General Strategy for the Synthesis of Natural and Unnatural Dialkylmaleic Anhydrides

Starting from alkylidenesuccinimides, a wide range of dialkylmaleic anhydrides have been synthesized via the generation of a carbanion on a succinimide unit and its condensation with various alkyl halides as the key reaction

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

Synthesis, anticancer and antimicrobial evaluation of new pyridyl and thiazolyl clubbed hydrazone scaffolds

A series of new hydrazones bearing pyridyl and thiazolyl scaffolds have been synthesized and evaluated for their in vitro anticancer and antimicrobial activities. The anticancer activity was evaluated against the A549 lung cancer cell line. The eight hydrazone derivatives have shown better anticancer activity than positive control doxorubicin against the A549 lung cancer cell line. The antimicrobial activity was evaluated against bacterial and fungal pathogens by using well diffusion method. The four hydrazone derivatives have displayed good antimicrobial activities. Molecular docking studies of the synthesized hydrazone derivatives revealed good binding via hydrogen bond interactions with key residues on active sites as well as neighboring residues with an active site of Focal adhesion kinase (PDB ID 2JKO). A computational study for the prediction of absorption, distribution, metabolism, and excretion (ADME) properties of all compounds has also been performed.</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

Computational Exploration of Anti-cancer Potential of Flavonoids against Cyclin-Dependent Kinase 8: An <i>In Silico</i> Molecular Docking and Dynamic Approach

Over the centuries, cancer has been considered one of the significant health threats. It holds the position in the list of deadliest diseases over the globe. In women, breast cancer is the most common among many cancers and is the second most common cancer all over the world, while lung cancer is the first. Cyclin-dependent kinase 8 (CDK8) has been identified as a critical oncogenic driver that is found in breast cancer and associated with tumor progression. Flavonoids were virtually screened against CDK8 using molecular docking, drug-likeness, ADMET prediction, and a molecular dynamics (MD) simulation approach to determine the potential flavonoid structure against CDK8. The results indicated that ZINC000005854718 showed the highest negative binding affinity of −10.7 kcal/mol with the targeted protein and passed all the drug-likeness parameters. Performed molecular dynamics simulation showed that docked complex systems have good conformational stability over 100 ns in different temperatures (298, 300, 305, 310, and 320 K). The comparison between calculated binding free energy via MM/PB(GB)SA methods and binding affinity calculated via molecular docking suggested tight binding of ZINC000005854718 with targeted protein. The results concluded that ZINC000005854718 has drug-like properties with tight and stable binding with the targeted protein

Synthesis of New Amide Linked Biphenoloxy 1,2,3-Triazoles as Antitubercular and Antimicrobial Agents

New 1,2,3-triazoles bearing biphenoloxymethyl and acetanilido moieties (5a-5l) have been synthesized, starting from 4-phenylphenol (1) following click chemistry approach. The synthesized compounds have been thoroughly characterized by their 1H NMR, 13C NMR and HRMS spectral data. These compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and antimicrobial activity against pathogenic microbia. Among the screened compounds, 5a and 5i have displayed notable antitubercular activity with MIC 25 µg/mL. Compounds 5a, 5b, 5c, 5 g, 5i and 5 l have shown effective inhibition against most of tested pathogens. Molecular docking results of compounds 5a and 5i show the binding modes of the synthesized compounds into the active site of mycobacterial enoyl reductase. The synthesized compounds have also been analyzed for their ADME properties. By considering all these results, the present research work will offer a promising lead series for discovery of emerging potent antitubercular agents.</p