Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays
- Authors: Kimuda, Magambo Phillip , Laming, Dustin , Hoppe, Heinrich C , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124675 , vital:35647 , https://doi:10.3390/molecules24010142
- Description: Pteridine reductase 1 (PTR1) is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. Currently there are no anti-folate based Human African Trypanosomiasis (HAT) chemotherapeutics in use. Thus, successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1) has implications in the exploitation of anti-folates. We carried out molecular docking of a ligand library of 5742 compounds against TbPTR1 and identified 18 compounds showing promising binding modes. The protein-ligand complexes were subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. In this study, we identified five compounds which showed low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism (mutual reduction in potency) when used in combination with the known TbDHFR inhibitor, WR99210. This gave an indication that the compounds might inhibit both TbPTR1 and TbDHFR. RUBi016 showed an additive effect in the isobologram assay. Overall, our results provide a basis for scaffold optimization for further studies in the development of HAT anti-folates.
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Synthesis, antiplasmodial and antitrypanosomal evaluation of a series of novel 2-oxoquinoline-based thiosemicarbazone derivatives
- Authors: Darrell, Oliver T , Hulushe, Siyabonga T , Mtshare, Thanduxolo Elihle , Beteck, Richard M , Isaacs, Michelle , Laming, Dustin , Khanye, Setshaba D , Hoppe, Heinrich C , Krause, Rui W M
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123117 , vital:35407 , https://doi.org/10.17159/0379-4350/2018/v71a25
- Description: Herein a series of novel thiosemicarbazones (TSCs) derived from 2-oxoquinoline scaffold is reported, and the target compounds have been successfully synthesized and characterized using standard spectroscopic techniques. The in vitro biological activities of synthesized molecules were evaluated against Plasmodium falciparum malaria parasites (strain 3D7), Trypanosoma brucei brucei parasites (strain 427) and HeLa cells. All the compounds displayed modest or no activity at a concentration of 20 μM and percentage viability of >50 % was often observed. Except for compound 9o, none of the final compounds exhibited cytotoxic effects against HeLa cells at 20 μM.
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Cinnamoyl-Oxaborole Amides: Synthesis and Their in Vitro Biological Activity.
- Authors: Gumbo, Maureen , Beteck, Richard M , Mandizvo, Tawanda , Seldon, Ronnett , Warner, Digby F , Hoppe, Heinrich C , Isaacs, Michelle , Laming, Dustin , Tam, Christina C , Cheng, Luisa W , Liu, Nicole , Land, Kirkwood , Khanye, Setshaba D
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/122879 , vital:35362 , https://doi.org/10.3390/molecules23082038
- Description: Due to the increased interest in their application in the treatment of infectious diseases, boron-containing compounds have received a significant coverage in the literature. Herein, a small set of novel cinnamoly-oxaborole amides were synthesized and screened against nagana Trypanosoma brucei brucei for antitrypanosomal activity. Compound 5g emerged as a new hit with an in vitro IC50 value of 0.086 μM against T. b. brucei without obvious inhibitory activity against HeLa cell lines. The same series was also screened against other human pathogens, including Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), for which moderate to weak activity (10 to >125 μM) was observed. Similarly, these compounds exhibited moderate activity against the human protozoal pathogen Trichomonas vaginalis with no observed effect on common microbiome bacterial species. The cross-species inhibitory activity presents the possibility of these compounds serving as broad-spectrum antibiotics for these prevalent three human pathogens.
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