

toledo151327611162838
440
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This open access ETD is published by University of Toledo and OhioLINK.