In vitro apoptotic effect on human lymphatic filarial parasite by piperidine derivatives and thymidine reversal study
| Autor: | Namdev Togre, Sandeep P. Bahekar, M. B. Patil, Hemant S. Chandak, Nikita R. Agrawal, Sahitya Rao, Kalyan Goswami, Priyanka Bhoj, R. D. Sharma |
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| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
Chalcone 030231 tropical medicine Tetrazolium Salts Thymidylate synthase Brugia malayi 030308 mycology & parasitology 03 medical and health sciences chemistry.chemical_compound Elephantiasis Filarial 0302 clinical medicine Piperidines Dihydrofolate reductase Animals Humans Microfilariae 0303 health sciences General Veterinary biology Cytochrome c Acridine orange Thymidylate Synthase General Medicine biology.organism_classification Molecular biology Molecular Docking Simulation Tetrahydrofolate Dehydrogenase Filaricides Infectious Diseases chemistry Insect Science biology.protein Folic Acid Antagonists Parasitology Ethidium bromide Thymidine |
| Zdroj: | Parasitology Research. 119:165-175 |
| ISSN: | 1432-1955 0932-0113 |
| DOI: | 10.1007/s00436-019-06492-7 |
| Popis: | A novel library of synthetic piperidine derivatives was used to screen against human lymphatic filarial parasite Brugia malayi. Piperidine has earlier been reported to have effect against parasites including rodent filarial nematodes. Compounds with hydroxyl substitutions (4Q and 4H) showed marked antifilarial effect. Molecular docking of 4H derivative showed more favorable thermodynamic parameters against thymidylate synthase of B. malayi than human counterpart. A wide difference between IC50 and LD50 ensured the therapeutic safety of the candidates against the filarial parasites. Addition of thymidine to the treatment regimen led to a significant reversal of antifilarial effect of 4H that confirmed inhibition of thymidylate synthase as pharmacological rationale. Apoptosis induced in the parasite as a consequence of probable inhibition of thymidylate synthase was studied by acridine orange/ethidium bromide fluorescent staining and poly (ADP-ribose) polymerase activity inhibition. Involvement of mitochondria was confirmed by decreased 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) conversion and increased cytosolic cytochrome c level in 4H treated microfilariae, compared with the untreated microfilariae. Moreover, Michael adduct of chalcone targeting dihydrofolate reductase and piperidine targeting thymidylate synthase demonstrated synergistic effect on the parasite, indicating the importance of inhibition of DNA synthesis by combined effect. In conclusion, piperidine derivatives with hydroxyl substitution have a great therapeutic potential with an apoptotic rationale involving mitochondrial pathway, due to possible inhibition of parasitic thymidylate synthase. |
| Databáze: | OpenAIRE |
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