Improved Synthesis of the Novel Anti-Tuberculosis Drug SQ109 and Synthesis of Nitroso-ene Analogs

Despite the advances made in the middle of the 20th century to combat tuberculosis, the current short-course therapy has been met with challenges from multi-drug resistant strains of bacteria as well as the inability of providing these drugs to immunocompromised patients with HIV. Recent advances have been made to develop new drugs that are faster acting, more effective against drug-resistant strains, and more compatible with treatments for other diseases. SQ109 (1) has shown very promising activity against Mycobacterium tuberculosis (Mtb), but exhibits low oral bioavailability. This project was begun to develop stronger and more potent analogs of SQ109 by using nitroso ene chemistry and testing them against various strains of bacteria, including Mtb. The synthesis of SQ109 was improved from original reports to allow for a more scalable synthesis. Also, two precursor analogs of the compound in the attempted syntheses were found to be surprisingly biologically active. Nitroso-ene chemistry was performed on these as well as some other simple isoprenoids in order to discover even more compounds with antibacterial activity.