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  3. Synthesis of novel morpholine, thiomorpholine and N-substituted piperazine coupled 2-(thiophen-2-yl)dihydroquinolines as potent inhibitors of Mycobacterium tuberculosis

Synthesis of novel morpholine, thiomorpholine and N-substituted piperazine coupled 2-(thiophen-2-yl)dihydroquinolines as potent inhibitors of Mycobacterium tuberculosis

  • Eur J Med Chem. 2019 Feb 15:164:171-178. doi: 10.1016/j.ejmech.2018.12.043.
Sandeep Kumar Marvadi 1,  Vagolu Siva Krishna 2,  Dharmarajan Sriram 2,  Srinivas Kantevari 3
Affiliations

Affiliations

  • 1 Fluro & Agrochemicals Division, CSIR- Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India.
  • 2 Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, 500078, Telangana, India.
  • 3 Fluro & Agrochemicals Division, CSIR- Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India; Academy of Scientific and Innovative Research, CSIR- Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India. Electronic address: ksrinivas@iict.res.in.
PMID: 30594675 DOI: 10.1016/j.ejmech.2018.12.043
Abstract

A series of novel morpholine, thiomorpholine and N-substituted piperazine coupled 2-(thiophen-2-yl)dihydroquinolines 7a-p was designed and synthesized from 2-acetyl thiophene in six step reaction sequence involving modified Bohlmann-Rahtz and Vilsmeier-Haack-Arnold reactions as key transformations. 2-(Thiophen-2-yl)dihydroquinoline was formylated and subsequently chlorinated using DMF-POCl3. The resulting aldehyde was reduced to give an alcohol and then converted to bromide using PBr3. Further coupling of bromide with morpholine, thiomorpholine and N-substituted piperazines resulted in the desired quinolines 7a-p in very good yields. All the new derivatives 7a-p were characterized by their NMR and mass spectral analysis. In vitro screening of new compounds for antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB), resulted in two derivatives 7f and 7p as most potent antitubercular agents (MIC:1.56 μg/mL) with lower cytotoxicity profiles.

Keywords

Mycobacterium tuberculosis; Piperazine; Quinoline; Thiophene; Vilsmeier-Haack-Arnold reaction.

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