Apoptotic impact on Brugia malayi by sulphonamido-quinoxaline: search for a novel therapeutic rationale
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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.
KeywordsQuinoxaline Brugia malayi Apoptosis c-Met kinase Lymphatic filariasis
We would like to extend our tribute to the Late Dr. MVR Reddy, for his active contribution in this work.
Compliance with ethical standards
The animals used for the experimental purpose were approved by the Institutional Animal Ethics Committee (IAEC), MGIMS, Sevagram, Maharashtra, which follows the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) norms. Peripheral blood mononuclear cells (PBMCs; 1 × 106 cells/mL) of healthy human volunteers, of age 25 to 30 with informed consent, were collected and have been performed in accordance with the ethical recommendations of the Institutional Ethical Committee, MGIMS, Sevagram.
Conflict of interest
The authors declare that they have no conflict of interest.
- Behm CA, Bendig MM, McCarter JP, Sluder AE (2004) WHO/TDR scientific working group on ‘RNA interference as a means of identifying drug targets for filariasis’ report: 1Google Scholar
- Bennuru S, Meng Z, Ribeiro JM, Semnani RT, Ghedin E, Chan K, Lucas DA, Veenstra TD, Nutman TB (2011) Stage-specific proteomic expression patterns of the human filarial parasite Brugia malayi and its endosymbiont Wolbachia. Proc Natl Acad Sci U S A 108:9649–9654CrossRefPubMedPubMedCentralGoogle Scholar
- Bhattacharjee J (2016) Mass drugs administration in India—a failure story. Epidemiology: Open Access 6:252Google Scholar
- Ganapaty S, Ramalingam P, BabuRao CH (2008) SAR study: impact of hydrazide hydrazones and sulfonamide side chain on in vitro antimicrobial activity of quinoxaline. Int J Pharmacology Biology 2:13–18Google Scholar
- Organ SL, Tsao MS (2011) An overview of the c-MET signaling pathway. Ther Adv Med Oncol 3(1_suppl):S7–S19Google Scholar
- World Health Organization. Lymphatic filariasis: fact sheet updated on March 2017 http://www.who.int/mediacentre/factsheets/fs102/en/