title: The potential of quinoline derivatives for the treatment of Toxoplasma gondii infection.
abstract: Here we reported our investigation, as part of our drug repositioning effort, on anti-Toxoplasma properties of newly synthesized quinoline compounds. A collection of 4-aminoquinoline and 4-piperazinylquinoline analogs have recently been synthesized for use in cancer chemotherapy. Some analogs were able to outperform chloroquine, a quinoline derivative drug which is commonly used in the treatment of malaria and other parasitic infections. Herein 58 compounds containing one or two quinoline rings were examined for their effectiveness as potential anti-Toxoplasma compounds. Of these 58 compounds, 32 were efficient at inhibiting Toxoplasma growth (IC50<100 μM). Five compounds with single and simple quinoline rings exhibited similar cLogP values of ∼2 and IC50 values between 5 and 6 μM, with one exception of 8-hydroxyquinoline whose IC50 value was 213 nM. The addition of one hydroxyl group at position 8 caused a 40-fold increase in the inhibitory effect of quinoline. A significant improvement in anti-Toxoplasma effect among quinoline derivatives was detected in B11, B12, B23, and B24, whose structures carry two quinoline rings, and their resultant cLogP values are ⩾7. Among these compounds, B23 was the most effective compound with IC50 value of 425±35 nM, and TI value of 4.9. It was also noted that compounds with at least one quinoline ring, displaying anti-Toxoplasma effects were capable of causing the disappearance of the apicoplast, a plastid-like organelle. When treated with quinoline, 8-hydroxyquinoline or B23, 40-45% of the parasites lost their apicoplasts. Our findings recapitulate the properties of quinoline derivatives in diminishing apicoplast. This could aid further investigations of anti-parasitic treatments specific to Apicomplexan. More importantly, B12 and B23 which harbor superior anti-cancer properties than chloroquine, have effective anti-Toxoplasma activity. These compounds therefore have significant potential for future development of chemotherapeutic agents for patients suffering from breast cancers and parasitic infection.
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Dema
authors.initials: D
authors.lastname: Kadri
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Crater
authors.affiliation: Tumour Biology Group, Advanced Medical Research Institute of Canada, Northeast Cancer Centre, Health Sciences North, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada; Northern Ontario School of Medicine, 935 Ramsey Lake Road, Sudbury, Ontario P3E 2C6, Canada.
authors.forename: Hoyun
authors.initials: H
authors.lastname: Lee
authors.affiliation: Tumour Biology Group, Advanced Medical Research Institute of Canada, Northeast Cancer Centre, Health Sciences North, 41 Ramsey Lake Road, Sudbury, Ontario P3E 5J1, Canada.
authors.forename: V Raja
authors.initials: VR
authors.lastname: Solomon
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada. Electronic address: anans@uwindsor.ca.
authors.forename: Sirinart
authors.initials: S
authors.lastname: Ananvoranich
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D020128:Inhibitory Concentration 50; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014122:Toxoplasma / Q000187:drug effects* / Q000254:growth & development; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D011804:Quinolines
keywords: Apicoplast; Quinoline derivatives; Toxoplasma gondii