Tuberculosis (TB) is an airborne infectious disease that that has long been preventable and curable. Caused by bacillus Mycobacterium tuberculosis, TB remains to be a global health problem heightened by recently identified multidrug resistant TB (MDR-TB) strains. Mycobacterium smegmatis MshC catalyzes the ATP-dependent condensation of GlcN-Ins and L-cysteine to form L-Cys-GlcN-Ins, the penultimate step in mycothiol biosynthesis. Mycothiol facilitates the detoxification process by removing alkylating agent bound L-cysteine. By inhibiting the MshC enzyme, the detoxification process lies in an arrested state. In order to design the inhibitors we focused on substrate analogues and natural product based small molecules. We proceeded by designing fluoro and azido based substrate analogues. The synthesis of the desired target molecule begins with partial protection of myo-inositol to give 2,3:4,5-di-O-cyclohexilidene-D/L-myo-inositol. Treatment of myo-inositol with 1-(R)-menthylchloro-formate, followed by benzylation and resolution gives the protected D-isomer of myo-inositol in exceptionally good yields and purity. Deprotection under basic conditions led to the acceptor. Glycosylation with the required glucosyltrichloroacetimidate donors, followed by global deprotection gave the desired molecule. Heterocyclic molecules have the potential of being anti-bacterial molecules and Tetrahydroquinolines (THIQ) are one of them. They represent one of the important “Privileged Scaffolds” amongst natural products. But the synthesis of THIQ has proved to be tricky over the years. We aim at the use of well-known reaction, Pictet Spengler to achieve cyclization with better yields and diastereoselectivity against use of Asymmetric reduction or Chemical or Enzymatic resolution. We also attempted the synthesis of Mycothiol, the substrate for the enzyme MST (mycothiol S-transferase). During this process few hurdles were encountered, due to which we had to opt for alternative synthetic scheme. These molecules will be helpful in better understanding the roles of the enzymes MshC and MST.

Use of substrate analogues and Tetrahydroisoquinolines (THIQ) as potential inhibitors for Mycobacterium tuberculosis enzyme MshC and synthesis of mycothiol

253rd National Meeting (2017)

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