328971-36-4Relevant articles and documents
Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation
Padalino, Gilda,El-Sakkary, Nelly,Liu, Lawrence J.,Liu, Chenxi,Harte, Danielle S.G.,Barnes, Rachel E.,Sayers, Edward,Forde-Thomas, Josephine,Whiteland, Helen,Bassetto, Marcella,Ferla, Salvatore,Johnson, George,Jones, Arwyn T.,Caffrey, Conor R.,Chalmers, Iain,Brancale, Andrea,Hoffmann, Karl F.
, (2021)
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.
ANTIBACTERIAL AND ANTIPARASITIC QUINOXALINE-2,3-DIAMINE DERIVATIVES
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Page/Page column 15; 16, (2021/01/23)
A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a patient infected with pathogenic organisms; wherein X and Y are each independently selected from C, N, O and S, provided at least one of X and Y is N, O or S; wherein R1 and R2 are each independently selected from an optionally substituted C1-C8 alkyl, C1-C8 alkenyl, aryl, heteroaryl or alkylaryl group; and wherein Z is selected from H, -CN, -NO2, -NR3R4, -NR5(CO)R6; C1-C4 alkyl, C1-C4 alkoxy, -(CO)WR12, hydroxy, amino, thiol, chloro, fluoro, CF3, CHF2 or CH2F groups. The compounds may be effective in treating patients/animals infected with parasites selected from Schistosoma, Haemonchus, Eimeria, Echinococcus, Dirofilaria, Fasciola or Plasmodium parasites. Additionally or alternatively, the compounds of formula (I) may be effective in treating patients infected with pathogenic bacteria selected from S. aureus, MRSA and Enterococcus faecalis.
Activities of quinoxaline, nitroquinoxaline, and [1,2,4]triazolo [4,3-a]quinoxaline analogs of mmv007204 against schistosoma mansoni
Debbert, Stefan L.,Hintz, Mikaela J.,Bell, Christian J.,Earl, Kenya R.,Forsythe, Grant E.,H?berli, Cécile,Keiser, Jennifer
supporting information, (2021/03/04)
The reliance on one drug, praziquantel, to treat the parasitic disease schistosomiasis in millions of people a year shows the need to further develop a pipeline of new drugs to treat this disease. Recently, an antimalarial quinoxaline derivative (MMV007204) from the Medicines for Malaria Venture (MMV) Malaria Box demonstrated promise against Schistosoma mansoni. In this study, 47 synthesized compounds containing quinoxaline moieties were first assayed against the larval stage of this parasite, newly transformed schistosomula (NTS); of these, 16 killed over 70% NTS at 10mM. Further testing against NTS and adult S. mansoni yielded three compounds with 50% inhibitory concentrations (IC50s) of#0.31mM against adult S. mansoni and selectivity indices of$8.9. Administration of these compounds as a single oral dose of 400mg/kg of body weight to S. mansoni-infected mice yielded only moderate worm burden reduction (WBR) (9.3% to 46.3%). The discrepancy between these compounds' good in vitro activities and their poor in vivo activities indicates that optimization of their pharmacokinetic properties may yield compounds with greater bioavailabilities and better antischistosomiasis activities in vivo.
