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.
Highlights
Lymphatic filariasis (LF), caused by the infection of filarial nematodes is the second leading cause of long-term disability to date[1]
We describe the molecular mechanism of action of the novel sulfa drug, 4,7-dimethyl-3,4,7,8-tetrahydro-3λ6-[1,2]thiazino[4,3-f] quinoline-3,3,8-trione that has been found to be potent against the filarial nematode but is non-toxic to mammalian hosts
This study is a maiden report on a novel class of antifilarial compound of which synthesis has been inspired from a very bioactive natural molecule belonging to quinolone based sulfa drugs
Summary
This study is a maiden report on a novel class of antifilarial compound of which synthesis has been inspired from a very bioactive natural molecule belonging to quinolone based sulfa drugs. The wide spectrum of bioactivity of these compounds provided us the clue that these compounds can act over both unicellular as well as multicellular targets, prompted us to develop a hybrid molecule, i.e. coumarin and quinolone fused benzosultam, which may serve as a potential antifilarial drug without having any toxicity on non-targeted cells. The concentrations of 8l tested were not lethal to the C6/36 cells infected with Wolbachia but the endobacteria were depleted from the cells in a dose dependent manner This specific action against Wolbachia revealed that 8l could be very effective in treating the human filarial infections W. bancrofti, O. volvulus, Brugia spp. and some Mansonella spp., due to their dependence on the endosymbionts for survival. 8l is an efficacious antifilarial agent and and is safe for possible development as a drug for treating lymphatic filariasis
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