Molecular mechanism underlying antileishmanial effect of oxabicyclo[3.3.1]nonanones: inhibition of key redox enzymes of the pathogen

Abstract

We report oxabicyclo[3.3.1]nonanones as inhibitors of key redox enzymes, trypanothione synthetase (TryS), and trypanothione reductase (TryR) of Leishmania. Further, detailed cellular effects of 4-(4,4,8-Trimethyl-7-oxo-3-oxabicyclo[3.3.1]non-2-yl)-benzoic acid methyl ester, a oxabicyclo[3.3.1]nonanones, on the parasite were investigated. As these compounds inhibit key redox enzymes (TryR amd TryS), treatment of these compounds resulted in increased reactive oxygen species (ROS), mitochondrial membrane damage, activation of caspase like proteases, and DNA damage that finally leads to apoptosis. Although the compound has modest IC50 value against parasite (4.9±0.4 μM), they identify a novel chemical space to design and develop drugs based on these compounds against the Leishmania parasite. This is first report of oxabicyclo[3.3.1]nonanones as antileishmanial.

Keywords: 2′,7′-dichlorodihydrofluorescein diacetate acetyl ester; Drug design; Enzyme inhibition; H(2)DCFDA; Leishmaniasis; N-acetylcysteine; NAC; Oxabicyclo[3.3.1]nonanones; PI; Protein biochemistry; ROS; TryR; TryS; Trypanothione reductase; Trypanothione synthetase; propidium iodide; reactive oxygen species; trypanothione reductase; trypanothione synthetase.