Synthesis and in vitro anti-protozoan activities of nitrofuran-based azine derivatives

Abstract

Neglected tropical diseases (NTDs) are a group of diverse infectious conditions that are closely connected to poverty and affects more than a billion people worldwide. Leishmaniasis is a vector-borne NTD that is caused by the Leishmania parasite. Up to one million new cases of leishmaniasis are reported annually and current treatments are limited to a few chemotherapeutic drugs with significant toxicity, administration, cost, and parasite resistance issues. Therefore, there is an urgent need to search for new, safe, and affordable antileishmanial drugs. In this study, the antileishmanial activity of several nitrofuran-based azine derivatives was investigated. The synthesised derivatives consist of three active pharmacophores, namely the nitrofuran, hydrazone and aromatic ring. Nitrofurans possess a broad range of biological activity against various diseases, including leishmaniasis. Therefore, in this study two sub-series of compounds (nitrofuran and nitrothiophene derivatives) were synthesised using the two-step process of hydrazone formation and Schiff base reactions. The derivatives were screened for activity against L. donovani and L. major promastigotes. The antileishmanial activity ranged from good (IC₅₀ = 0.42 μM) to no activity (IC₅₀ >100 μM), with the nitrofuran sub-series exhibiting better activity compared to the nitrothiophene sub-series. The cytotoxicity of the compounds ranged from moderately toxic to non-toxic (IC50 11.56- >100 μM). Compounds 3a, 5a and 7a had good activity against all three Leishmania strains and were non-toxic, thus are potential anti-promastigote hits for further investigation. These derivatives could serve as building blocks for the development of future antileishmanial agents.