Synthesis, antitubercular evaluation and molecular docking studies of phthalimide bearing 1,2,3-triazoles

In a search for safer and potent antitubercular agents, here a library of newly substituted dioxoisoindolinylmethyl-triazolyl-N-phenylacetamide derivatives (5a–l) has been synthesized via click chemistry approach. All synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H37Rv (MTB). Among the screened compounds, 5d, 5e, 5h, and 5l showed good antitubercular activity. The compounds 5d and 5l have shown very effective antitubercular activity against Mycobacterium tuberculosis H37Rv (MTB) with MIC 12.5 μg/mL. All the newly synthesized compounds were thoroughly characterized by 1H NMR, 13C NMR, and HRMS spectral data. We further performed exploratory docking studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase to demonstrate the mechanism of antitubercular activity.</p

<i>In vitro</i> and <i>in silico</i> exploration of newly synthesized triazolyl- isonicotinohydrazides as potent antitubercular agents

In the present study, we have reported the synthesis of novel isoniazid-triazole derivatives (4a-r), via the click chemistry approach. The synthesized isoniazid-triazole derivatives have potent in vitro antitubercular activity against the Mycobacterium tuberculosis (MTB) H37Rv strain. Among these compounds, 4b, 4f, 4g, 4j, 4k, 4m, 4o, 4p, and 4r were found to be the most active ones with a MIC value of 0.78 μg/mL. This activity is better than ciprofloxacin (MIC value = 1.56 μg/mL) and ethambutol (MIC value = 3.12 μg/mL). The compounds, 4a, 4c, 4d, 4e, 4h, 4i, 4l, and 4n have displayed activity equal to ciprofloxacin (MIC value = 1.56 μg/mL). The cytotoxicity of the active isoniazid-triazole derivatives was studied against RAW 264.7 cell line by MTT assay at 25 μg/mL concentration and no toxicity was observed. Moreover, in-vitro results were supported by in-silico studies with the known antitubercular target (PanK). The drug-likeness, density functional study, molecular docking, and molecular dynamics simulation studies of isoniazid-triazole derivatives validated the ability to form a stable complex with Pantothenate kinase (PanK), which will result in inhibiting the Pantothenate kinase (PanK). Therefore, the results obtained indicate that this class of compounds may offer candidates for future development, and positively provide drug alternatives for tuberculosis treatment. Communicated by Ramaswamy H. Sarma</p