PUBLICATION
Synthesis, in vitro, and in vivo (Zebra fish) antitubercular activity of 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides
- Authors
- Marvadi, S.K., Krishna, V.S., Surineni, G., Srilakshmi Reshma, R., Sridhar, B., Sriram, D., Kantevari, S.
- ID
- ZDB-PUB-200203-3
- Date
- 2020
- Source
- Bioorganic chemistry 96: 103626 (Journal)
- Registered Authors
- Keywords
- Dihydroquinoline, Hydrazinecarbothioamides, Molecular docking, Mycobacterium tuberculosis, Nutrient starvation, Zebra fish
- MeSH Terms
-
- Animals
- Antitubercular Agents/chemical synthesis
- Antitubercular Agents/chemistry*
- Antitubercular Agents/therapeutic use*
- Disease Models, Animal
- Drug Design
- Humans
- Hydrazines/chemical synthesis
- Hydrazines/chemistry*
- Hydrazines/therapeutic use*
- Microbial Sensitivity Tests
- Molecular Docking Simulation
- Mycobacterium tuberculosis/drug effects*
- Quinolones/chemical synthesis
- Quinolones/chemistry
- Quinolones/therapeutic use
- Structure-Activity Relationship
- Thioamides/chemical synthesis
- Thioamides/chemistry*
- Thioamides/therapeutic use*
- Tuberculosis/drug therapy*
- Zebrafish
- PubMed
- 32007719 Full text @ Bioorg. Chem.
Citation
Marvadi, S.K., Krishna, V.S., Surineni, G., Srilakshmi Reshma, R., Sridhar, B., Sriram, D., Kantevari, S. (2020) Synthesis, in vitro, and in vivo (Zebra fish) antitubercular activity of 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides. Bioorganic chemistry. 96:103626.
Abstract
We, herein, describe the synthesis of a series of novel aryl tethered 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides 4a-v, which showed in vitro and in vivo antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. The intermediates dihydro-6H-quinolin-5-ones 3a-v were synthesized from β-enaminones, reacting with cyclochexane-1,3-dione/5,5-dimethylcyclohexane-1,3-dione and ammonium acetate using a modified Bohlmann-Rahtz reaction conditions. They were further reacted with thiosemicarbazide to give the respective hydrazine carbothioamides 4a-v. All the new analogues 4a-v, were characterized by their NMR and mass spectral data analysis. Among the twenty-two compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), two compounds, 4e and 4j, exhibited the highest inhibition with an MIC of 0.39 µg/mL. Compounds 4a, 4g, and 4k were found to inhibit Mtb at an MIC of 0.78 µg/mL. Hydrazinecarbothioamides 4a-k, exhibited enhanced activity than dihydroquinolinones 3a-k. The observed increase in potency provides a clear evidence that hydrazinecarbothioamide is a potential pharmacophore, collectively imparting synergistic effect in enhancing antitubercular activity of the dihydroquinolinone core. The in vivo (Zebra fish) antimycobacterial screening of the in vitro active molecules led to the identification of a hit compound, 4j, with significant activity in the Mtb nutrient starvation model (2.2-fold reduction). Docking studies of 4j showed a hydrogen bond with the P156 residue of the protein.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping