A Facile Synthesis and Discovery of Highly Functionalized Tetrahydro-pyridines and Pyridines as Antimycobacterial Agents

• Published in: Chemical & pharmaceutical bulletin Vol. 58; no. 5; pp. 602 - 610
• Main Authors: Raju, Suresh Kumar, Stephen, Michael Rajesh, Subbu, Perumal, Debjani, Banerjee, Perumal, Yogeeswari, Dharmarajan, Sriram
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.05.2010; Japan Science and Technology Agency
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Ethambutol - pharmacology; Humans; Mannich reaction; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Pyrazinamide - pharmacology; pyridinecarboxylate; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; stereochemistry
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.58.602

The four-component reaction of ethyl-3-oxo-4-(arylsulfanyl)butanoate, substituted aromatic aldehydes and ammonium acetate afforded novel ethyl 4-hydroxy-2,6-diaryl-5-(arylsulfanyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylates. These tetrahydro-pyridine esters upon dehydrogenation with dichlorodicyanobenzoquinone (DDQ) afforded highly functionalized pyridines in excellent yields. These novel heterocycles were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv using agar dilution method. Among the compounds screened, ethyl 2,6-di(2-bromophenyl)-4-hydroxy-5-(phenylsulfanyl)-3-pyridinecarboxylate was found to be the most active with a minimum inhibitory concentration of 1.33 μM against Mycobacterium tuberculosis and is 5.74 and 38.17 times more potent than the first line anti-tuberculosis (TB) drugs, ethambutol and pyrazinamide respectively.