Authors

N G Berry¹; K E Price¹; M Pye¹; C Armstrong²; L Imlay²; D Hodge²; C Pidathala¹; A S Lawrenson¹; R Sharma¹; J Park²; M Mikati²; N Tolia²; A R Odom²; P M O'Neill¹;  ¹ University of Liverpool, UK;  ² Washington University, St Louis, United States

Discussion

The development of effective antimalarial chemotherapeutics remains one of the major challenges within drug discovery. Malaria remains a major threat to global health, with ~198 million cases per year and 584,000 deaths annually, primarily in children under the age of five.^¹ 

The non-mevalonate (or MEP) pathway has been validated as a target for treatment of malaria and has the added advantage that it is absent in humans.² Our objective is to deliver a lead candidate molecule suitable for clinical development, targeting P.falciparum IspD (PfIspD).

Following a chemoinformatics-led high throughput screen, the 1,2-benzoisothiazolone (BITZ) chemotype was identified as a promising PfIspD inhibitor.³ Further inhibitors have been used to develop structure-activity relationship (SAR) around the PfIspD active site.

We have identified some of the most potent PfIspD inhibitors to date which also possess impressive whole cell activity. We have confirmed an essential covalent interaction between the BITZ core and cysteine residue in the PfIspD active site. We are also exploring a second chemical series of non-covalent PfIspD inhibitors, based around the tetrahydro-β-carboline chemotype. This series display low nM activity at PfIspD and provides a contrasting SAR and mechanism of inhibition.

1. World Health Organization, World Malaria Report, 2014.

2. A. R. Odom and W. C. Van Voorhis, Mol Biochem Parasit, 2010, 170, 108-111.

3. K. E. Price, C. M. Armstrong, L. S. Imlay, D. M. Hodge, C. Pidathala, N. J. Roberts, J. Park, M. Mikati, R. Sharma, A. S. Lawrenson, N. H. Tolia, N. G. Berry, P. M. O’Neill, A. R. Odom, Scientific Reports, 2016, 6, 36777.