New carbazole anti-bacterials

Project ID: 2228cd1364 (You will need this ID for your application)

UCL Lead department: Chemistry

Project Summary:

Background and Importance: In 2021, 1.6 million people died from tuberculosis (TB) and a further 10 million are estimated to have developed active TB. However, only a small number of new anti-TB drugs have been released onto the market over the last 40 years. Some Mycobacterium tuberculosis strains, in the meantime, have acquired genetic mutations that render them resistant to most antibiotics. In recent work we have established that the NSAID carprofen can selectively inhibit the growth of M. tuberculosis.
Who you will be working with: This is a collaborative project between Helen Hailes (primary supervisor), and Tom Sheppard and Sanjib Bhakta (subsidiary supervisors). Project aims and workplan overview: Building upon the activity of carprofen, a carbazole, in recent work we have designed, synthesised, and evaluated several carbazoles which exhibited improved anti-mycobacterial potencies and selectivities. The aim of this project is to synthesize novel carbazoles, to systematically improve anti-mycobacterial activities, and probe the mode of action. Y1 will focus on optimising the synthetic route and modifying ring A of the carbazole. Compounds will be screened in vitro to determine anti-mycobacterial activities and establish structure-activity relationships (SARs). In Y2 modifications to rings B and C will be carried out to probe the SAR. In Y3-4 modifications to X to improve metabolic stabilities will be explored, together with other improvements to enhance drug-like properties. Labelled analogues will be prepared for mechanism of action studies. Y4 thesis will be written-up + submitted. Who we are looking for: For this project we are seeking a talented organic chemist able to design synthesise and characterise new compounds for biological screening. Also, to rationalise bioactivity data with a view to enhancing the potency and drugability of compounds. They will need to work in an interdisciplinary environment, interacting with researchers working on treatments for M. tuberculosis.