Details

Autor(en) / Beteiligte

• Lone, Mehak Saba
• Mubarak, Mohamad Mosa
• Nabi, Syed Ayaz
• Wani, Farhat Ramzan
• Amin, Shaista
• Nabi, Sayima
• Kantroo, Hadiya Amin
• Samim, Mohammed
• Shafi, Syed
• Ahmad, Shamim
• Ahmad, Zahoor
• Rizvi, Syed Ovais
• Javed, Kalim

Titel

Isonicotinoyl-butanoic acid hydrazone derivatives as anti-tubercular agents: In-silico studies, synthesis, spectral characterization and biological evaluation

Ist Teil von

• Medicinal chemistry research, 2023-05, Vol.32 (5), p.808-826

Ort / Verlag

New York: Springer US

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• A series of novel 4-(2-isonicotinoylhydrazono)-4-aroylbutanoic acid derivatives (3a-n) were designed, synthesized and characterized by 1 H-NMR, 13 C-NMR, and mass spectroscopic analyses. The synthesized compounds evaluated for anti-tubercular activity against various M. tb strains showed potent anti-tubercular activity with MIC = 1 µg/ml for 3a, 3b, 3i and 3j against both H37Ra and H37Rv M. tb strains. MBC demonstrated that the synthesized compounds showed good bacteriocidal effect against both H37Ra and H37Rv M. tb strains with equivalent MIC and MBC values. All the compounds were found moderately active against the INH-resistant clinical isolates of M. tb with MIC 64 µg/ml. The most active compounds of the series (3a, 3b and 3i) were evaluated as non-cytotoxic towards normal human cell lines. In-silico docking studies and binding interactions of the synthesized compounds and INH revealed binding affinity towards the active site of the protein target M. tb InhA complexed with NADH (PDB ID: 4DRE). Among the most active compounds, 3a exhibited better binding affinity of -7.798 kcal/mol as compared to standard, INH (−6.925 kcal/mol). Compound 3a displayed hydrogen bonding between nitrogen of the pyridine ring and NH of VAL 65 and aromatic hydrogen bonding with C = O of LYS 63. Both phenyl ring and pyridine ring of the compound 3a exhibited π-π stacking interactions with phenyl ring of PHE 41 and hydrogen bonding between carboxylic oxygen of compound 3a and SER 20. Physicochemical properties and pharmacokinetic profiling assessed for the synthesized compounds were found to follow Lipinski’s rule using Swiss ADME online prediction tools. These findings make them promising candidates for the future development of new anti-tubercular agents. Highlights 4-(2-Isonicotinoylhydrazono)butanoic acid derivatives 3a-n were designed, synthesized and evaluated against avirulent ( H37Ra ), virulent ( H37Rv ) and Isoniazid-Resistant clinical isolates of M. tuberculosis (M.tb) . Compounds showed moderate to good anti-tubercular activity against avirulent, virulent as well as the drug resistant clinical isolates of Mycobacterium tuberculosis (M.tb) . MBC of the synthesized compounds exhibited similar values for both avirulent (H37Ra) and virulent (H37Rv) strains. Molecular docking studies of the compounds using protein target Mycobacterium tuberculosis InhA in complex with NADH (PDB ID: 4DRE) determined binding interactions of the synthesized compounds with the protein target. The cytotoxicity of the most active compounds of the series ( 3a , 3b and 3i ) evaluated based on percentage viability against three normal human cell lines including Human Embyonic Kindey cell line (HEK-293), Murine Hepatocyte cell line (AML12) and Lung Macrophage cell line (RAW-264) showed least percentage growth inhibition at different concentrations making the compounds nontoxic even upto 1000 µM. Physicochemical properties, pharmacokinetic profile and drug likeness studies of the synthesized compounds using Swiss ADME online prediction tools.