Apoptotic impact on Brugia malayi by sulphonamido-quinoxaline: search for a novel therapeutic rationale

Abstract

Human lymphatic filariasis although not fatal but poses serious socioeconomic burden due to associated disability. This is reflected by the huge magnitude of the estimated disability-adjusted life years of about 5.09 million. Therefore, following WHO mandate, our earlier studies on antifilarial drug development revealed the significance of apoptosis. Apoptotic impact has been implicated in anticancer rationale of several drugs. In this study, we explored the antifilarial potential of sulphonamido-quinoxaline compounds, shown to be specific inhibitor for c-Met kinase in human cancer cells. Out of studied compounds, Q4, showing favorable drug-likeness and medicinal chemistry properties on bioinformatics platform along with subsequently recorded lowest IC₁₀₀ value, was considered as a suitable antifilarial candidate. Significant apoptosis due to mitochondrial involvement was recorded in drug-treated parasite unlike untreated control. In spite of homology between human c-Met kinase and Brugia malayi counterpart, comparative docking result of this compound showed more favorable binding parameters with the parasitic target. The wide gap between IC₁₀₀ and LD₅₀ values further confirmed the therapeutic safety. We propose sulphonamido-quinoxaline derivative as a lead candidate for antifilarial drug development. Further study is warranted to authenticate parasitic c-Met kinase as a novel therapeutic target reminiscent of anticancer rationale implicating inhibition of proliferation.

Keywords: Apoptosis; Brugia malayi; Lymphatic filariasis; Quinoxaline; c-Met kinase.