ACS Medicinal Chemistry Letters · 2017 · 43 citations · 15 references
PharmacyMedicinal ChemistryPharmacologyDrug DiscoveryLead OptimizationParasitologyAntiparasitic AgentsAntiparasitic PharmacologyAntiparasitic TherapyEnzyme InhibitionProtozoal InfectionsProtozoan PathogenesisHit ValidationHuman African TrypanosomiasisIn Vivo Efficacy TestingOral TreatmentStructure - Activity Relationship OptimizationTreatment Of TrypanosomiasisTrypanosomatid-host InteractionsTrypanosome Infections
High Resolution Image Download MS PowerPoint Slide A high throughput screening and subsequent hit validation identified compound 1 as an inhibitor of Trypanosoma brucei parasite growth. Extensive structure–activity relationship optimization based on antiparasitic activity led to the highly potent compounds, 1-(4-fluorobenzyl)-3-(4-dimethylamino-3-chlorophenyl)-2-thiohydantoin ( 68 ) and 1-(2-chloro-4-fluorobenzyl)-3-(4-dimethylamino-3-methoxyphenyl)-2-thiohydantoin ( 76 ), with a T. brucei EC 50 of 3 and 2 nM, respectively. This represents >100-fold improvement in potency compared to compound 1 . In vivo efficacy experiments of 68 and 76 in an acute mouse model of Human African Trypanosomiasis showed a 100% cure rate after 4 days of oral treatment at 50 mg/kg twice per day.
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S-Glucosylated hydantoins as new antiviral agents
A. A. EL‐BARBARY, Ahmed I. Khodair, Erik B. Pedersen et al. · Journal of Medicinal Chemistry · 1994 · 129 citations