Postgraduate research opportunities

Advances in medicine development using decracemisation by crystallisation to give single enantiomer drug molecules – facilitating the drug pipeline and production

Drug development; Drug discovery; chiral synthesis, organic synthesis, decracemisation by crystallisation, Veidma Ripening, medicinal chemistry, single crystal X-ray crystallography, XRPD, HPLC, pharmaceutical analysis

Number of places

1

Opens

21 February 2020

Deadline

31 March 2021

Duration

36 Months

Eligibility

Prospective applicants must have experience and/or knowledge in synthetic organic chemistry and/or analytical chemistry.

Project Details

Modern medicine and the development of the drug pipeline is dependent on the ability for the pharmaceutical industry to produce molecules of known absolute configuration. Both the pharmacokinetic and pharmacodynamic parameters of medicines are affected by chirality. Techniques such as asymmetric synthesis, enzymatic synthesis and dynamic resolution are readily employed towards obtaining molecules with the desired enantiopurity. However, many of these techniques are time consuming, inefficient and expensive which results in increased production costs or early stage bottlenecks in the discovery programs and the subsequent elimination of scaffolds in development.1

As an example, research in our lab in the area of anti-tubercular drug development has focussed on the development of achiral molecules due to the highlighted problems such as the exploitation of the thiacetazone 1 and 2-aminothiazole-5-carboxylate 2 scaffolds.2-5 However, we are now exploiting and developing recent advances in deracemisation by crystallisation to afford new chiral intermediates that can be used as building blocks in the development of new and existing drug molecules.6-8 Currently we are focussing on thiolactomycin 3 and linezolid 4 analogues using a three stage process (figure 1) which culminates in the reversible deracemisation of the conglomerate crystal form of the racemic substrate (figure 2) and to which this PhD project will be based.

 

Techniques used:

 

Synthetic organic chemistry, NMR, IR, LCMS/HPLC, polarimetry, crystallisation, Crystal-16 solubility measurement, single crystal X-ray crystallography, DSC and X-ray diffraction

 

Funding Details

Applicant will need to self-fund, find sponsorship for tuition and bench fees of £9000 per annum for duration of studies

Supervisor

Primary Supervisor: Dr Geoff Coxon

Email: geoff.coxon@strath.ac.uk

 

Secondary Supervisor: Prof Joop ter Horst

Email: joop.terhorst@strath.ac.uk

Further information

 

Chambers, M. S.; Thomas, E. J., Total Synthesis of (5s)-Thiolactomycin - Revision of the Absolute-Configuration of the Natural Product. J Chem Soc Chem Comm 1989, (1), 23-24.

 

Alahari, A.; Trivelli, X.;  Guerardel, Y.;  Dover, L. G.;  Besra, G. S.;  Sacchettini, J. C.;  Reynolds, R. C.;  Coxon, G. D.; Kremer, L., Thiacetazone, an antitubercular drug that inhibits cyclopropanation of cell wall mycolic acids in mycobacteria. PLoS One 2007, 2 (12), e1343.

Al-Balas, Q.; Anthony, N. G.;  Al-Jaidi, B.;  Alnimr, A.;  Abbott, G.;  Brown, A. K.;  Taylor, R. C.;  Besra, G. S.;  McHugh, T. D.;  Gillespie, S. H.;  Johnston, B. F.;  Mackay, S. P.; Coxon, G. D., Identification of 2-aminothiazole-4-carboxylate derivatives active against Mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH. PLoS One 2009, 4 (5), e5617.

Coxon, G. D.; Craig, D.;  Corrales, R. M.;  Vialla, E.;  Gannoun-Zaki, L.; Kremer, L., Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues. PLoS One 2013, 8 (1), e53162.

Halloum, I.; Viljoen, A.;  Khanna, V.;  Craig, D.;  Bouchier, C.;  Brosch, R.;  Coxon, G.; Kremer, L., Resistance to Thiacetazone Derivatives Active against Mycobacterium abscessus Involves Mutations in the MmpL5 Transcriptional Repressor MAB_4384. Antimicrob Agents Chemother 2017, 61 (4).

Sogutoglu, L. C.; Steendam, R. R. E.;  Meekes, H.;  Vlieg, E.; Rutjes, F. P. J. T., Viedma ripening: a reliable crystallisation method to reach single chirality. Chem Soc Rev 2015, 44 (19), 6723-6732.

Steendam, R. R. E.; ter Horst, J. H., Scaling Up Temperature Cycling-Induced Deracemization by Suppressing Nonstereoselective Processes. Cryst Growth Des 2018, 18 (5), 3008-3015.

Steendam, R. R. E.; ter Horst, J. H., Continuous Total Spontaneous Resolution. Cryst Growth Des 2017, 17 (8), 4428-4436.

Contact us

Primary Supervisor: Dr Geoff Coxon

Email: geoff.coxon@strath.ac.uk

How to apply

Applicants can apply using the University PEGASUS Application System https://www.strath.ac.uk/science/strathclydeinstituteofpharmacybiomedicalsciences/studywithus-postgraduate/phd/ 

This project is also suitable for PhD Plus https://www.strath.ac.uk/science/strathclydeinstituteofpharmacybiomedicalsciences/studywithus-postgraduate/phdplus/ 

This project is also suitable for Joint PhD

https://www.strath.ac.uk/science/strathclydeinstituteofpharmacybiomedicalsciences/studywithus-postgraduate/jointphd/