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Design, synthesis, electrochemistry and anti-trypanosomatid hit/lead identification of nitrofuranylazines.

ABSTRACT: Chagas disease and leishmaniasis are vector-borne infectious diseases affecting both humans and animals. These neglected tropical diseases can be fatal if not treated. Hundreds to thousands of new Chagas disease and leishmaniasis cases are being reported by the WHO every year, and currently available treatments are insufficient. Severe adverse effects, impractical administrations and increased pathogen resistance against current clinical treatments underscore a serious need for the development of new drugs to curb these ailments. In search for such drugs, we investigated a series of nitrofuran-based azine derivatives. Herein, we report the design, synthesis, electrochemistry, and biological activity of these derivatives against promastigotes and amastigotes of Leishmania major, and L. donovani strains, as well as epimastigotes and trypomastigotes of Trypanosoma cruzi. Two leishmanicidal early leads and one trypanosomacidal hit with submicromolar activity were uncovered and stand for further in vivo investigation in the search for new antitrypanosomatid drugs. Future objective will focus on the identification of involved biological targets with the parasites.

SUBMITTER: Saayman M

PROVIDER: S-EPMC10583827 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Design, synthesis, electrochemistry and anti-trypanosomatid hit/lead identification of nitrofuranylazines.

Saayman Maryna M Kannigadu Christina C Aucamp Janine J Janse van Rensburg Helena D HD Joseph Cassiem C Swarts Andrew J AJ N'Da David D DD

RSC medicinal chemistry 20230816 10

Chagas disease and leishmaniasis are vector-borne infectious diseases affecting both humans and animals. These neglected tropical diseases can be fatal if not treated. Hundreds to thousands of new Chagas disease and leishmaniasis cases are being reported by the WHO every year, and currently available treatments are insufficient. Severe adverse effects, impractical administrations and increased pathogen resistance against current clinical treatments underscore a serious need for the development o ...[more]

PMID: 37859713

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Project description:Schistosomiasis is a neglected disease of poverty that is caused by infection with blood fluke species contained within the genus Schistosoma. For the last 40 years, control of schistosomiasis in endemic regions has predominantly been facilitated by administration of a single drug, praziquantel. Due to limitations in this mono-chemotherapeutic approach for sustaining schistosomiasis control into the future, alternative anti-schistosomal compounds are increasingly being sought by the drug discovery community. Herein, we describe a multi-pronged, integrated strategy that led to the identification and further exploration of the quinoxaline core as a promising anti-schistosomal scaffold. Firstly, phenotypic screening of commercially available small molecules resulted in the identification of a moderately active hit compound against Schistosoma mansoni (1, EC50 = 4.59 μM on schistosomula). Secondary exploration of the chemical space around compound 1 led to the identification of a quinoxaline-core containing, non-genotoxic lead (compound 22). Compound 22 demonstrated substantially improved activities on both intra-mammalian (EC50 = 0.44 μM, 0.20 μM and 84.7 nM, on schistosomula, juvenile and adult worms, respectively) and intra-molluscan (sporocyst) S. mansoni lifecycle stages. Further medicinal chemistry optimisation of compound 22, resulting in the generation of 20 additional analogues, improved our understanding of the structure-activity relationship and resulted in considerable improvements in both anti-schistosome potency and selectivity (e.g. compound 30; EC50 = 2.59 nM on adult worms; selectivity index compared to the HepG2 cell line = 348). Some derivatives of compound 22 (e.g. 31 and 33) also demonstrated significant activity against the two other medically important species, Schistosoma haematobium and Schistosoma japonicum. Further optimisation of this class of anti-schistosomal is ongoing and could lead to the development of an urgently needed alternative to praziquantel for assisting in schistosomiasis elimination strategies.

Dataset Information

Design, synthesis, electrochemistry and anti-trypanosomatid hit/lead identification of nitrofuranylazines.

Publications

Design, synthesis, electrochemistry and anti-trypanosomatid hit/lead identification of nitrofuranylazines.

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