Christoph Lehmann
photo: Christoph Lehmann May 2020;
source: private
8-Nitrobenzothiazinones (BTZs) are distinguished by very potent antimycobacterial activity. Their molecular target is the enzyme DprE1 which is located in the periplasmatic space.
DprE1 is essential for the biosynthesis of arabinanes in Mycobacterium tuberculosis. Together with DprE2, it catalyses the epimerisation of decaprenyl-P-ribofuranose (DPR) to decaprenyl-P-D-arabinofuranose (DPA). DPA is the only precursor for lipoarabinomannanes und arabinogalactanes, which quantitatively and qualitatively constitute very important parts of the mycobacterial cell wall.
Two BTZs (BTZ043 und PBTZ169) are right now in clinical development. Nevertheless, the analysis and synthesis of new BTZ derivatives goes on. For the most part, research focusses on the improvement of water solubility and pharmacokinetic parameters.
My research focusses on exactly this. Taking into account BTZ derivatives published during the last ten years and structure-activity relationships, new substances are synthesised and analysed for activity against several mycobacteria (mainly M. tb and M. aurum). As a result of my synthetic work, apart from new BTZs with novel substitution patterns I found substances which differ significantly from the “classic” BTZs. The thiazinone ring was modified, originating in further modifications including opening of the BTZ heterocycle. They, too, proved to be active against Mycobacterium tuberculosis. The tests with Mycobacterium tuberculosis are conducted in the labs of different cooperation partners.
Talks:
3rd TRI-SUSTAIN Graduate School 2018 (Gaborone, Botswana):
Methylated Benzothiazinones - Synthesis and biological evaluation
Poster presentations:
Pharma Research Day 2019 (Martin-Luther-Universität, Halle): Open-ring analogues of antimycobacterial benzothiazinones (C. Lehmann, A. Richter, H. Asfaw, P. Imming)
Tuberculosis Drug Discovery and Development, Gordon Research Conference 2019 (Castelldefels, Italien): Nitroaromatic molecules as potential DprE1 inhibitors with antimycobacterial activity (A. Richter, C. Lehmann, H. Asfaw, Y. Av-Gay, P. Imming)
Tuberculosis Drug Discovery and Development, Gordon Research Conference 2017 (Lucca, Italien): Tri- and hexameric cyclo(depsi)peptides: Comparison of synthesis, properties and antimycobacterial activity (C. Lehmann, H. Asfaw, M. Klemm, A. Beuchel, K. Laqua, F. Cunningham, M. S. Martinez-Martinez, J. C. Cuevas-Zurita, L. Ballell-Pages, P. Imming)