Dataset Information

Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries.

ABSTRACT: From a screening campaign that included mixture-based libraries containing more than 6 million compounds, a lead series of bis-cyclic guanidines was identified as the most promising. Lead optimization resulted in the identification of potent (IC50 < 500 nM) and selective compounds within this series as well as potent and selective monoguanidines.

SUBMITTER: Giulianotti MA

PROVIDER: S-EPMC5554901 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries.

Giulianotti Marc A MA Vesely Brian A BA Azhari Ala A Souza Ashley A LaVoi Travis T Houghten Richard A RA Kyle Dennis E DE Leahy James W JW

ACS medicinal chemistry letters 20170710 8

From a screening campaign that included mixture-based libraries containing more than 6 million compounds, a lead series of bis-cyclic guanidines was identified as the most promising. Lead optimization resulted in the identification of potent (IC<sub>50</sub> < 500 nM) and selective compounds within this series as well as potent and selective monoguanidines. ...[more]

PMID: 28835792

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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

Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries.

Publications

Identification of a Hit Series of Antileishmanial Compounds through the Use of Mixture-Based Libraries.

Similar Datasets

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