Tryptanthrin Analogues as Inhibitors of Enoyl-acyl Carrier Protein Reductase: Activity against Mycobacterium tuberculosis, Toxicity, Modeling of Enzyme Binding

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Author(s): Gheorghe H Duca, Serghei Pogrebnoi, Veaceslav Boldescu, Fatma Aksakal, Andrei Uncu, Vladimir Valica, Livia Uncu, Simona Negreș, Florica Nicolescu, Fliur Macaev*.

Journal Name: Current Topics in Medicinal Chemistry

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A new group of tryptanthrin analogues were obtained and evaluated for their activity against Mycobacterium tuberculosis H37Rv. Tryptanthrin is a known inhibitor of Mtb enoyl-acyl carrier protein reductase (InhA) and modifications in its structure gave a group of 5H-[1,3,4]thiadiazolo[2,3- b]quinazolin-5-one analogues with antimycobacterial various potency. The most active compound in the series, 2-(propylthio)-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one, exhibited the superior inhibition activity (up to 100%) against mycobacterial growth at MIC 6.5 μg/mL and demonstrated a very low per oral toxicity in animals falling under the category 5 according to GHS classification. Molecular modeling studies were performed to investigate the binding mechanisms of the synthesized ligands with InhA. Binding energies and non-covalent interactions stabilizing the ligand-receptor complexes were obtained from the results of molecular docking.

Keywords: tryptanthrin, Mycobacterium tuberculosis, enoyl-acyl carrier protein reductase, drug design, enzyme models, thiadiazole, quinazolinone

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(E-pub Ahead of Print)
DOI: 10.2174/1568026619666190304125740
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