Towards the Synthesis of 5-Bromo-Tryptamine − 2-Cyclopropyl-Quinazolinone Hybrids as Potential Broad Spectrum Efflux Pump Inhibitors

Abstract

Efflux pumps (EPs) are trans-membrane proteins that contribute to the rise in drug resistant (DR) bacteria. EPs nullify antibiotics by ejecting them out of the cell before they can perform their mechanism of action. Therefore, efflux pump inhibitors (EPIs), which can restore the function of obsolete drugs, are of high interest. EPs differ in structure across gram-negative bacteria (GNB) and gram-positive bacteria (GPB), so, drugs typically target very few EPs. The goal of the current study focuses on synthesizing a molecular hybrid to develop a broad-spectrum EPI capable of targeting a wide variety of EPs. Indole analogs have been used in the past to target NorA, an EP belonging to the ubiquitous S. aureus. Additionally, bromination along the indole skeleton can increase its penetration ability. For its utility against a common gram-positive strain, it was selected for this study. Quinazolinones are bioactive compounds that have also been used against EPs (MexAB-Opr and AcrAB) found in E. aerogenes and P. aeruginosa. A synthesis route was successfully established for 5-bromo-tryptamine through reducing 5-bromo-3-(2-nitrovinyl)-indole in a two-step process using NaBH4 (23%) and LiAlH4 (126%). The quinazolinone compounds were synthesized (8-277%) through three different pathways and then hybridized with tryptamine (16-86%).