Rational design and synthesis of novel diphenyl ether derivatives as antitubercular agents.

A series of triclosan mimic diphenyl ether derivatives have been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The binding mode of the compounds at the active site of enoyl-acyl carrier protein reductase of M. tuberculosis has been explored. Among them, compound 10b was found to possess antitubercular activity (minimum inhibitory concentration =12.5 µg/mL) comparable to triclosan. All the synthesized compounds exhibited low levels of cytotoxicity against Vero and HepG2 cell lines, and three compounds 10a, 10b, and 10c had a selectivity index more than 10. Compound 10b was also evaluated for log P, pKa, human liver microsomal stability, and % protein binding, in order to probe its druglikeness. Based on the antitubercular activity and druglikeness profile, it may be concluded that compound 10b could be a lead for future development of antitubercular drugs.

Current and emerging "at-site" pain medications: a review.

The myriad pain pathophysiology has intrigued and challenged humanity for centuries. In this regard, the traditional pain therapies such as opioids and nonsteroidal anti-inflammatory drugs have been highly successful in treating acute and chronic pain. However, their drawback includes adverse events such as psychotropic effects, addiction potential, and gastrointestinal toxicities, to mention a few. These factors combined with the likelihood of an increase in chronic pain conditions due to an aging population calls for the development of novel mechanism-based or "site-specific" agents to target novel pain pathways. In this regard, rapid progress has been made in understanding the molecular mechanisms of novel pain targets such as cannabinoid receptors, fatty acid hydrolase, voltage-gated and ligand-gated ion channels such as P2 receptors, transient receptor potential channels and glial cell modulators. Accordingly, preclinical studies indicate that the site-specific/selective agents exhibit sufficient efficacy and reduced side effects such as lack of psychotropic effects indicating their clinical potential. This review provides a brief summary of some "at-site" pain targets and their role in the pain pathophysiology, and describes the efforts in developing some small molecules as novel pain therapeutics.