Synthesis and antitubercular activity of new 1,3,4-oxadiazoles bearing pyridyl and thiazolyl scaffolds

• Published in: Bioorganic & medicinal chemistry letters 2016-08, Vol.26 (15), p.3646-3651
• Main Authors: Dhumal, Sambhaji T., Deshmukh, Amarsinh R., Bhosle, Manisha R., Khedkar, Vijay M., Nawale, Laxman U., Sarkar, Dhiman, Mane, Ramrao A.
• Format: Article
• Language: English
• Subjects: 1,3,4-Oxadiazole; Antitubercular activity; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Cell Line, Tumor; Cytotoxicity; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular docking; Molecular Docking Simulation; Molecular Structure; Mycobacterium bovis; Mycobacterium bovis - drug effects; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Pyridine; Structure-Activity Relationship; Thiazole
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.05.093

New 2-pyridinylsubstituted thiazolyl-5-aryl-1,3,4-oxadiazoles (6a–o) have been synthesized via novel synthetic route. Among these compounds, 6f, 6j, 6l and 6o have revealed promising activity against M. bovis BCG. The molecular docking and drug likeness on the basis of ADME profile of the new entities have also been reported. [Display omitted] In search of more potent and safe new antitubercular agents, here new 2-pyridinyl substituted thiazolyl-5-aryl-1,3,4-oxadiazoles (6a–o), have been designed and synthesized using thionicotinamide as a starting, following novel multistep synthetic route. An intermediate, pyridinyl substituted thiazolyl acid hydrazide (4) when condensed with benzoic acids/nicotinic acids (5a–o) in the presence of silica supported POCl3 yielded better to excellent yields of the title compounds. All the synthesized compounds (6a–o) and intermediate acid hydrazide (4) have been screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG. Amongst them, 6f, 6j, 6l and 6o have revealed promising activity against M. bovis BCG at concentrations less than 3μg/mL. These compounds have shown low cytotoxicity (CC50: >100μg/mL) towards four human cancer cell lines. Molecular docking study has also been performed against mycobacterial enoyl reductase (InhA) enzyme to gain an insight into the binding modes of these molecules and recorded good binding affinity. The ADME properties the title products have also been analyzed.