Hit-To-Lead Optimization for Neglected Diseases and Bacterial Infections

Manetsch Lab

The process in which a compound identified to have biological activity is improved upon in potency and/or properties, is known as hit-to-lead optimization. The research of the Manetsch laboratory focuses on the use of synthetic chemistry in close conjunction with liquid chromatography coupled to mass spectrometry (LC/MS) to achieve this optimization. Structure-activity relationship (SAR) studies, in parallel with structure-property relationship (SPR) studies guide the direction of our synthesis, while various LC/MS-based assays are routinely utilized for the assessment of key physicochemical properties in order  to determine and identify property liabilities, which critically affect the outcome of in vivo efficacy studies.

Our laboratory applies hit-to-lead optimization to the research of the following diseases:

  • Neglected tropical diseases: Malaria and leishmania

  • Bacterial diseases: MRSA and acinetobacter baumanni

Selected Publications:

ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity.

Maignan J R, Lichorowic C L, Giarrusso J, Blake L D, Casandra D, Mutka T S, LaCrue A N, Burrows J N, Willis P A, Kyle D E, Manetsch R. J Med Chem 2016; 59, 6943-6960.  

Design and synthesis of orally bioavailable piperazine substituted 4(1H)–quinolones with potent antimalarial activity: structure−activity and structure−property relationship studies

Neelarapu, R; Maignan, J R; Lichorowic, C L; Monastyrskyi, A; Mutka, T S; Lacrue, A N; Blake, L D; Casandra, D; Mashkouri, S; Burrows, J N; Manetsch, R . J Med Chem 2018; 61, 1450–1473.

Orally Bioavailable 6-Chloro-7-methoxy-4(1H)-quinolones Efficacious against Multiple Stages of Plasmodium.

Cross, R. M.; Flanigan, D. L.; Monastyrskyi, A.; LaCrue, A. N.; Saenz, F. E.; Maignan, J. R.; Mutka, T. S.; White, K. L.; Shackleford, D. M.; Bathurst, I.; et al. J. Med. Chem. 2014, accepted.

Quinolone-3-diarylethers: A new class of drugs for a new era of malaria eradication.

Nilsen, A.; LaCrue, A.; White, K. L.; Forquer, I. P.; Cross, R. M.; Marfurt, J.; Mather, M. W.; Delves, M. J.; Shackleford, D. M.; Saenz, F. E.; Morrisey, J. M.; Steuten, J.; Mutka, T.; Li, Y.; Wirjanata, G.; Ryan, E.; Duffy, S.; Kelly, J. X.; Sebayang, B. F.; Zeeman, A-M.; Noviyanti, R.; Sinden, R. E.; Kocken, C. H. M.; Price, R. N.; Avery, V. M.; Angulo-Barturen, I.; Jiménez-Díaz, M. B.; Ferrer, S.; Herreros, E.; Sanz, L. M.; Benito, F. J. G.; Bathurst, I.; Burrows, J.; Siegl, P.; Guy, R. K.; Winter, R. W.; Vaidya, A. B.; Charman, S. A.; Kyle, D. E.; Manetsch, R.; Riscoe, M. K. Sci Transl Med. 2013, 5, 177.

Endochin optimization: structure-activity and structure-property relationship studies of 3-substituted 2-methyl-4(1H)-quinolones with antimalarial activity.

​Cross, R. M.; Monastyrskyi, A.; Mutka, T. S.; Burrows, J. N.; Kyle, D. E.; Manetsch, R. J. Med. Chem. 2010, 53, 7076–7094.

Antileishmanial activity of a series of N2,N4-disubstituted quinazoline-2,4-diamines.

Van Horn, K. S.; Zhu, X.; Pandharkar, T.; Yang, S.; Vesely, B.; Vanaerschot, M.; Dujardin, J.-C.; Rijal, S.; Kyle, D. E.; Wang, M. Z.; et al. J. Med. Chem. 2014, 57, 5141–5156.

Antibacterial activity of a series of N2,N4-disubstituted quinazoline-2,4-diamines.

Van Horn, K. S.; Burda, W. N.; Fleeman, R.; Shaw, L. N.; Manetsch, R. J. Med. Chem. 2014, 57, 3075–3093.