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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.

A sudden increase in life-threatening COVID-19 infections around the world inflicts global crisis and emotional trauma. In current study two druggable targets, namely SARS-COV-2 M pro and CCR-5 were selected due to their significant nature in the viral life cycle and cytokine molecular storm respectively. The systematic drug repurposing strategy has been utilized to recognize inhibitory mechanism through extensive in silico investigation of novel Maraviroc analogues as promising inhibitors against SARS-CoV-2 M pro and CCR-5. The dual inhibition specificity approach implemented in present study using molecular docking, molecular dynamics (MD), principal component analysis (PCA), free energy landscape (FEL) and MM/PBSA binding energy studies. The proposed Maraviroc analogues obtained from in silico investigation could be easily synthesized and constructive in developing significant drug against COVID-19 pandemic, with essentiality of their in vivo / in vitro evaluation to affirm the conclusions of this study. This will further fortify the concept of single drug targeting dual inhibition mechanism for treatment of COVID-19 infection and complications.

The sharp spurt in positive cases of novel coronavirus-19 (SARS-CoV-2) worldwide has created a big threat to human. In view to expedite new drug leads for COVID-19, Main Proteases (M pro ) of novel Coronavirus (SARS-CoV-2) has emerged as a crucial target for this virus. Nitric oxide (NO) inhibits the replication cycle of SARS-CoV. Inhalation of nitric oxide is used in the treatment of severe acute respiratory syndrome. Herein, we evaluated the phenyl furoxan, a well-known exogenous NO donor to identify the possible potent inhibitors through in silico studies such as molecular docking as per target analysis for candidates bound to substrate binding pocket of SARS-COV-2 M pro . Molecular dynamics (MD) simulations of most stable docked complexes (M pro - 22 and M pro - 26 ) helped to confirm the notable conformational stability of these docked complexes under dynamic state. Furthermore, Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations revealed energetic contributions of key residues of M pro in binding with potent furoxan derivatives 22 , 26 . In the present study to validate the molecular docking, MD simulation and MM-PBSA results, crystal structure of M pro bound to experimentally known inhibitor X77 was used as control and the obtained results are presented herein. We envisaged that spiro-isoquinolino-piperidine-furoxan moieties can be used as effective ligand for SARS-CoV-2 M pro inhibition due to the presence of key isoquinolino-piperidine skeleton with additional NO effect.Communicated by Ramaswamy H. Sarma.