title: Design, synthesis, anti-schistosomal activity and molecular docking of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives.
abstract: Schistosomiasis remains one of the most prevalent parasitic infections and has significant public health consequences. Praziquantel (PZQ) is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Herein we report a series of novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives, which were synthesized, characterized and tested as anti-schistosomal agents in vitro. Among all tested compounds, compounds 4a, 5b, and 7b at different tested concentrations (50, 100, and 200 μg/mL) showed the highest schistosomicidal activity. Among those 3 compounds, compound 7b was the most potent anti-schistosomal one. Moreover, all tested compound, at 50 μg/mL concentration, significantly reduced oviposition of adult worms in vitro. Furthermore, both compound 4a and 7b, as well as compound 6a, completely diminished egg deposition. To clarify the possible mechanism by which novel 8-hydroxyquinoline-5-sufonyl 1,4-diazepine derivatives act as anti-schistosomal agents, molecular docking of all new compounds was carried out using Molsoft ICM pro 3.5-0a to investigate the binding affinity and binding mode to thioredoxin glutathione reductase enzyme (TGR), a potential drug target for anti-schistosomal agents. The docking results revealed moderate to high affinity of the new compounds towards TGR. Compound 7b scored the highest binding energy (-101.13 kcal/mol) against TGR crystal structure forming eight hydrogen bonds with the amino acid residues at the binding site of the receptor. This result indicates that compound 7b could exert its effect through inhibition of TGR, which is a vital enzyme for schistosome survival.
authors.affiliation: Department of Medicinal Chemistry, National Research Center, Dokki, Cairo, Egypt. eweas1@gmail.com
authors.forename: Ahmad F
authors.initials: AF
authors.lastname: Eweas
authors.forename: Gamal
authors.initials: G
authors.lastname: Allam
authors.forename: Abdelaziz S A
authors.initials: AS
authors.lastname: Abuelsaad
authors.forename: Abdul Hamid
authors.initials: AH
authors.lastname: ALGhamdi
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Maghrabi
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D012547:Schistosoma / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D012552:Schistosomiasis / Q000188:drug therapy / Q000469:parasitology; D012556:Schistosomicides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: C582064:5-((2,4-diphenyl-3H-pyrido(3,4-b)(1,4)diazepin-3-yl)sulfonyl)quinolin-8-ol; D001381:Azepines; D006912:Hydroxyquinolines; D012556:Schistosomicides; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase