Quinolone-fused cyclic sulfonamide as a novel benign antifilarial agent

Abstract

Search of potent antifilarial drugs has been a major thrust area in tropical medicine research over the decades. Herein, we report 4,7-dimethyl-3,4,7,8-tetrahydro-3λ6-[1,2]thiazino[4,3-f]quinoline-3,3,8-trione (8l) as a new class of antifilarial agent which is extremely potent, with lethality against all the developmental stages (oocyte, microfilaria and adult) of the filarial parasite Setaria cervi. Molecular investigation on its mode of action revealed that 8l is a typical inducer of reactive oxygen species that triggers oxidative stress inside the filarid and further signals induction of apoptosis by activating both intrinsic and extrinsic pathways. Moreover, 8l is also active against Wolbachia, the essential endosymbiont of several human infectious filarids. Selective toxicity against filarial parasites and non-toxic nature in rat model were found as unique traits of 8l to be a future medicine. Taken en masse, this maiden report on a novel quinolone fused cyclic sulfonamide presents a promising therapeutic lead for lymphatic filariasis in future.

Polyphenol enriched ethanolic extract of Cajanus scarabaeoides (L.) Thouars exerts potential antifilarial activity by inducing oxidative stress and programmed cell death

“…Levels of the enzymatic antioxidants such as glutathione S-transferase, superoxide dismutase, catalase, glutathione reductase, and nonenzymatic antioxidant i.e. glutathione were estimated following the methods depicted in our earlier reports [15, 16, 20, 25, 26, 27].…”

“…Reduced glutathione (GSH) was estimated following Mukherjee et al [15, 27]. 150 μl of lysate from control and the treated parasites was mixed with 5% perchloric acid.…”

“…The glutathione S-transferase (GST) activity was determined in the cell-free supernatant following method of Mukherjee et al[27]. In 1 ml of assay cocktail comprising 980 μl of PBS (pH 6.5), 0.1 mol/L CDNB (1-chloro-2,4-dinitrobenzene) and 0.1 mol/L GSH, 100 μl of cell-free supernatant was added and incubated at 30°C for 5 min.…”

“…Catalase activity was assayed following the method described in Mukherjee et al [15, 27]. 40 μl of the cell-free supernatant obtained from the parasite homogenate was added to the assay mixture containing 3 ml of H 2 O 2 -phosphate buffer (0.002 mol/L H 2 O 2 prepared in 0.067 M PBS (pH 7.0) (0.1mol/L Na 2 HPO 4 and 0.1mol/L KH 2 PO 4 ).…”

“…Cytotoxicity of EECs was investigated using peritoneal macrophages of Wistar rat [27]. Cells were seeded into a 24 well culture plate in complete DMEM and exposed to different concentrations of each solvent extract, containing 1% DMSO as a control.…”