Discovery of 6,7-dihydro-3H-pyrano[4,3-c]isoxazol-3-ones as a new class of pathogen specific anti-leptospiral agents
| Autor: | Kalimuthusamy Natarajaseenivasan, Charles Solomon Akino Mercy, Andivelu Ilangovan, Palaniappan Sakthivel, Karikalacholan Sivasankari |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Serotype medicine.drug_class Lipoproteins In silico Antibiotics 01 natural sciences Cell Line Microbiology Mice 03 medical and health sciences chemistry.chemical_compound Drug Discovery medicine Animals Humans Leptospirosis Cytotoxicity Oxazoles Pathogen Leptospira Pharmacology Mice Inbred BALB C Natural product Dose-Response Relationship Drug Strain (chemistry) 010405 organic chemistry Organic Chemistry General Medicine Survival Analysis Anti-Bacterial Agents 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology chemistry Bacterial outer membrane Bacterial Outer Membrane Proteins |
| Zdroj: | European Journal of Medicinal Chemistry. 125:29-40 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2016.09.020 |
| Popis: | A simple and efficient method for the synthesis of a series of 6,7-dihydro-3H-pyrano[4,3-c]isoxazol-3-one derivatives starting from 5-carboalkoxy-2,3-dihydropyranone (5-CDHPs) has been developed. Pyranoisoxazolones 10a-j, dihydronaphthopyran-4-one (DHNPs) class of natural product 12b and 12c and its analogues 12a and 13a-c were preliminarily screened against pathogenic leptospiral serovar Autumnalis strain N2 at various concentrations. Six pyranoisoxazolones, 10b, 10d, 10f, 10g, 10i and 10j which displayed very good anti-leptospiral activity was taken for secondary screening against twelve strains of pathogenic and one non-pathogenic leptospiral serovars. While all the compounds displayed significant anti-leptospiral activity against the pathogenic serovars at MIC of 62.5–500 μg/mL. Compounds 10d, 10g and 10j did not show any significant effect on non-pathogenic serovar. Inhibition of leptospires at a significant level by pyranoisoxazolone 10g was confirmed using RT-qPCR assay. In vivo treatment of BALB/c mice with compound 10g revealed that, it has 95% survivability against the pathogenic strain Canicola and also showed inhibition of renal colonization of leptospires. Compound 10g was found to show cytotoxicity against THP-1 cells only at higher concentration (≥75 μg/mL). Effective binding of compound 10g with leptospiral outer membrane protein LipL32 observed via in silico molecular docking provided a suitable explanation for pathogen specificity of compound 10g. Antibiotics acting against leptospirosis in human are very few. The results obtained from in vitro, in vivo and in silico study reveals that 6,7-dihydro-3H-pyrano[4,3-c]isoxazol-3-ones class of compounds are lead molecules for further development as pathogen specific anti-leptospiral agents. |
| Databáze: | OpenAIRE |
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