| dc.description.abstract | Leishmaniasis is a neglected tropical disease (NTD) caused by the Leishmania parasite and this devastating vector-borne disease affects millions of people worldwide. There are up to 1 million new infections reportedly occurring on a yearly basis, in more than three clinical manifestation forms. The currently available treatments are limited to a handful of drugs that show significant toxicity, are delivered through invasive administration methods, are expensive and are threatened by emergence of parasitic resistance. Hence it is necessary to develop new, affordable and effective antileishmanial drugs.
5-Nitrofurans (NFs) are redox-active anti-infective drugs used to treat various infectious diseases. Research has shown that drugs containing nitro groups like NFs exhibit a wide spectrum of anti-infective activity against various diseases such as bacterial, mycobacterial, parasites and cancer. These drugs are very active owing to the presence of the nitro group that produces free radical species. These free radicals react with the pathogen cell wall enzymes and become lethal to the microorganisms.
Nifuroxazide (NFX) is one of the clinical nitrofurans (cNFs) in use as a treatment for gastro-intestinal infections. NFX contains the nitro moiety as well as a second hydrazone moiety that increases the activity of the drug. Studies have shown that NFX also possesses a variety of anti-infective activity including antiparasitic activity. However, the absorption of the drug from the intestinal tract is limited and the use of the drug may lead to various toxic effects associated with the generation of free radicals. These shortcomings may be overcome through hybridization, thus the possibility of NFX to act as a parent drug for the development of a new antiparasitic drug is promising.
This study evaluated nifuroxazide-based sulfonyl and benzyl analogues for their antileishmanial activity. The analogues contained three biologically active pharmacophores i.e., nitrofuran, hydrazone and sulfonyl or benzyl moiety and were synthesised in a single-step reaction. These analogues were screened for their toxicity on Vero cells and their antileishmanial activity against the promastigote forms of Leishmania donovani (1S and 9515) and L. major IR-173.
The activities of the synthesised analogues ranged from excellent, IC50 = 0.08 μM to moderate, IC50 = 9.74 μM. The tert-butyl substituted derivatives 1h, 2d were found to be the most potent of both series, possessing nanomolar activity against all three strains of Leishmania. The cytotoxicity
of the analogues ranged from moderately toxic to non-toxic. Overall, eight sulfonyl (1d, 1e, 1f, 1g, 1h, 1j, 1k and 1l) and six benzyl (2b, 2c, 2d, 2e, 2f and 2g) analogues showed promise as anti-promastigote hit/lead compounds due to their high selectivity and activity as well as their low cytotoxicity and may serve as possible building blocks for future antileishmanial drug development. | en_US |
