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Synthesis and structure of azole-fused indeno[2,1-c]quinolines and their anti-mycobacterial properties.

Authors
  • Upadhayaya, Ram Shankar
  • Shinde, Popat D
  • Sayyed, Aftab Y
  • Kadam, Sandip A
  • Bawane, Amit N
  • Poddar, Avijit
  • Plashkevych, Oleksandr
  • Földesi, Andras
  • Chattopadhyaya, Jyoti
Type
Published Article
Journal
Organic & Biomolecular Chemistry
Publisher
The Royal Society of Chemistry
Publication Date
Dec 21, 2010
Volume
8
Issue
24
Pages
5661–5673
Identifiers
DOI: 10.1039/c0ob00445f
PMID: 20927480
Source
Medline
License
Unknown

Abstract

Prompted by our discovery of a new class of conformationally-locked indeno[2,1-c]quinolines as anti-mycobacterials, compounds 2a and 3a (Fig. 1; MIC < 0.39 μg mL(-1) and 0.78 μg mL(-1), respectively)(14) with a freely rotating C2-imidazolo substituent, we herein describe the synthesis of pentacyclic azole-fused quinoline derivatives 4 and 5, in which we have restricted the rotation of the C2-imidazolo moiety by fusing it to the adjacent quinoline-nitrogen to give a five-membered fused azole heterocycle. The idea of locking the flexibility of the system by conformational constraint was simply to reduce its entropy, thereby reducing the overall free-energy of its binding to the target receptor. Out of 22 different azole-fused indeno[2,1-c]quinoline derivatives, seven structurally distinct compounds, 9, 15, 17, 25, 27, 28 and 29, have shown 79-99% growth inhibition of Mycobacterium tuberculosis H37Rv at a fixed dose of 6.25 μg mL(-1). The efficacies of these compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of single dose on day one. Of these, two compounds, 9 and 28, inhibited growth of M. tuberculosis very effectively at MIC < 0.39 μg mL(-1) (0.89 μM and 1 μM, respectively). These active compounds 9, 15, 17, 25, 27, 28 and 29 were screened for their cytotoxic effect on mammalian cells (human monocytic cell line U937), which showed that the human cell survival is almost unperturbed (100% survival), except for compound 25, hence these new compounds with new scaffolds have been identified as potent anti-mycobacterials, virtually with no toxicity. Thus these "hit" molecules constitute our important "leads" for further optimization by structure-activity relationship against TB.

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