Submit Manuscript  

Article Details


Tryptanthrin analogues as inhibitors of enoyl-acyl carrier protein reductase: activity against Mycobacterium tuberculosis, toxicity, modeling of enzyme binding

Author(s):

Gheorghe H Duca, Serghei Pogrebnoi, Veaceslav Boldescu, Fatma Aksakal, Andrei Uncu, Vladimir Valica, Livia Uncu, Simona Negreș, Florica Nicolescu and Fliur Macaev*  

Abstract:


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

Affiliation:

Laboratory of Organic Synthesis and Biopharmaceuticals, Institute of Chemistry, Chisinau, Laboratory of Organic Synthesis and Biopharmaceuticals, Institute of Chemistry, Chisinau, Laboratory of Organic Synthesis and Biopharmaceuticals, Institute of Chemistry, Chisinau, Department of Chemistry, Gebze Technical University, Kocaeli, Scientific Center for Drug Research, “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Scientific Center for Drug Research, “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Scientific Center for Drug Research, “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Department of Pharmacology and Clinical Pharmacy, ”Carol Davila” University of Medicine and Pharmacy, Bucharest, Department of Pharmacology and Clinical Pharmacy, ”Carol Davila” University of Medicine and Pharmacy, Bucharest, Laboratory of Organic Synthesis and Biopharmaceuticals, Institute of Chemistry, Chisinau



Full Text Inquiry