Indole-fused spirochromenes as potential anti-tubercular agents: design,synthesis and in vitro evaluation

Molecular Diversity - As part of an ongoing effort to develop new anti-tubercular agents, a series of novel indole-fused spirochromene hybrids (7a–l) were efficiently synthesized in excellent...     

A stereo,regioselective synthesis and discovery of antimycobaterium tuberculosis activity of novel β-lactam grafted spirooxindolopyrrolidine hybrid heterocycles

A stereo- and regioselective synthesis of hitherto unexplored novel class of β-lactam embedded spirooxindolopyrrolidine hybrid heterocycles have been accomplished via ionic liquid accelerated [3 + 2]-cycloaddition reaction process. The expected unusual lactonization/lactamization product could not be observed even in traces. The in vitro antimycobacterium tubercular activity of the synthesized spiroheterocyclic hybrids were assessed against Mycobacterium tuberculosis H37Rv. Among them, the compounds with no substitution and chlorosubstitution on the oxindole ring showed the most potent activity with a MIC 0.78 μg/mL and 1.56 μg/mL, respectively which were two-fold and equal activity than the standard drug, ethambutol (MIC = 1.56 μg/mL).     

Synthesis of novel 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxamides as potent inhibitors of Mycobacterium tuberculosis

A series of novel 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxamides was designed, synthesized, and evaluated for antitubercular activity. The required 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxylic acid intermediate was prepared by oxidizing the respective aldehyde with sodium chlorite and 30% H2O2. Further, the acid was coupled with various aryl, alkyl, and heterocyclic amines using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and hydroxybenzotriazole to give the desired 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxamides in excellent yields. All the new compounds were characterized by their NMR and mass spectral analysis. Screening of all new compounds for in vitro antimycobacterial activity against M. tuberculosis H37Rv (Mtb) resulted in five analogs with MIC 3.12 µg/cm3 as promising antitubercular agents with lower cytotoxicity profiles.     

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.     

Design and Synthesis of New Aryloxy‐linked Dimeric 1,2,3‐Triazoles via Click Chemistry Approach: Biological Evaluation and Molecular Docking Study

A quest for more potent new antitubercular agents has prompted to design and synthesize aryloxy‐linked dimeric 1,2,3‐triazoles ( 4a – j ), from azides ( 2a‐e ) and bis(prop‐2‐yn‐1‐yloxy)benzene ( 3a – b ) on 1,3‐dipolar cycloaddition reaction via copper (I)‐catalyzed click chemistry approach with good to better yields. The titled compounds ( 4a – j ) were designed using molecular hybridization approach by assembling various bioactive pharmacophoric fragments in a single molecular framework. All the synthesized compounds have been screened for their in vitro antitubercular, antifungal, and antioxidant activities against their respective strains. Among them, 4h and 4i show the highest antifungal activity, whereas compounds 4h , 4i , and 4j have revealed promising antitubercular activity against their respective strains. In addition to this, most of the synthesized compounds were found as potent antifungal and antioxidant agents. A significant network of bonded and non‐bonded interactions stabilized these molecules into the active site of fungal CYP51 that is realized from the obtained well‐placed docking poses and the associated thermodynamic interactions with the enzyme. The synthesized compounds have also been analyzed for absorption, distribution, metabolism, and excretion properties.